乳癌抑制基因Tob1的功能与辐射增敏作用研究
|
摘要
乳癌是女性最常见的恶性肿瘤,具有发病率高、侵袭性强、发病早期即可发生远处转移等特点,是危害女性健康的主要恶性疾病之一。乳癌的发生机制错综复杂,涉及大量基因或基因以外的变化和众多相互交通的细胞信号通路,这为人们寻找安全理想的乳癌诊疗方法带来极大挑战。因此,对乳癌发生、发展机制的研究一直是近年来乳癌研究中的主要方向之一。
肿瘤抑制基因主要的生物学功能是通过抑制细胞的恶性转化从而抑制肿瘤的发生,其编码蛋白产物主要参与对细胞周期进程的调控并能诱导细胞凋亡,此外还可参与对细胞间粘附力、蛋白酶活性等与肿瘤侵袭性或转移性相关的功能调节;肿瘤抑制基因的突变或其正常功能的改变往往引起细胞恶性转化,最终导致癌变。近年来对肿瘤抑制基因广泛、深入的研究为乳癌的临床诊治提供了重要的理论依据和实验基础,肿瘤抑制基因也因此成为乳癌发生机制中的一个研究热点。
Tob1基因(transducer of ERBB2, 1)属于TOB/BTG抗增殖家族,已知该家族所有成员都具有抗细胞增殖活性和细胞周期负性调控作用。众多研究报道Tob1基因可通过对cyclin D1的表达调控参与对细胞周期进程的调控,并在多种人类肿瘤中均具有肿瘤抑制基因特征。然而Tob1在恶性肿瘤发生中的具体作用机制至今尚不完全清楚,其在乳癌发生、发展中的相关功能研究也未见报道。
本研究首先通过Western Blot法、Northern Blot法以及免疫组化染色法对多种人类乳癌细胞及乳癌组织中Tob1的表达情况进行了检测,结果发现在多种乳腺肿瘤细胞及多数乳癌组织中Tob1的表达水平均有不同程度的下降或缺失。采用MTT生存分析法发现由重组腺病毒介导的外源性Tob1能显著抑制乳癌细胞的生长;而在实验动物模型中,Tob1的高水平表达还可以显著抑制乳腺肿瘤的生长以及肿瘤新生血管的形成。综合体内、体外以及动物实验结果,首次证实Tob1在乳癌的发生、发展过程中发挥肿瘤抑制因子作用。
随后,为阐明Tob1发挥乳癌抑制功能的具体作用机制,采用流式细胞术分析了Tob1的高水平表达对细胞周期进程及细胞凋亡的影响,结果显示外源性Tob1可引起乳癌细胞中细胞周期G0/G1期以及G2/M期阻滞,并能显著增加细胞凋亡的发生,这一结果与采用Western Blot法和RT-PCR法检测到的细胞周期G1期调控关键因子cyclin D1的表达下降以及凋亡相关因子Bax的表达水平的下降相一致。
雌激素(estrogen)/雌激素受体(estrogen receptor, ER)信号通路的异常激活是乳癌发生的重要机制之一,本实验采用GST捕获法、免疫共沉淀法等检测了Tob1与ER间的相互作用。实验中采用自行构建的一系列可表达Tob1全长、各片段缺失体以及“LXXLL”模序突变体的重组表达质粒载体进行Tob1的功能研究,结果发现Tob1可以和ER发生相互结合,而且这种结合作用与Tob1的氨基末端有关,但并不完全依赖于LXXLL模序。此外,荧光素酶活性测定结果显示Tob1可显著抑制ER的转录活性。上述结果共同提示Tob1可能通过雌激素/ER信号通路在乳癌的发生过程中发挥重要生物学作用。
采用相同实验方法,还检测到Tob1不仅与ER信号通路下游关键调控因子cyclin D1存在体内外相互作用,并能显著抑制cyclin D1的转录活性。综合Tob1对cyclin D1不同表达水平的调控作用,初步阐明了Tob1对乳癌的细胞周期进程及细胞生长产生影响的具体分子机制。
最后通过集落形成实验、TUNEL法、宿主细胞修复实验以及Western Blot法,首次证实重组腺病毒介导的Tob1高水平表达可通过对受照射细胞中凋亡相关基因的表达调控,增强辐射诱导的细胞凋亡;外源性Tob1通过对DNA损伤修复通路中关键因子的表达调控,抑制受照射细胞的DNA损伤修复能力;Tob1可能分别通过上述机制增加人类乳癌细胞对电离辐射的敏感性。
总之,本研究首次证实Tob1可分别通过对细胞周期进程的调控以及对细胞周期凋亡的诱导发挥乳癌抑制因子作用,同时Tob1可通过对乳癌细胞中DNA损伤修复的调控作用而增强乳癌细胞对放射治疗的敏感性。这些研究结果为乳癌的发生机制提供了新的理论基础和实验依据,结合后续动物模型实验和临床前实验,将为人类征服这一恶性肿瘤性疾病提供新的研究手段和工具。
Breast cancer is one of the most common malignancies of women in China and the world,which results from genetic or epigenetic changes of both malignant cells and the host cells interacting with the tumor, involving numerous cross-talking pathways. The complex underlying mechanisms lead to poor understanding of breast carcinogenesis, so as to difficulties in finding efficient, safe and selective therapeutics of breast cancer.
Tumor suppress genes can reduce and inhibit the alteration of normal cells’turning into tumor cells, and the functions of their protein products fall into several categories including repression of genes essential for the cell cycle, coupling the cell cycle to DNA damage, inducing apoptosis, blocking loss of contact inhibition, and inhibiting metastasis etc. Many studies suggest that any mutation of one or more tumor suppressor genes will increase the probability of carcinogenesis. Over the last decade, the growing knowledge of tumor suppressor genes and proteins associated with the development and progression of breast cancer has provided us the foundation on mechanisms contributing to breast carcinogenesis, as well as the better opportunities for therapy of this disease.
Tob1 (transducer of ERBB2, 1) is a member of the TOB/BTG antiproliferative protein family characterized by its anti-proliferative activity with the abilities to regulate cell cycle negatively in the periphery. Some previous studies suggest that Tob1 plays a role in the control of G1-S progression by suppressing cyclin D1 expression, and therefore may act as a tumor suppressor gene. However, it remains unknown whether and how Tob1functions in breast carcinogenesis ,and it is the purpose of this study to elucidate these issues.
By using Western Blot, Northern Blot and immunohistochemistry staining assays, it first demonstrated a lower or un-detectable level of Tob1 expression in human breast cancer cell lines and human breast cancer tissues compared to normal controls in this study. Enhanced expression of Tob1 notably inhibited in vitro growth of breast cancer cells. By using animal models with nude mice, it was found that Tob1 over-expression significantly suppressed tumor growth and angiogenesis. Taken together with in vitro, in vivo experiments and clinic data, all these results suggest that Tob1 may function as a tumor suppressor in breast cancer development and progression.
In order to study the specific pathways and underlying mechanism(s) contributing to Tob1 anti-tumor activity in breast cancer, the effects of Tob1 on cell cycle regulation and apoptosis was examined by flow-cytometry assay, and the result showed an increased expression of Tob1 which caused a cell cycle G0/G1 and G2/M arrest ,and programmed cell death (apoptosis) induction associated with a down-regulation of cyclin D1, a key regulator of G1-to-S phase progression of the cell cycle, and a up-regulation of Bax, a pro-apoptotic Bcl-2 family protein.
Abnormal activation of Estrogen/ER singling plays an important role in breast cancer development, progression and therapy. By using Co-immunoprecipitation, Western blot and GST pull-down assays, a series of recombinant vectors expressing wild type, truncation and“LXXLL”mutation Tob1 were constructed to analyze in vitro and in vivo association of Tob1 with ER. It was found that Tob1’s interacting with ER required the N-terminus of Tob1 but not the LXXLL motif within the N-terminus. Luciferase promoter assays revealed that Tob1 significantly inhibited the estrogen-driven ER transcription activation, proposing Tob1 as an important mediator in the estrogen/ER signaling pathway in breast carcinogenesis.
Tob1 was also found to be associated with cyclin D1, one of the important downstream regulators of estrogen/ER signaling pathway. Demonstrated by in vitro and in vivo binding assays, Tob1 also suppressed the activity of cyclin D1 promoter. Together, these results provided a potential pathway for Tob1’s mediating cell cycle progression and cell growth.
Finally, the results revealed for the first time that Tob1 increased sensitivity of breast cancer cells to ionizing radiation, by ways of reduction or inhibition of expression of critical proteins in DNA repair process such as DNA-dependent protein kinase (DNA-PK), Ku70, Ku80 and X-ray-sensitive complementation group 4 (XRCC4) as well as enhancement of radiation-mediated Bax expression.
In summary, it has been demonstrated that Tob1 either functions as a tumor suppressor gene in breast cancer progression by mediating cell cycle progression and apoptosis induction or acts as a radiosensitizor in breast cancer therapy by regulating DNA damage repair. Therefore, it will put forward our understanding in promotion of diagnosis and radiotherapy for breast cancer.
肿瘤抑制基因主要的生物学功能是通过抑制细胞的恶性转化从而抑制肿瘤的发生,其编码蛋白产物主要参与对细胞周期进程的调控并能诱导细胞凋亡,此外还可参与对细胞间粘附力、蛋白酶活性等与肿瘤侵袭性或转移性相关的功能调节;肿瘤抑制基因的突变或其正常功能的改变往往引起细胞恶性转化,最终导致癌变。近年来对肿瘤抑制基因广泛、深入的研究为乳癌的临床诊治提供了重要的理论依据和实验基础,肿瘤抑制基因也因此成为乳癌发生机制中的一个研究热点。
Tob1基因(transducer of ERBB2, 1)属于TOB/BTG抗增殖家族,已知该家族所有成员都具有抗细胞增殖活性和细胞周期负性调控作用。众多研究报道Tob1基因可通过对cyclin D1的表达调控参与对细胞周期进程的调控,并在多种人类肿瘤中均具有肿瘤抑制基因特征。然而Tob1在恶性肿瘤发生中的具体作用机制至今尚不完全清楚,其在乳癌发生、发展中的相关功能研究也未见报道。
本研究首先通过Western Blot法、Northern Blot法以及免疫组化染色法对多种人类乳癌细胞及乳癌组织中Tob1的表达情况进行了检测,结果发现在多种乳腺肿瘤细胞及多数乳癌组织中Tob1的表达水平均有不同程度的下降或缺失。采用MTT生存分析法发现由重组腺病毒介导的外源性Tob1能显著抑制乳癌细胞的生长;而在实验动物模型中,Tob1的高水平表达还可以显著抑制乳腺肿瘤的生长以及肿瘤新生血管的形成。综合体内、体外以及动物实验结果,首次证实Tob1在乳癌的发生、发展过程中发挥肿瘤抑制因子作用。
随后,为阐明Tob1发挥乳癌抑制功能的具体作用机制,采用流式细胞术分析了Tob1的高水平表达对细胞周期进程及细胞凋亡的影响,结果显示外源性Tob1可引起乳癌细胞中细胞周期G0/G1期以及G2/M期阻滞,并能显著增加细胞凋亡的发生,这一结果与采用Western Blot法和RT-PCR法检测到的细胞周期G1期调控关键因子cyclin D1的表达下降以及凋亡相关因子Bax的表达水平的下降相一致。
雌激素(estrogen)/雌激素受体(estrogen receptor, ER)信号通路的异常激活是乳癌发生的重要机制之一,本实验采用GST捕获法、免疫共沉淀法等检测了Tob1与ER间的相互作用。实验中采用自行构建的一系列可表达Tob1全长、各片段缺失体以及“LXXLL”模序突变体的重组表达质粒载体进行Tob1的功能研究,结果发现Tob1可以和ER发生相互结合,而且这种结合作用与Tob1的氨基末端有关,但并不完全依赖于LXXLL模序。此外,荧光素酶活性测定结果显示Tob1可显著抑制ER的转录活性。上述结果共同提示Tob1可能通过雌激素/ER信号通路在乳癌的发生过程中发挥重要生物学作用。
采用相同实验方法,还检测到Tob1不仅与ER信号通路下游关键调控因子cyclin D1存在体内外相互作用,并能显著抑制cyclin D1的转录活性。综合Tob1对cyclin D1不同表达水平的调控作用,初步阐明了Tob1对乳癌的细胞周期进程及细胞生长产生影响的具体分子机制。
最后通过集落形成实验、TUNEL法、宿主细胞修复实验以及Western Blot法,首次证实重组腺病毒介导的Tob1高水平表达可通过对受照射细胞中凋亡相关基因的表达调控,增强辐射诱导的细胞凋亡;外源性Tob1通过对DNA损伤修复通路中关键因子的表达调控,抑制受照射细胞的DNA损伤修复能力;Tob1可能分别通过上述机制增加人类乳癌细胞对电离辐射的敏感性。
总之,本研究首次证实Tob1可分别通过对细胞周期进程的调控以及对细胞周期凋亡的诱导发挥乳癌抑制因子作用,同时Tob1可通过对乳癌细胞中DNA损伤修复的调控作用而增强乳癌细胞对放射治疗的敏感性。这些研究结果为乳癌的发生机制提供了新的理论基础和实验依据,结合后续动物模型实验和临床前实验,将为人类征服这一恶性肿瘤性疾病提供新的研究手段和工具。
Breast cancer is one of the most common malignancies of women in China and the world,which results from genetic or epigenetic changes of both malignant cells and the host cells interacting with the tumor, involving numerous cross-talking pathways. The complex underlying mechanisms lead to poor understanding of breast carcinogenesis, so as to difficulties in finding efficient, safe and selective therapeutics of breast cancer.
Tumor suppress genes can reduce and inhibit the alteration of normal cells’turning into tumor cells, and the functions of their protein products fall into several categories including repression of genes essential for the cell cycle, coupling the cell cycle to DNA damage, inducing apoptosis, blocking loss of contact inhibition, and inhibiting metastasis etc. Many studies suggest that any mutation of one or more tumor suppressor genes will increase the probability of carcinogenesis. Over the last decade, the growing knowledge of tumor suppressor genes and proteins associated with the development and progression of breast cancer has provided us the foundation on mechanisms contributing to breast carcinogenesis, as well as the better opportunities for therapy of this disease.
Tob1 (transducer of ERBB2, 1) is a member of the TOB/BTG antiproliferative protein family characterized by its anti-proliferative activity with the abilities to regulate cell cycle negatively in the periphery. Some previous studies suggest that Tob1 plays a role in the control of G1-S progression by suppressing cyclin D1 expression, and therefore may act as a tumor suppressor gene. However, it remains unknown whether and how Tob1functions in breast carcinogenesis ,and it is the purpose of this study to elucidate these issues.
By using Western Blot, Northern Blot and immunohistochemistry staining assays, it first demonstrated a lower or un-detectable level of Tob1 expression in human breast cancer cell lines and human breast cancer tissues compared to normal controls in this study. Enhanced expression of Tob1 notably inhibited in vitro growth of breast cancer cells. By using animal models with nude mice, it was found that Tob1 over-expression significantly suppressed tumor growth and angiogenesis. Taken together with in vitro, in vivo experiments and clinic data, all these results suggest that Tob1 may function as a tumor suppressor in breast cancer development and progression.
In order to study the specific pathways and underlying mechanism(s) contributing to Tob1 anti-tumor activity in breast cancer, the effects of Tob1 on cell cycle regulation and apoptosis was examined by flow-cytometry assay, and the result showed an increased expression of Tob1 which caused a cell cycle G0/G1 and G2/M arrest ,and programmed cell death (apoptosis) induction associated with a down-regulation of cyclin D1, a key regulator of G1-to-S phase progression of the cell cycle, and a up-regulation of Bax, a pro-apoptotic Bcl-2 family protein.
Abnormal activation of Estrogen/ER singling plays an important role in breast cancer development, progression and therapy. By using Co-immunoprecipitation, Western blot and GST pull-down assays, a series of recombinant vectors expressing wild type, truncation and“LXXLL”mutation Tob1 were constructed to analyze in vitro and in vivo association of Tob1 with ER. It was found that Tob1’s interacting with ER required the N-terminus of Tob1 but not the LXXLL motif within the N-terminus. Luciferase promoter assays revealed that Tob1 significantly inhibited the estrogen-driven ER transcription activation, proposing Tob1 as an important mediator in the estrogen/ER signaling pathway in breast carcinogenesis.
Tob1 was also found to be associated with cyclin D1, one of the important downstream regulators of estrogen/ER signaling pathway. Demonstrated by in vitro and in vivo binding assays, Tob1 also suppressed the activity of cyclin D1 promoter. Together, these results provided a potential pathway for Tob1’s mediating cell cycle progression and cell growth.
Finally, the results revealed for the first time that Tob1 increased sensitivity of breast cancer cells to ionizing radiation, by ways of reduction or inhibition of expression of critical proteins in DNA repair process such as DNA-dependent protein kinase (DNA-PK), Ku70, Ku80 and X-ray-sensitive complementation group 4 (XRCC4) as well as enhancement of radiation-mediated Bax expression.
In summary, it has been demonstrated that Tob1 either functions as a tumor suppressor gene in breast cancer progression by mediating cell cycle progression and apoptosis induction or acts as a radiosensitizor in breast cancer therapy by regulating DNA damage repair. Therefore, it will put forward our understanding in promotion of diagnosis and radiotherapy for breast cancer.
引文
1.杨书良,段海凤,时志民等.浅议乳癌的预防与早期发现及早期诊断.中国妇幼保健. 2005; 20(16):2072-2074.
2. Lerebours F, Lidereau R. Molecular alterations in sporadic breast cancer. Crit Rev Oncol Hematol. 2002; 44: 121–141.
3. Balmain A, Gray J, Ponder B. The genetics and genomics of cancer. Nat Genet. 2003; 33(suppl):238–244.
4. Osborne C, Wilson P, Tripathy D. Oncogenes and tumor suppressor genes in breast cancer: potential diagnostic and therapeutic applications. Oncologist. 2004; 9(4):361-77.
5. Ioakim-Liossi A, Karakitsos P, Markopoulos C et al. p53 protein expression and oestrogen and progesterone receptor status in invasive ductal breast carcinomas. Cytopathology. 2001; 12:197–202.
6. Andersen TI, Gaustad A, Ottestad L et al. Genetic alterations of the tumour suppressor gene regions 3p, 11p, 13q, 17p, and 17q in human breast carcinomas. Genes Chromosomes Cancer. 1992; 4:113–121.
7. Walsh T, Casadei S, Coats KH et al. Spectrum of mutations in BRCA1, BRCA2, CHEK2, and TP53 in families at high risk of breast cancer. JAMA. 2006; 295: 1379–88.
8. Mills GB, Lu Y, Fang X et al. The role of genetic abnormalities of PTEN and the phosphatidylinositol 3-kinase pathway in breast and ovarian tumorigenesis, prognosis, and therapy. Semin Oncol. 2001; 28(suppl 16):125–141.
9. Fujiwara T, Tanaka N, Kanazawa S et al. Multicenter phase I study of repeated intratumoral delivery of adenoviral p53 in patients with advanced non-small-cell lung cancer. J Clin Oncol. 2006; 24(11):1689-99.
10. Matsuda S, Rouault J, Magaud J, Berthet C. In search of a function for the TIS21/PC3/BTG1/TOB family. FEBS Lett. 2001; 497(2-3):67-72.
11. Matsuda S, Kawamura-Tsuzuku J, Ohsugi M et al. Tob, a novel protein that interacts with p185ERBB2, is associated with anti-proliferative activity. Oncogene. 1996; 12:705-13.
12. Maekawa M, Nishida E, Tanoue T. Identification of the Anti-proliferative protein Tob as a MAPK substrate. J Biol Chem. 2002; 277(40):377783-7.
13. Yoshida Y, Nakamura T, Komoda M et al. Mice lacking a transcriptional corepressor Tob are predisposed to cancer. Genes Dev. 2003; 17(10):1201-6.
14. Ito Y, Suzuki T, Yoshida H, Tomoda C, Uruno T, Takamura Y, et al. Phosphorylation and inactivation of Tob contributes to the progression of papillary carcinoma of the thyroid. Cancer Lett. 2005; 220: 237-42.
15. Yanagie H, Sumimoto H, Nonaka Y, Matsuda S, Hirose I, Hanada S, et al. Inhibition of human pancreatic cancer growth by the adenovirus-mediated introduction of a novel growth suppressing gene, tob, in vitro. Adv Exp Med Biol. 1998; 451: 91-6.
1.Matsuda S, Rouault J, Magaud J, Berthet C. In search of a function for the TIS21/PC3/BTG1/TOB family. FEBS Lett. 2001; 497:67-72.
2.Matsuda S, Kawamura-Tsuzuku J, Ohsugi M et al. Tob, a novel protein that interacts with p185ERBB2, is associated with anti-proliferative activity. Oncogene. 1996; 12:705-13.
3.Yoshida Y, Nakamura T, Komoda M et al. Mice lacking a transcriptional corepressor Tob are predisposed to cancer. Genes Dev. 2003; 17:1201-6.
4.Lebovic DI, Baldocchi RA, Mueller MD, Taylor RN. Altered expression of a cell-cycle suppressor gene, Tob-1, in endometriotic cells by cDNA array analyses. Fertil Steril. 2002; 78:849-54.
5.Ito Y, Suzuki T, Yoshida H, Tomoda C, Uruno T, Takamura Y, et al. Phosphorylation and inactivation of Tob contributes to the progression of papillary carcinoma of the thyroid. Cancer Lett. 2005; 220:237-42.
6.Yanagie H, Sumimoto H, Nonaka Y, Matsuda S, Hirose I, Hanada S, et al. Inhibition of human pancreatic cancer growth by the adenovirus-mediated introduction of a novel growth suppressing gene, tob, in vitro. Adv Exp Med Biol. 1998; 451:91-6.
7.Balmain A, Gray J, Ponder B. The genetics and genomics of cancer. Nat Genet. 2003; 33:238–244.
8.Lerebours F, Lidereau R. Molecular alterations in sporadic breast cancer. Crit Rev Oncol Hematol. 2002; 44:121–141.
9.Osborne C, Wilson P, Tripathy D. Oncogenes and tumor suppressor genes in breast cancer: potential diagnostic and therapeutic applications. Oncologist. 2004; 9:361-77.
10.Maekawa M, Nishida E, Tanoue T. Identification of the Anti-proliferative protein Tob as a MAPK substrate. J Biol Chem. 2002; 277:377783-7.
11.Zhang J, Zou W, Luo C, Li B, Wang J, Sun L, Qian Q, Liu X. An armed oncolytic adenovirus system, ZD55-gene, demonstrating potent antitumoral efficacy. Cell Res. 2003; 13:481-489.
12.Thor AD, Moore DH II, Edgerton SM et al. Accumulation of p53 tumor suppressor gene protein: an independent marker of prognosis in breast cancers. J Natl Cancer Inst. 1992; 84:845–855.
13.Ioakim-Liossi A, Karakitsos P, Markopoulos C et al. p53 protein expression and oestrogen and progesterone receptor status in invasive ductal breast carcinomas. Cytopathology. 2001; 12:197-202.
14.Fitzgibbons PL, Page DL, Weaver D et al. Prognostic factors in breast cancer. Arch Pathol Lab Med. 2000; 124:966-978.
15.Kerbel RS. Inhibition of tumor angiogenesis as a strategy to circumvent acquired resistance to anti-cancer therapeutic agents. BioEssays. 1991; 13:31-36.
16. Griffioen AW, Molema G. Angiogenesis: Potentials for pharmacologic intervention in the treatment of cancer, cardiovascular diseases, and chonic inflammation. Pharmacal Rev. 2000; 52:238-262.
17. Folkman J. Tumor angiogenesis: Therapeutic implication. N Engl J Med. 1971; 285; 1182-1186.
1. Lebovic DI, Baldocchi RA, Mueller MD, Taylor RN. Altered expression of a cell-cycle suppressor gene, Tob-1, in endometriotic cells by cDNA array analyses. Fertil Steril. 2002; 78(4):849-54.
2. Caldon CE, Daly RJ, Suntherland RL et al. Cell cycle control in breast cancer cells. J Cell Biochem. 2006; 97(2):261-74.
3. Zhang J, Zou W, Luo C, Li B, Wang J, Sun L, Qian Q, Liu X. An armed oncolytic adenovirus system, ZD55-gene, demonstrating potent antitumoral efficacy. Cell Res. 2003; 13(6):481-489.
4. Steeg PS, Zhou Q. Cyclins and breast cancer. Breast Cancer Res Treat. 1998; 52:17–28.
5. Samuel C, Alicia G, Carlos MC et al. Estrogen-signaling pathway: A link between breast cancer and melatonin oncostatic actions. Cancer Detection and Prevention. 2006; 30:118–128.
6. Jensen EV, Jordan VC. The estrogen receptor: A model for molecular medicine. Clin Cancer Res. 2003; 9:1980–1989.
7. Rouault JP, Prevot D, Berthet C et al. Interaction of BTG1 and p53-regulated BTG2 gene products with mCaf1, the murine homolog of a component of the yeast CCR4 transcriptional regulatory complex. J Biol Chem. 1998; 273(35): 22563-22569.
8. Prevot D, Morel AP, Voeltzel T et al. Relationships of the antiproliferative proteins BTG1 and BTG2 with CAF1, the human homolog of a component of the yeast CCR4 transcriptional complex: involvement in estrogen receptor alpha signaling pathway. J Biol Chem. 2001; 276(13):9640-8.
9. Fu M, Wang C, Li Z et al. Minireview: Cyclin D1: Normal and Abnormal Functions. Endocrinology. 2004; 145(12):5439-47.
10. Osborne C, Wilson P, Tripathy D. Oncogenes and tumor suppressor genes in breast cancer: potential diagnostic and therapeutic applications. Oncologist. 2004; 9(4):361-77.
11. Smith CL. Cross-talk between peptide growth factor and estrogen receptor signaling pathways. Biol Reprod. 1998, 58:627~632.
12. Cunliffe HE, Ringner M, Bilke S et al. The gene expression response of breast cancer to growth regulators: Patterns and correlation with tumor expression profiles. Cancer Res. 2003;63: 7158–7166.
1. Kufe D, Weichselbaum R. Radiation therapy: activation for gene transcription and the development of genetic radiotherapy-therapeutic strategies in oncology. Cancer Biol Ther. 2003; 2: 326-9.
2. Robson T, Worthington J, McKeown SR, Hirst DG. Radiogenic therapy: novel approaches for enhancing tumor radiosensitivity. Technol Cancer Res Treat. 2005; 4: 343-61.
3. Freyta SO, Kim JH, Brown SL, Barton K, Lu M, Chung M. Gene therapy strategies to enhance the effectiveness of cancer radiotherapy. Curr Opin Mol Ther. 2004; 6: 513-24.
4. Lumniczky K, Safrany G. Cancer gene therapy: combination with radiation therapy and the role of bystander cell killing in the anti-tumor effect. Pathol Oncol Res. 2006; 12: 118-24.
5. Jackson SP. Sensing and repairing DNA double-strand breaks. Carcinogenesis. 2002; 23: 687-96.
6. Han Z, Wang H, Hallahan DE. Radiation-guided gene therapy of cancer. Technol Cancer Res Treat. 2006; 5: 437-44.
7. Ferguson, D. O. and Alt, F. W. DNA double strand break repair and chromosomal translocation: lessons from animal models. Oncogene. 2001; 20: 5572-9.
8. Bassing CH, Swat W, Alt FW. The mechanism and regulation of chromosomal V(D)J recombination. Cell. 2002; 109 (Suppl.): S45-S55.
9. Matsuda S, Kawamura-Tsuzuku J, Ohsugi M, et al. Tob, a novel protein that interacts with p185ERBB2, is associated with anti-proliferative activity. Oncogene. 1996; 12: 705-13.
10. Suzuki T, K-Tsuzuku J, Ajima R, Nakamura T, Yoshida Y, Yamamoto T. Phosphorylation of three regulatory serines of Tob by Erk1 and Erk2 is required for Ras-mediated cell proliferation and transformation. Genes Dev. 2002; 16: 1356-70.
11. Yoshida Y, Nakamura T, Komada M, Satoh H, Suzuki T, Tsuzuku JK et al. Micelacking a transcriptional corepressor Tob are predisposed to cancer. Genes Dev. 2003; 17: 1201-6.
12. Ito Y, Suzuki T, Yoshida H, Tomoda C, Uruno T, Takamura Y, et al. Phosphorylation and inactivation of Tob contributes to the progression of papillary carcinoma of the thyroid. Cancer Lett. 2005; 220: 237-42.
13. Yanagie H, Sumimoto H, Nonaka Y, Matsuda S, Hirose I, Hanada S, et al. Inhibition of human pancreatic cancer growth by the adenovirus-mediated introduction of a novel growth suppressing gene, tob, in vitro. Adv Exp Med Biol. 1998; 451: 91-6.
14. Xia F, Powell SN. The molecular basis of radiosensitivity and chemosensitivity in the treatment of breast cancer. Semin Radiat Oncol. 2002; 12: 296-304.
15. Suzuki T, K-Tsuzuku J, Ajima R, Nakamura T, Yoshida Y, Yamamoto T. Phosphorylation of three regulatory serines of Tob by Erk1 and Erk2 is required for Ras-mediated cell proliferation and transformation. Genes Dev. 2002; 16: 1356-70.
16. Cho HN, Lee YJ, Cho CK, Lee SJ, Lee YS. Downregulation of ERK2 is essential for the inhibition of radiation-induced cell death in HSP25 overexpressed L929 cells. Cell Death Differ. 2002; 9: 448-56.
17. Kawate H, Wu Y, Ohnaka K, Nawata H, Takayanagi R. Tob proteins suppress steroid hormone receptor-mediated transcriptional activation. Mol Cell Endocrinol. 2005; 230: 77-86.
18. Toillon RA, Magne N, Laios I, Lacroix M, Duvillier H, Lagneaux L, et al. Interaction between estrogen receptor alpha, ionizing radiation and (anti-) estrogens in breast cancer cells. Breast Cancer Res Treat. 2005; 93: 207-15.
19. Paulsen GH, Strickert T, Marthinsen AB, Lundgren S. Changes in radiation sensitivity and steroid receptor content induced by hormonal agents and ionizing radiation in breast cancer cells in vitro. Acta Oncol.1996; 35: 1011-9.
20. Fan S, Wang J, Yuan R, Rockwell S, Andres J, Zlatapolskiy A, et al. Scatter factor protects epithelial and carcinoma cells against apoptosis induced by DNA damaging-agents. Oncogene. 1998; 17: 131-41.
21. Walensky LD. BCL-2 in the crosshairs: tipping the balance of life and death. Cell Death Differ. 2006; 13: 1339-50.
22. Adams JM and Cory S. Life-or-death decisions by the Bcl-2 protein family. Trends in Biochemical Sciences. 2001; 26: 61-6.
23. Thomadaki H and Scorilas A. BCL2 family of apoptosis-related genes: functions and clinical implications in cancer. Crit Rev Clin Lab Sci. 2006; 43: 1-67.
24. Rainbow AJ. Repair of radiation-induced DNA breaks in human adenovirus. Radiat Res. 1974; 60: 155-64.
25. Featherstone C, Jackson SP. Ku, a DNA repair protein with multiple cellular functions? Mutat Res. 1999; 434: 3-15.
26. Tuteja R, Tuteja N. Ku autoantigen: a multifunctional DNA-binding protein. Crit Rev Biochem Mol Biol. 2000; 35: 1-33.
27. Kurimasa A, Ouyang H, Dong LJ,Wang S, Li X, Cordon-Cardo C, et al. Catalytic subunit of DNA-dependent protein kinase: impact on lymphocyte development and tumorigenesis. Proc Natl Acad Sci USA. 1999; 96: 1403-8.
28. Nussenzweig A, Chen C, da Costa Soares V, Sanchez M, Sokol K, Nussenzweig MC, et al. Requirement for Ku80 in growth and immunoglobulin V(D)J recombination. Nature (Lond). 1996; 382: 551-5.
29. Ouyang H, Nussenzweig A, Kurimasa A, Soares VC, Li X, Cordon-Cardo C et al. Ku70 is required for DNA repair but not for TCR gene recombination in vivo. J Exp Med. 1997; 186: 921-9.
1. Lerebours F, Lidereau R. Molecular alterations in sporadic breast cancer. Crit Rev Oncol Hematol. 2002; 44: 121–141.
2. Balmain A, Gray J, Ponder B. The genetics and genomics of cancer. Nat Genet. 2003; 33(suppl):238–244.
3.杨书良,段海凤,时志民等.浅议乳癌的预防与早期发现及早期诊断.中国妇幼保健. 2005; 20(16):2072-2074.
4. Osborne C, Wilson P, Tripathy D. Oncogenes and tumor suppressor genes in breast cancer: potential diagnostic and therapeutic applications. Oncologist. 2004; 9(4): 361 -77.
5. Knudson AG Jr. Mutation and cancer: statistical study of retinoblastoma. Proc Natl Acad Sci USA . 1971, 68:820–823.
6. Takahashi T, Nau MM, Chiba I et al. p53: a frequent target for genetic abnormalities in lung cancer. Science. 1989, 246:491–494.
7. Nigro JM, Baker SJ, Preisinger AC et al. Mutations in the p53 gene occur in diverse human tumour types. Nature. 1989, 342:705–708.
8. Hollstein M, Sidransky D, Vogelstein B et al. p53 mutations in human cancers. Science. 1991, 253:49–53.
9. Agrawal A, Yang J, Murphy RF, Aqrawal DK. Regulation of the p14ARF- Mdm2- p53 pathway: an overview in breast cancer. Exp Mol Pathol .2006, 81(2): 115-22.
10. Levine AJ. p53, the cellular gatekeeper for growth and division. Cell. 1997, 88:323–331.
11. Lane DP, Lu X, Hupp T et al. The role of the p53 protein in the apoptotic response. Philos Trans R Soc Lond B Biol Sci. 1994, 345:277–280.
12. Zou Z, Gao C, Nagaich AK et al. p53 regulates the expression of the tumor suppressor gene maspin. J Biol Chem. 2000, 275:6051–6054.
13. Wales MM, Biel MA, el Deiry W et al. p53 activates expression of HIC-1, a new candidate tumor suppressor gene on 17p13.3. Nat Med. 1995, 1:570–577.
14. Mashimo T, Watabe M, Hirota S et al. The expression of the KAI1 gene, a tumor metastasis suppressor, is directly activated by p53. Proc Natl Acad Sci USA. 1998,95:11307–11311.
15. Thor AD, Moore DH II, Edgerton SM et al. Accumulation of p53 tumor suppressor gene protein: an independent marker of prognosis in breast cancers. J Natl Cancer Inst. 1992, 84:845–855.
16. Ioakim-Liossi A, Karakitsos P, Markopoulos C et al. p53 protein expression and oestrogen and progesterone receptor status in invasive ductal breast carcinomas. Cytopathology. 2001, 12:197–202.
17. Fitzgibbons PL, Page DL, Weaver D et al. Prognostic factors in breast cancer. College of American Pathologists Consensus Statement 1999. Arch Pathol Lab Med. 2000, 124:966–978.
18. Moll UM, Slade N. p63 and p73: roles in development and tumor formation. Mol Cancer Res .2004, 2:371– 386.
19. Lang GA, Iwakuma T, Suh YA et al. Gain of function of a p53 hot spot mutation in a mouse model of Li-Fraumeni syndrome. Cell. 2004, 119:861– 872.
20. Olive KP, Tuveson DA, Ruhe ZC et al. Mutant p53 gain of function in two mouse models of Li-Fraumeni syndrome. Cell. 2004, 119:847– 860.
21. Barbareschi M, Pecciarini L, Cangi MG, et al. p63, a p53 homologue, is a selective nuclear marker of myoepithelial cells of the human breast. Am J Surg Pathol. 2001, 25:1054–1060.
22. DiRenzo J, Signoretti S, Nakamura N, et al. Growth factor requirements and basal phenotype of an immortalized mammary epithelial cell line. Cancer Res. 2002, 62:89–98.
23. Kaghad M, Bonnet H, Yang A et al. Monoallelically expressed gene related to p53 at 1p36, a region frequently deleted in neuroblastoma and other human cancers. Cell .1997, 90: 809–819.
24. Jost CA, Marin MC, Kaelin WG. P73 is a human p53-related protein that can induce apoptosis. Nature .1997, 389: 191–194.
25. Shishikura T, Ichimiya S, Ozaki T et al. Mutational analysis of the p73 gene in human breast cancers. Int J Cancer .1999, 84: 321–325.
26. Flores ER, Sengupta S, Miller JB et al. Tumor predisposition in mice mutant for p63 and p73: evidence for broader tumor suppressor functions for the p53 family. Cancer Cell. 2005, 7:363– 373.
27. Koker MM, Kleer CG. P63 expression in breast cancer: a highly sensitive and specific marker of metaplastic carcinoma. Am J Surg Pathol .2004, 28(11): 1506-12.
28. Zeimet AG, Marth C. Why did p53 gene therapy fail in ovarian cancer? Lancet Oncol. 2003, 4:415–422.
29. Fujiwara T, Tanaka N, Kanazawa S et al. Multicenter phase I study of repeated intratumoral delivery of adenoviral p53 in patients with advanced non-small-cell lung cancer. J Clin Oncol. 2006, 24(11):1689-99.
30. Russo AA, Jeffrey PD, Patten AK et al. Crystal structures of the p27Kip1 cyclin-dependent-kinase inhibitor bound to the cyclin A-Cdk 2 complex. Nature. 1996, 382:325–331.
31. St Croix B, Florenes VA, Rak JW et al. Impact of the cyclin-dependent kinase inhibitor p27Kip1 on resistance of tumor cells to anticancer agents. Nat Med. 1996, 2:1204–1210.
32. Onishi T, Hruska, K. Expression of p27Kip1 in osteoblast-like cells during differentiation with parathyroid hormone. Endocrinology. 1997, 138:1995–2004.
33. Ophascharoensuk V, Fero ML, Hughes J et al. The cyclin-dependent kinase inhibitor p27Kip1 safeguards against inflammatory injury. Nat Med. 1998, 4:575–580.
34. Spirin KS, Simpson JF, and Takeuchi S et al. p27/Kip1 mutation found in breast cancer. Cancer Res. 1996, 56:2400–2404.
35. Esposito V, Baldi A, De Luca A et al. Prognostic role of the cyclin-dependent kinase inhibitor p27 in non-small cell lung cancer. Cancer Res. 1997, 57:3381–3385.
36. Loda M, Cukor B, Tam SW et al. Increased proteasome-dependent degradation of the cyclin-dependent kinase inhibitor p27 in aggressive colorectal carcinomas. Nat Med. 1997, 3:231–234.
37. Catzavelos C, Bhattacharya N, Ung YC et al. Decreased levels of the cell-cycle inhibitor p27Kip1 protein: prognostic implications in primary breast cancer. Nat Med. 1997, 3:227–230.
38. Porter PL, Malone KE, Heagerty PJ et al. Expression of cell-cycle regulators p27Kip1 and cyclin E, alone and in combination, correlate with survival in young breast cancer patients. Nat Med. 1997, 3:222–225.
39. Fredersdorf S, Burns J, Milne AM et al. High level expression of p27 (kip1) and cyclin D1 in some human breast cancer cells: inverse correlation between theexpression of p27 (kip1) and degree of malignancy in some human breast and colorectal cancers. Proc Natl Acad Sci USA. 1997, 94:6380–6385.
40. Tan P, Cady B, Wanner M et al. The cell cycle inhibitor p27 is an independent prognostic marker in small (T1a, b) invasive breast carcinoma. Cancer Res. 1997, 57:1259–1263.
41. Hall JM, Lee MK, Newman B et al. Linkage of early-onset familial breast cancer to chromosome 17q21. Science. 1990, 250:1684–1689.
42. Miki Y, Swensen J, Shattuck-Eidens D et al. A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. Science. 1994, 266:66–71.
43. Ford D, Easton DF, Peto J. Estimates of the gene frequency of BRCA1 and its contribution to breast and ovarian cancer incidence. Am J Hum Genet. 1995, 57:1457–1462.
44. Roa BB, Boyd AA, Volcik K et al. Ashkenazi Jewish population frequencies for common mutations in BRCA1 and BRCA2. Nat Genet. 1996, 14:185–187.
45. Ford D, Easton DF, and Stratton M et al. Genetic heterogeneity and penetrance analysis of the BRCA1 and BRCA2 genes in breast cancer families. The Breast Cancer Linkage Consortium. Am J Hum Genet. 1998, 62:676–689.
46. Easton DF, Bishop DT, Ford D et al. Genetic linkage analysis in familial breast and ovarian cancer: results from 214 families. The Breast Cancer Linkage Consortium. Am J Hum Genet. 1993, 52:678–701.
47. Rahman N, Stratton MR. The genetics of breast cancer susceptibility. Ann Rev Genet. 1998, 32:95–121.
48. Walsh T, Casadei S, Coats KH et al. Spectrum of mutations in BRCA1, BRCA2, CHEK2, and TP53 in families at high risk of breast cancer. JAMA. 2006, 295:1379–88.
49. Couch FJ, DeShano ML, Blackwood MA et al. BRCA1 mutations in women attending clinics that evaluate the risk of breast cancer. New Engl J Med. 1997, 336:1409–1415.
50. Sobol H, Stoppa-Lyonnet D, Bressac-de-Paillerets B et al. Truncation at conserved terminal regions of BRCA1 protein is associated with highly proliferating hereditary breast cancers. Cancer Res. 1996, 56:3216–3219.
51. Bienstock RJ, Darden T, Wiseman R et al. Molecular modeling of theamino-terminal zinc ring domain of BRCA1. Cancer Res. 1996, 56:2539–2545.
52. Ruffner H, Joazeiro CA, Hemmati D et al. Cancer-predisposing mutations within the RING domain of BRCA1: loss of ubiquitin protein ligase activity and protection from radiation hypersensitivity. Proc Natl Acad Sci USA. 2001, 98(9):5134-9.
53. Stark JM, Pierce J, Oh J et al. Genetic steps of mammalian homologous repair with distinct mutagenic consequences. Mol Cell Biol. 2004, 24(21): 9305-16.
54. Scully R, Chen J, Ochs RL et al. Dynamic changes of BRCA1 subnuclear location and phosphorylation state are initiated by DNA damage. Cell. 1997, 90:425–435.
55. Boulton SJ. BRCA1-mediated ubiquitylation. Cell Cycle. 2006, 5(14):1481-6.
56. Rosen EM, Fan S, Pestell RG et al. BRCA1 gene in breast cancer. J Cell Physiol. 2003, 196(1):19–41.
57. Tait DL, Obermiller PS, Hatmaker AR et al. Ovarian cancer BRCA1 gene therapy: PhaseI and II trial differences in immune response and vector stability. Clin Cancer Res. 1999, 5:1708–1714.
58. Wooster R, Neuhausen SL, Mangion J et al. Localization of a breast cancer susceptibility gene, BRCA2, to chromosome 13q12-13. Science. 1994, 265:2088– 2090.
59. Wooster R, Bignell G, Lancaster J et al. Identification of the breast cancer susceptibility gene BRCA2. Nature. 1995, 378:789–792.
60. Thorlacius S, Sigurdsson S, Bjarnadottir H et al. Study of a single BRCA2 mutation with a high carrier frequency in a small population. Am J Hum Genet. 1997, 60:1079–1084.
61. Honrado E, Osorio A, Palasios J et al. Pathology and gene expression of hereditary breast tumors associated with BRCA1, BRCA2 and CHEK2 gene mutations. Oncogene. 2006, 25(43):5837-45.
62. Lin SR, Ting NS, Qin J et al. M phase-specific phosphorylation of BRCA2 by Polo-like kinase 1 correlates with the dissociation of the BRCA2-P/CAF complex. J Biol Chem. 2003, 278(38):35979-87.
63. Lee YM, Kim W. Association of human kinesin superfamily protein member 4 with BRCA2-associated factor 35. Biochem J. 2003, 374(Pt 2):497-503.
64. Venkitaraman AR, Cancer susceptibility and the functions of BRCA1 and BRCA2. Cell. 2002, 108:171–182.
65. American Society of Clinical Oncology. American Society of Clinical Oncology policy statement update: genetic testing for cancer susceptibility. J Clin Oncol. 2003, 21:2397–2406.
66. Bartek J, Falck J, Lukas J. CHK2 kinase--a busy messenger. Nat Rev Mol Cell Biol. 2001, 2: 877–886.
67. Kastan M, Bartek J. Cell-cycle checkpoints and cancer. Nature. 2004, 432: 316–323.
68. Li J, Williams BL, Haire LF et al. Phosphorylation by protein kinase CK2: a signaling switch for the caspase-inhibiting protein ARC.Mol Cell. 2002, 9: 1045–1054.
69. Lukas C, Falck J, Bartkova J et al. Distinct spatiotemporal dynamics of mammalian checkpoint regulators induced by DNA damage. Nat Cell Biol. 2003, 5: 255–260.
70. Ahn J, Urist M, Prives C. The Chk2 protein kinase. DNA Repair. 2004, 3: 1039– 1047.
71. Bartek J, Lukas J. Chk1 and Chk2 kinases in checkpoint control and cancer. Cancer Cell. 2003, 3: 421–429.
72. Bell DW, Varley JM, Szydlo TE et al. Heterozygous germ line hCHK2 mutations in Li-Fraumeni syndrome. Science. 1999, 286:2528–2531.
73. Sodha N, Williams R, Mangion J et al. The value of rapid functional assays of germline p53 status in LFS and LFL families. Science. 2000, 289: 359.
74. Vahteristo P, Bartkova J, Eerola H et al. A CHEK2 genetic variant contributing to a substantial fraction of familial breast cancer. Am J Hum Genet. 2002, 71:432–438.
75. Gerike A, Munson M, Ross AH. Regulation of the PTEN phosphatase. Gene. 2006, 374:1-9.
76. Simpson L, Parsons R. PTEN: life as a tumor suppressor. Exp Cell Res. 2001, 264:29–41.
77. Mills GB, Lu Y, Fang X et al. The role of genetic abnormalities of PTEN and the phosphatidylinositol 3-kinase pathway in breast and ovarian tumorigenesis, prognosis, and therapy. Semin Oncol. 2001, 28(suppl 16):125–141.
78. Nelen MR, van Staveren WC, Peeters EA et al. Germline mutations in the PTEN/MMAC1 gene in patients with Cowden disease. Hum Mol Genet. 1997, 6:1383–1387.
79. Savitsky K, Bar-Shira A, Gilad S et al. A single ataxia telangiectasia gene with aproduct similar to PI-3 kinase. Science. 1995, 268: 1749–1753.
80. Bosotti R, Isacchi A, Sonnhammer FL. FAT: a novel domain in PIK-related kinases. Trends Biochem Sci. 2000, 25: 225–227.
81. Ahmed M, Rhaman N. ATM and breast cancer susceptibility. Oncogene. 2006, 25(43):5906-5911.
82. Shiloh Y. ATM and related protein kinases: safeguarding genome integrity. Nat Rev Cancer. 2003, 3:155–168.
83. Khanna KK. Cancer risk and the ATM gene: a continuing debate. J Natl Cancer Inst. 2000, 92:795–802.
84. Lee WH, Bookstein R, Hong F et al. Human retinoblastoma susceptibility gene: cloning, identification, and sequence. Science. 1987, 235:1394–1399.
85. Simin K, Wu H, Lu L er al. pRb inactivation in mammary cells reveals common mechanisms for tumor initiation and progression in divergent epithelia. PLOS Biol. 2004, 2(2):E22.
86. Zheng L, Lee WH. The retinoblastoma gene: a prototypic and multifunctional tumor suppressor. Exp Cell Res. 2001, 264(1):2-18.
87. Andersen TI, Gaustad A, Ottestad L et al. Genetic alterations of the tumour suppressor gene regions 3p, 11p, 13q, 17p, and 17q in human breast carcinomas. Genes Chromosomes Cancer. 1992, 4:113–121.
88. Sherr CJ, McCormick F. The Rb and p53 pathways in cancer. Cancer Cell. 2002, 2: 103–112.
89. Dyson N, Buchkovich K, Whyte P et al. The cellular 107K protein that binds to adenovirus E1A also associates with the large T antigens of SV40 and JC virus. Cell. 1989, 58: 249–255.
90. Aprelikova ON, Fang BS, Meissner EG et al. BRCA1-associated growth arrest is RB dependent. Proc Natl Acad Sci USA. 1999, 96:11866-71.
91. Kerangueven F, Essioux L, Dib A et al. Loss of heterozygosity and linkage analysis in breast carcinoma: indication for a putative third susceptibility gene on the short arm of chromosome 8. Oncogene. 1995, 10:1023–1026.
92. Rocco JW, Sidransky D. Exp. p16 (MTS-1/CDKN2/INK4a) in cancer progression. Cell Res. 2001, 264:42–55.
93. Sherr CJ, McCormick F. The RB and p53 pathways in cancer. Cancer Cell. 2002,2:103–112.
94. McDermott KM, Zhang J, Holst CR et al. p16 (INK4a) prevents centrosome dysfunction and genomic instability in primary cells. PLoS Biol. 2006, 4:e51.
95. Xu L, Sgroi D, Sterner CJ et al. Mutational analysis of CDKN2 (MTS1/p16ink4) in human breast carcinomas. Cancer Res. 1994, 54: 5262–4.
96. Kamb A, Gruis NA, Weaver-Feldhaus J et al. A cell cycle regulator potentially involved in genesis of many tumor types. Science. 1994, 264:436–40.
97. Silva J, Silva JM, Dominguez G et al. Concomitant expression of p16INK4a and p14ARF in primary breast cancer and analysis of inactivation mechanisms. J Pathol. 2003, 199:289–97.
98. Jones PA, Laird PW. Cancer epigenetics comes of age. Nat Genet. 1999, 21:163–7.
99. Lehmann U, Langer F, Feist H et al. Quantitative assessment of promoter hypermethylation during breast cancer development. Am J Pathol. 2002, 160:605–12.
100. Sheng S. The promise and challenge toward the clinical application of maspin in cancer. Front Biosci. 2004,9:2733-45.
101. Pemberton PA, Tipton AR, Pavloff N et al. Maspin is an intracellular serpin that partitions into secretory vesicles and is present at the cell surface. J Histochem Cytochem. 1997, 45:697-1706.
102. Katz AB and Taichman LB. A partial catalog of proteins secreted by epidermal keratinocytes in culture. J Invest Dermatol. 1999, 112:818-821.
103. Zou Z, Anisowicz A, HendrixMJC, et al.Maspin, a serpin with tumor-suppressing activity in human mammary epithelial cells.Science. 1994, 263: 526–9.
104. Maass N, Nagasaki K, Ziebart M et al. Expression and regulation of tumor suppressor gene maspin in breast cancer. Clin Breast Cancer. 2002, 3(4):281-7.
105. Maass N, Hojo T, Ueding M et al. Expression of the tumor suppressor gene Maspin in human pancreatic cancers. Clin Cancer Res. 2001, 7:812-817.
106. Umekita Y, Hiipakka RA and Liao S. Rat and human maspins: structures, metastatic suppressor activity and mutation in prostate cancer cells. Cancer Lett. 1997, 113:87-93.
107. Boltze C, Schneider-Stock R, and Meyer F et al. Roessner: Maspin in thyroid cancer: its relationship with p53 and clinical outcome. Oncol Rep. 2003, 10; 1783-1787.
108. Heighway J, Knapp T, Boyce L et al. Lasek and P. Rickert: Expression profiling ofprimary non-small cell lung cancer for target identification. Oncogene. 2002, 21:7749-7763.
109. Sood AK, Fletcher MS, Gruman LM et al. The paradoxical expression of maspin in ovarian carcinoma. Clin Cancer Res. 2002, 8:2924-2932.
110. Matsuda S, Rouault J, Magaud J, Berthet C. In search of a function for the TIS21/PC3/BTG1/TOB family. FEBS Lett. 2001; 497(2-3):67-72.
111. Matsuda S, Kawamura-Tsuzuku J, Ohsugi M et al. Tob, a novel protein that interacts with p185erbB2, is associated with anti-proliferative activity. Oncogene. 1996, 12: 705-13.
112. Yoshida Y, Von Bubnoff A, Ikematsu N et al. Tob proteins enhance inhibitory Smad-receptor interactions to repress BMP signaling. Mech Dev. 2003, 120(5): 629- 37.
113. Yoshida Y, Nakamura T, Komoda M et al. Mice lacking a transcriptional corepressor Tob are predisposed to cancer. Genes Dev. 2003; 17(10):1201-6.
114. Ito Y, Suzuki T, Yoshida H, Tomoda C, Uruno T, Takamura Y, et al. Phosphorylation and inactivation of Tob contributes to the progression of papillary carcinoma of the thyroid. Cancer Lett 2005; 220: 237-42.
115. Yanagie H, Sumimoto H, Nonaka Y, Matsuda S, Hirose I, Hanada S, et al. Inhibition of human pancreatic cancer growth by the adenovirus-mediated introduction of a novel growth suppressing gene, tob, in vitro. Adv Exp Med Biol 1998; 451: 91-6.
116. Jiao Y, Ge C, Meng Q, Cao J, Tong J, Fan S. Adenovirus-Mediated Expression of Tob1 Sensitizes Breast Cancer Cells to Ionizing Radiation. Acta Pharmacologica Sinica. 2007(In press)
2. Lerebours F, Lidereau R. Molecular alterations in sporadic breast cancer. Crit Rev Oncol Hematol. 2002; 44: 121–141.
3. Balmain A, Gray J, Ponder B. The genetics and genomics of cancer. Nat Genet. 2003; 33(suppl):238–244.
4. Osborne C, Wilson P, Tripathy D. Oncogenes and tumor suppressor genes in breast cancer: potential diagnostic and therapeutic applications. Oncologist. 2004; 9(4):361-77.
5. Ioakim-Liossi A, Karakitsos P, Markopoulos C et al. p53 protein expression and oestrogen and progesterone receptor status in invasive ductal breast carcinomas. Cytopathology. 2001; 12:197–202.
6. Andersen TI, Gaustad A, Ottestad L et al. Genetic alterations of the tumour suppressor gene regions 3p, 11p, 13q, 17p, and 17q in human breast carcinomas. Genes Chromosomes Cancer. 1992; 4:113–121.
7. Walsh T, Casadei S, Coats KH et al. Spectrum of mutations in BRCA1, BRCA2, CHEK2, and TP53 in families at high risk of breast cancer. JAMA. 2006; 295: 1379–88.
8. Mills GB, Lu Y, Fang X et al. The role of genetic abnormalities of PTEN and the phosphatidylinositol 3-kinase pathway in breast and ovarian tumorigenesis, prognosis, and therapy. Semin Oncol. 2001; 28(suppl 16):125–141.
9. Fujiwara T, Tanaka N, Kanazawa S et al. Multicenter phase I study of repeated intratumoral delivery of adenoviral p53 in patients with advanced non-small-cell lung cancer. J Clin Oncol. 2006; 24(11):1689-99.
10. Matsuda S, Rouault J, Magaud J, Berthet C. In search of a function for the TIS21/PC3/BTG1/TOB family. FEBS Lett. 2001; 497(2-3):67-72.
11. Matsuda S, Kawamura-Tsuzuku J, Ohsugi M et al. Tob, a novel protein that interacts with p185ERBB2, is associated with anti-proliferative activity. Oncogene. 1996; 12:705-13.
12. Maekawa M, Nishida E, Tanoue T. Identification of the Anti-proliferative protein Tob as a MAPK substrate. J Biol Chem. 2002; 277(40):377783-7.
13. Yoshida Y, Nakamura T, Komoda M et al. Mice lacking a transcriptional corepressor Tob are predisposed to cancer. Genes Dev. 2003; 17(10):1201-6.
14. Ito Y, Suzuki T, Yoshida H, Tomoda C, Uruno T, Takamura Y, et al. Phosphorylation and inactivation of Tob contributes to the progression of papillary carcinoma of the thyroid. Cancer Lett. 2005; 220: 237-42.
15. Yanagie H, Sumimoto H, Nonaka Y, Matsuda S, Hirose I, Hanada S, et al. Inhibition of human pancreatic cancer growth by the adenovirus-mediated introduction of a novel growth suppressing gene, tob, in vitro. Adv Exp Med Biol. 1998; 451: 91-6.
1.Matsuda S, Rouault J, Magaud J, Berthet C. In search of a function for the TIS21/PC3/BTG1/TOB family. FEBS Lett. 2001; 497:67-72.
2.Matsuda S, Kawamura-Tsuzuku J, Ohsugi M et al. Tob, a novel protein that interacts with p185ERBB2, is associated with anti-proliferative activity. Oncogene. 1996; 12:705-13.
3.Yoshida Y, Nakamura T, Komoda M et al. Mice lacking a transcriptional corepressor Tob are predisposed to cancer. Genes Dev. 2003; 17:1201-6.
4.Lebovic DI, Baldocchi RA, Mueller MD, Taylor RN. Altered expression of a cell-cycle suppressor gene, Tob-1, in endometriotic cells by cDNA array analyses. Fertil Steril. 2002; 78:849-54.
5.Ito Y, Suzuki T, Yoshida H, Tomoda C, Uruno T, Takamura Y, et al. Phosphorylation and inactivation of Tob contributes to the progression of papillary carcinoma of the thyroid. Cancer Lett. 2005; 220:237-42.
6.Yanagie H, Sumimoto H, Nonaka Y, Matsuda S, Hirose I, Hanada S, et al. Inhibition of human pancreatic cancer growth by the adenovirus-mediated introduction of a novel growth suppressing gene, tob, in vitro. Adv Exp Med Biol. 1998; 451:91-6.
7.Balmain A, Gray J, Ponder B. The genetics and genomics of cancer. Nat Genet. 2003; 33:238–244.
8.Lerebours F, Lidereau R. Molecular alterations in sporadic breast cancer. Crit Rev Oncol Hematol. 2002; 44:121–141.
9.Osborne C, Wilson P, Tripathy D. Oncogenes and tumor suppressor genes in breast cancer: potential diagnostic and therapeutic applications. Oncologist. 2004; 9:361-77.
10.Maekawa M, Nishida E, Tanoue T. Identification of the Anti-proliferative protein Tob as a MAPK substrate. J Biol Chem. 2002; 277:377783-7.
11.Zhang J, Zou W, Luo C, Li B, Wang J, Sun L, Qian Q, Liu X. An armed oncolytic adenovirus system, ZD55-gene, demonstrating potent antitumoral efficacy. Cell Res. 2003; 13:481-489.
12.Thor AD, Moore DH II, Edgerton SM et al. Accumulation of p53 tumor suppressor gene protein: an independent marker of prognosis in breast cancers. J Natl Cancer Inst. 1992; 84:845–855.
13.Ioakim-Liossi A, Karakitsos P, Markopoulos C et al. p53 protein expression and oestrogen and progesterone receptor status in invasive ductal breast carcinomas. Cytopathology. 2001; 12:197-202.
14.Fitzgibbons PL, Page DL, Weaver D et al. Prognostic factors in breast cancer. Arch Pathol Lab Med. 2000; 124:966-978.
15.Kerbel RS. Inhibition of tumor angiogenesis as a strategy to circumvent acquired resistance to anti-cancer therapeutic agents. BioEssays. 1991; 13:31-36.
16. Griffioen AW, Molema G. Angiogenesis: Potentials for pharmacologic intervention in the treatment of cancer, cardiovascular diseases, and chonic inflammation. Pharmacal Rev. 2000; 52:238-262.
17. Folkman J. Tumor angiogenesis: Therapeutic implication. N Engl J Med. 1971; 285; 1182-1186.
1. Lebovic DI, Baldocchi RA, Mueller MD, Taylor RN. Altered expression of a cell-cycle suppressor gene, Tob-1, in endometriotic cells by cDNA array analyses. Fertil Steril. 2002; 78(4):849-54.
2. Caldon CE, Daly RJ, Suntherland RL et al. Cell cycle control in breast cancer cells. J Cell Biochem. 2006; 97(2):261-74.
3. Zhang J, Zou W, Luo C, Li B, Wang J, Sun L, Qian Q, Liu X. An armed oncolytic adenovirus system, ZD55-gene, demonstrating potent antitumoral efficacy. Cell Res. 2003; 13(6):481-489.
4. Steeg PS, Zhou Q. Cyclins and breast cancer. Breast Cancer Res Treat. 1998; 52:17–28.
5. Samuel C, Alicia G, Carlos MC et al. Estrogen-signaling pathway: A link between breast cancer and melatonin oncostatic actions. Cancer Detection and Prevention. 2006; 30:118–128.
6. Jensen EV, Jordan VC. The estrogen receptor: A model for molecular medicine. Clin Cancer Res. 2003; 9:1980–1989.
7. Rouault JP, Prevot D, Berthet C et al. Interaction of BTG1 and p53-regulated BTG2 gene products with mCaf1, the murine homolog of a component of the yeast CCR4 transcriptional regulatory complex. J Biol Chem. 1998; 273(35): 22563-22569.
8. Prevot D, Morel AP, Voeltzel T et al. Relationships of the antiproliferative proteins BTG1 and BTG2 with CAF1, the human homolog of a component of the yeast CCR4 transcriptional complex: involvement in estrogen receptor alpha signaling pathway. J Biol Chem. 2001; 276(13):9640-8.
9. Fu M, Wang C, Li Z et al. Minireview: Cyclin D1: Normal and Abnormal Functions. Endocrinology. 2004; 145(12):5439-47.
10. Osborne C, Wilson P, Tripathy D. Oncogenes and tumor suppressor genes in breast cancer: potential diagnostic and therapeutic applications. Oncologist. 2004; 9(4):361-77.
11. Smith CL. Cross-talk between peptide growth factor and estrogen receptor signaling pathways. Biol Reprod. 1998, 58:627~632.
12. Cunliffe HE, Ringner M, Bilke S et al. The gene expression response of breast cancer to growth regulators: Patterns and correlation with tumor expression profiles. Cancer Res. 2003;63: 7158–7166.
1. Kufe D, Weichselbaum R. Radiation therapy: activation for gene transcription and the development of genetic radiotherapy-therapeutic strategies in oncology. Cancer Biol Ther. 2003; 2: 326-9.
2. Robson T, Worthington J, McKeown SR, Hirst DG. Radiogenic therapy: novel approaches for enhancing tumor radiosensitivity. Technol Cancer Res Treat. 2005; 4: 343-61.
3. Freyta SO, Kim JH, Brown SL, Barton K, Lu M, Chung M. Gene therapy strategies to enhance the effectiveness of cancer radiotherapy. Curr Opin Mol Ther. 2004; 6: 513-24.
4. Lumniczky K, Safrany G. Cancer gene therapy: combination with radiation therapy and the role of bystander cell killing in the anti-tumor effect. Pathol Oncol Res. 2006; 12: 118-24.
5. Jackson SP. Sensing and repairing DNA double-strand breaks. Carcinogenesis. 2002; 23: 687-96.
6. Han Z, Wang H, Hallahan DE. Radiation-guided gene therapy of cancer. Technol Cancer Res Treat. 2006; 5: 437-44.
7. Ferguson, D. O. and Alt, F. W. DNA double strand break repair and chromosomal translocation: lessons from animal models. Oncogene. 2001; 20: 5572-9.
8. Bassing CH, Swat W, Alt FW. The mechanism and regulation of chromosomal V(D)J recombination. Cell. 2002; 109 (Suppl.): S45-S55.
9. Matsuda S, Kawamura-Tsuzuku J, Ohsugi M, et al. Tob, a novel protein that interacts with p185ERBB2, is associated with anti-proliferative activity. Oncogene. 1996; 12: 705-13.
10. Suzuki T, K-Tsuzuku J, Ajima R, Nakamura T, Yoshida Y, Yamamoto T. Phosphorylation of three regulatory serines of Tob by Erk1 and Erk2 is required for Ras-mediated cell proliferation and transformation. Genes Dev. 2002; 16: 1356-70.
11. Yoshida Y, Nakamura T, Komada M, Satoh H, Suzuki T, Tsuzuku JK et al. Micelacking a transcriptional corepressor Tob are predisposed to cancer. Genes Dev. 2003; 17: 1201-6.
12. Ito Y, Suzuki T, Yoshida H, Tomoda C, Uruno T, Takamura Y, et al. Phosphorylation and inactivation of Tob contributes to the progression of papillary carcinoma of the thyroid. Cancer Lett. 2005; 220: 237-42.
13. Yanagie H, Sumimoto H, Nonaka Y, Matsuda S, Hirose I, Hanada S, et al. Inhibition of human pancreatic cancer growth by the adenovirus-mediated introduction of a novel growth suppressing gene, tob, in vitro. Adv Exp Med Biol. 1998; 451: 91-6.
14. Xia F, Powell SN. The molecular basis of radiosensitivity and chemosensitivity in the treatment of breast cancer. Semin Radiat Oncol. 2002; 12: 296-304.
15. Suzuki T, K-Tsuzuku J, Ajima R, Nakamura T, Yoshida Y, Yamamoto T. Phosphorylation of three regulatory serines of Tob by Erk1 and Erk2 is required for Ras-mediated cell proliferation and transformation. Genes Dev. 2002; 16: 1356-70.
16. Cho HN, Lee YJ, Cho CK, Lee SJ, Lee YS. Downregulation of ERK2 is essential for the inhibition of radiation-induced cell death in HSP25 overexpressed L929 cells. Cell Death Differ. 2002; 9: 448-56.
17. Kawate H, Wu Y, Ohnaka K, Nawata H, Takayanagi R. Tob proteins suppress steroid hormone receptor-mediated transcriptional activation. Mol Cell Endocrinol. 2005; 230: 77-86.
18. Toillon RA, Magne N, Laios I, Lacroix M, Duvillier H, Lagneaux L, et al. Interaction between estrogen receptor alpha, ionizing radiation and (anti-) estrogens in breast cancer cells. Breast Cancer Res Treat. 2005; 93: 207-15.
19. Paulsen GH, Strickert T, Marthinsen AB, Lundgren S. Changes in radiation sensitivity and steroid receptor content induced by hormonal agents and ionizing radiation in breast cancer cells in vitro. Acta Oncol.1996; 35: 1011-9.
20. Fan S, Wang J, Yuan R, Rockwell S, Andres J, Zlatapolskiy A, et al. Scatter factor protects epithelial and carcinoma cells against apoptosis induced by DNA damaging-agents. Oncogene. 1998; 17: 131-41.
21. Walensky LD. BCL-2 in the crosshairs: tipping the balance of life and death. Cell Death Differ. 2006; 13: 1339-50.
22. Adams JM and Cory S. Life-or-death decisions by the Bcl-2 protein family. Trends in Biochemical Sciences. 2001; 26: 61-6.
23. Thomadaki H and Scorilas A. BCL2 family of apoptosis-related genes: functions and clinical implications in cancer. Crit Rev Clin Lab Sci. 2006; 43: 1-67.
24. Rainbow AJ. Repair of radiation-induced DNA breaks in human adenovirus. Radiat Res. 1974; 60: 155-64.
25. Featherstone C, Jackson SP. Ku, a DNA repair protein with multiple cellular functions? Mutat Res. 1999; 434: 3-15.
26. Tuteja R, Tuteja N. Ku autoantigen: a multifunctional DNA-binding protein. Crit Rev Biochem Mol Biol. 2000; 35: 1-33.
27. Kurimasa A, Ouyang H, Dong LJ,Wang S, Li X, Cordon-Cardo C, et al. Catalytic subunit of DNA-dependent protein kinase: impact on lymphocyte development and tumorigenesis. Proc Natl Acad Sci USA. 1999; 96: 1403-8.
28. Nussenzweig A, Chen C, da Costa Soares V, Sanchez M, Sokol K, Nussenzweig MC, et al. Requirement for Ku80 in growth and immunoglobulin V(D)J recombination. Nature (Lond). 1996; 382: 551-5.
29. Ouyang H, Nussenzweig A, Kurimasa A, Soares VC, Li X, Cordon-Cardo C et al. Ku70 is required for DNA repair but not for TCR gene recombination in vivo. J Exp Med. 1997; 186: 921-9.
1. Lerebours F, Lidereau R. Molecular alterations in sporadic breast cancer. Crit Rev Oncol Hematol. 2002; 44: 121–141.
2. Balmain A, Gray J, Ponder B. The genetics and genomics of cancer. Nat Genet. 2003; 33(suppl):238–244.
3.杨书良,段海凤,时志民等.浅议乳癌的预防与早期发现及早期诊断.中国妇幼保健. 2005; 20(16):2072-2074.
4. Osborne C, Wilson P, Tripathy D. Oncogenes and tumor suppressor genes in breast cancer: potential diagnostic and therapeutic applications. Oncologist. 2004; 9(4): 361 -77.
5. Knudson AG Jr. Mutation and cancer: statistical study of retinoblastoma. Proc Natl Acad Sci USA . 1971, 68:820–823.
6. Takahashi T, Nau MM, Chiba I et al. p53: a frequent target for genetic abnormalities in lung cancer. Science. 1989, 246:491–494.
7. Nigro JM, Baker SJ, Preisinger AC et al. Mutations in the p53 gene occur in diverse human tumour types. Nature. 1989, 342:705–708.
8. Hollstein M, Sidransky D, Vogelstein B et al. p53 mutations in human cancers. Science. 1991, 253:49–53.
9. Agrawal A, Yang J, Murphy RF, Aqrawal DK. Regulation of the p14ARF- Mdm2- p53 pathway: an overview in breast cancer. Exp Mol Pathol .2006, 81(2): 115-22.
10. Levine AJ. p53, the cellular gatekeeper for growth and division. Cell. 1997, 88:323–331.
11. Lane DP, Lu X, Hupp T et al. The role of the p53 protein in the apoptotic response. Philos Trans R Soc Lond B Biol Sci. 1994, 345:277–280.
12. Zou Z, Gao C, Nagaich AK et al. p53 regulates the expression of the tumor suppressor gene maspin. J Biol Chem. 2000, 275:6051–6054.
13. Wales MM, Biel MA, el Deiry W et al. p53 activates expression of HIC-1, a new candidate tumor suppressor gene on 17p13.3. Nat Med. 1995, 1:570–577.
14. Mashimo T, Watabe M, Hirota S et al. The expression of the KAI1 gene, a tumor metastasis suppressor, is directly activated by p53. Proc Natl Acad Sci USA. 1998,95:11307–11311.
15. Thor AD, Moore DH II, Edgerton SM et al. Accumulation of p53 tumor suppressor gene protein: an independent marker of prognosis in breast cancers. J Natl Cancer Inst. 1992, 84:845–855.
16. Ioakim-Liossi A, Karakitsos P, Markopoulos C et al. p53 protein expression and oestrogen and progesterone receptor status in invasive ductal breast carcinomas. Cytopathology. 2001, 12:197–202.
17. Fitzgibbons PL, Page DL, Weaver D et al. Prognostic factors in breast cancer. College of American Pathologists Consensus Statement 1999. Arch Pathol Lab Med. 2000, 124:966–978.
18. Moll UM, Slade N. p63 and p73: roles in development and tumor formation. Mol Cancer Res .2004, 2:371– 386.
19. Lang GA, Iwakuma T, Suh YA et al. Gain of function of a p53 hot spot mutation in a mouse model of Li-Fraumeni syndrome. Cell. 2004, 119:861– 872.
20. Olive KP, Tuveson DA, Ruhe ZC et al. Mutant p53 gain of function in two mouse models of Li-Fraumeni syndrome. Cell. 2004, 119:847– 860.
21. Barbareschi M, Pecciarini L, Cangi MG, et al. p63, a p53 homologue, is a selective nuclear marker of myoepithelial cells of the human breast. Am J Surg Pathol. 2001, 25:1054–1060.
22. DiRenzo J, Signoretti S, Nakamura N, et al. Growth factor requirements and basal phenotype of an immortalized mammary epithelial cell line. Cancer Res. 2002, 62:89–98.
23. Kaghad M, Bonnet H, Yang A et al. Monoallelically expressed gene related to p53 at 1p36, a region frequently deleted in neuroblastoma and other human cancers. Cell .1997, 90: 809–819.
24. Jost CA, Marin MC, Kaelin WG. P73 is a human p53-related protein that can induce apoptosis. Nature .1997, 389: 191–194.
25. Shishikura T, Ichimiya S, Ozaki T et al. Mutational analysis of the p73 gene in human breast cancers. Int J Cancer .1999, 84: 321–325.
26. Flores ER, Sengupta S, Miller JB et al. Tumor predisposition in mice mutant for p63 and p73: evidence for broader tumor suppressor functions for the p53 family. Cancer Cell. 2005, 7:363– 373.
27. Koker MM, Kleer CG. P63 expression in breast cancer: a highly sensitive and specific marker of metaplastic carcinoma. Am J Surg Pathol .2004, 28(11): 1506-12.
28. Zeimet AG, Marth C. Why did p53 gene therapy fail in ovarian cancer? Lancet Oncol. 2003, 4:415–422.
29. Fujiwara T, Tanaka N, Kanazawa S et al. Multicenter phase I study of repeated intratumoral delivery of adenoviral p53 in patients with advanced non-small-cell lung cancer. J Clin Oncol. 2006, 24(11):1689-99.
30. Russo AA, Jeffrey PD, Patten AK et al. Crystal structures of the p27Kip1 cyclin-dependent-kinase inhibitor bound to the cyclin A-Cdk 2 complex. Nature. 1996, 382:325–331.
31. St Croix B, Florenes VA, Rak JW et al. Impact of the cyclin-dependent kinase inhibitor p27Kip1 on resistance of tumor cells to anticancer agents. Nat Med. 1996, 2:1204–1210.
32. Onishi T, Hruska, K. Expression of p27Kip1 in osteoblast-like cells during differentiation with parathyroid hormone. Endocrinology. 1997, 138:1995–2004.
33. Ophascharoensuk V, Fero ML, Hughes J et al. The cyclin-dependent kinase inhibitor p27Kip1 safeguards against inflammatory injury. Nat Med. 1998, 4:575–580.
34. Spirin KS, Simpson JF, and Takeuchi S et al. p27/Kip1 mutation found in breast cancer. Cancer Res. 1996, 56:2400–2404.
35. Esposito V, Baldi A, De Luca A et al. Prognostic role of the cyclin-dependent kinase inhibitor p27 in non-small cell lung cancer. Cancer Res. 1997, 57:3381–3385.
36. Loda M, Cukor B, Tam SW et al. Increased proteasome-dependent degradation of the cyclin-dependent kinase inhibitor p27 in aggressive colorectal carcinomas. Nat Med. 1997, 3:231–234.
37. Catzavelos C, Bhattacharya N, Ung YC et al. Decreased levels of the cell-cycle inhibitor p27Kip1 protein: prognostic implications in primary breast cancer. Nat Med. 1997, 3:227–230.
38. Porter PL, Malone KE, Heagerty PJ et al. Expression of cell-cycle regulators p27Kip1 and cyclin E, alone and in combination, correlate with survival in young breast cancer patients. Nat Med. 1997, 3:222–225.
39. Fredersdorf S, Burns J, Milne AM et al. High level expression of p27 (kip1) and cyclin D1 in some human breast cancer cells: inverse correlation between theexpression of p27 (kip1) and degree of malignancy in some human breast and colorectal cancers. Proc Natl Acad Sci USA. 1997, 94:6380–6385.
40. Tan P, Cady B, Wanner M et al. The cell cycle inhibitor p27 is an independent prognostic marker in small (T1a, b) invasive breast carcinoma. Cancer Res. 1997, 57:1259–1263.
41. Hall JM, Lee MK, Newman B et al. Linkage of early-onset familial breast cancer to chromosome 17q21. Science. 1990, 250:1684–1689.
42. Miki Y, Swensen J, Shattuck-Eidens D et al. A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. Science. 1994, 266:66–71.
43. Ford D, Easton DF, Peto J. Estimates of the gene frequency of BRCA1 and its contribution to breast and ovarian cancer incidence. Am J Hum Genet. 1995, 57:1457–1462.
44. Roa BB, Boyd AA, Volcik K et al. Ashkenazi Jewish population frequencies for common mutations in BRCA1 and BRCA2. Nat Genet. 1996, 14:185–187.
45. Ford D, Easton DF, and Stratton M et al. Genetic heterogeneity and penetrance analysis of the BRCA1 and BRCA2 genes in breast cancer families. The Breast Cancer Linkage Consortium. Am J Hum Genet. 1998, 62:676–689.
46. Easton DF, Bishop DT, Ford D et al. Genetic linkage analysis in familial breast and ovarian cancer: results from 214 families. The Breast Cancer Linkage Consortium. Am J Hum Genet. 1993, 52:678–701.
47. Rahman N, Stratton MR. The genetics of breast cancer susceptibility. Ann Rev Genet. 1998, 32:95–121.
48. Walsh T, Casadei S, Coats KH et al. Spectrum of mutations in BRCA1, BRCA2, CHEK2, and TP53 in families at high risk of breast cancer. JAMA. 2006, 295:1379–88.
49. Couch FJ, DeShano ML, Blackwood MA et al. BRCA1 mutations in women attending clinics that evaluate the risk of breast cancer. New Engl J Med. 1997, 336:1409–1415.
50. Sobol H, Stoppa-Lyonnet D, Bressac-de-Paillerets B et al. Truncation at conserved terminal regions of BRCA1 protein is associated with highly proliferating hereditary breast cancers. Cancer Res. 1996, 56:3216–3219.
51. Bienstock RJ, Darden T, Wiseman R et al. Molecular modeling of theamino-terminal zinc ring domain of BRCA1. Cancer Res. 1996, 56:2539–2545.
52. Ruffner H, Joazeiro CA, Hemmati D et al. Cancer-predisposing mutations within the RING domain of BRCA1: loss of ubiquitin protein ligase activity and protection from radiation hypersensitivity. Proc Natl Acad Sci USA. 2001, 98(9):5134-9.
53. Stark JM, Pierce J, Oh J et al. Genetic steps of mammalian homologous repair with distinct mutagenic consequences. Mol Cell Biol. 2004, 24(21): 9305-16.
54. Scully R, Chen J, Ochs RL et al. Dynamic changes of BRCA1 subnuclear location and phosphorylation state are initiated by DNA damage. Cell. 1997, 90:425–435.
55. Boulton SJ. BRCA1-mediated ubiquitylation. Cell Cycle. 2006, 5(14):1481-6.
56. Rosen EM, Fan S, Pestell RG et al. BRCA1 gene in breast cancer. J Cell Physiol. 2003, 196(1):19–41.
57. Tait DL, Obermiller PS, Hatmaker AR et al. Ovarian cancer BRCA1 gene therapy: PhaseI and II trial differences in immune response and vector stability. Clin Cancer Res. 1999, 5:1708–1714.
58. Wooster R, Neuhausen SL, Mangion J et al. Localization of a breast cancer susceptibility gene, BRCA2, to chromosome 13q12-13. Science. 1994, 265:2088– 2090.
59. Wooster R, Bignell G, Lancaster J et al. Identification of the breast cancer susceptibility gene BRCA2. Nature. 1995, 378:789–792.
60. Thorlacius S, Sigurdsson S, Bjarnadottir H et al. Study of a single BRCA2 mutation with a high carrier frequency in a small population. Am J Hum Genet. 1997, 60:1079–1084.
61. Honrado E, Osorio A, Palasios J et al. Pathology and gene expression of hereditary breast tumors associated with BRCA1, BRCA2 and CHEK2 gene mutations. Oncogene. 2006, 25(43):5837-45.
62. Lin SR, Ting NS, Qin J et al. M phase-specific phosphorylation of BRCA2 by Polo-like kinase 1 correlates with the dissociation of the BRCA2-P/CAF complex. J Biol Chem. 2003, 278(38):35979-87.
63. Lee YM, Kim W. Association of human kinesin superfamily protein member 4 with BRCA2-associated factor 35. Biochem J. 2003, 374(Pt 2):497-503.
64. Venkitaraman AR, Cancer susceptibility and the functions of BRCA1 and BRCA2. Cell. 2002, 108:171–182.
65. American Society of Clinical Oncology. American Society of Clinical Oncology policy statement update: genetic testing for cancer susceptibility. J Clin Oncol. 2003, 21:2397–2406.
66. Bartek J, Falck J, Lukas J. CHK2 kinase--a busy messenger. Nat Rev Mol Cell Biol. 2001, 2: 877–886.
67. Kastan M, Bartek J. Cell-cycle checkpoints and cancer. Nature. 2004, 432: 316–323.
68. Li J, Williams BL, Haire LF et al. Phosphorylation by protein kinase CK2: a signaling switch for the caspase-inhibiting protein ARC.Mol Cell. 2002, 9: 1045–1054.
69. Lukas C, Falck J, Bartkova J et al. Distinct spatiotemporal dynamics of mammalian checkpoint regulators induced by DNA damage. Nat Cell Biol. 2003, 5: 255–260.
70. Ahn J, Urist M, Prives C. The Chk2 protein kinase. DNA Repair. 2004, 3: 1039– 1047.
71. Bartek J, Lukas J. Chk1 and Chk2 kinases in checkpoint control and cancer. Cancer Cell. 2003, 3: 421–429.
72. Bell DW, Varley JM, Szydlo TE et al. Heterozygous germ line hCHK2 mutations in Li-Fraumeni syndrome. Science. 1999, 286:2528–2531.
73. Sodha N, Williams R, Mangion J et al. The value of rapid functional assays of germline p53 status in LFS and LFL families. Science. 2000, 289: 359.
74. Vahteristo P, Bartkova J, Eerola H et al. A CHEK2 genetic variant contributing to a substantial fraction of familial breast cancer. Am J Hum Genet. 2002, 71:432–438.
75. Gerike A, Munson M, Ross AH. Regulation of the PTEN phosphatase. Gene. 2006, 374:1-9.
76. Simpson L, Parsons R. PTEN: life as a tumor suppressor. Exp Cell Res. 2001, 264:29–41.
77. Mills GB, Lu Y, Fang X et al. The role of genetic abnormalities of PTEN and the phosphatidylinositol 3-kinase pathway in breast and ovarian tumorigenesis, prognosis, and therapy. Semin Oncol. 2001, 28(suppl 16):125–141.
78. Nelen MR, van Staveren WC, Peeters EA et al. Germline mutations in the PTEN/MMAC1 gene in patients with Cowden disease. Hum Mol Genet. 1997, 6:1383–1387.
79. Savitsky K, Bar-Shira A, Gilad S et al. A single ataxia telangiectasia gene with aproduct similar to PI-3 kinase. Science. 1995, 268: 1749–1753.
80. Bosotti R, Isacchi A, Sonnhammer FL. FAT: a novel domain in PIK-related kinases. Trends Biochem Sci. 2000, 25: 225–227.
81. Ahmed M, Rhaman N. ATM and breast cancer susceptibility. Oncogene. 2006, 25(43):5906-5911.
82. Shiloh Y. ATM and related protein kinases: safeguarding genome integrity. Nat Rev Cancer. 2003, 3:155–168.
83. Khanna KK. Cancer risk and the ATM gene: a continuing debate. J Natl Cancer Inst. 2000, 92:795–802.
84. Lee WH, Bookstein R, Hong F et al. Human retinoblastoma susceptibility gene: cloning, identification, and sequence. Science. 1987, 235:1394–1399.
85. Simin K, Wu H, Lu L er al. pRb inactivation in mammary cells reveals common mechanisms for tumor initiation and progression in divergent epithelia. PLOS Biol. 2004, 2(2):E22.
86. Zheng L, Lee WH. The retinoblastoma gene: a prototypic and multifunctional tumor suppressor. Exp Cell Res. 2001, 264(1):2-18.
87. Andersen TI, Gaustad A, Ottestad L et al. Genetic alterations of the tumour suppressor gene regions 3p, 11p, 13q, 17p, and 17q in human breast carcinomas. Genes Chromosomes Cancer. 1992, 4:113–121.
88. Sherr CJ, McCormick F. The Rb and p53 pathways in cancer. Cancer Cell. 2002, 2: 103–112.
89. Dyson N, Buchkovich K, Whyte P et al. The cellular 107K protein that binds to adenovirus E1A also associates with the large T antigens of SV40 and JC virus. Cell. 1989, 58: 249–255.
90. Aprelikova ON, Fang BS, Meissner EG et al. BRCA1-associated growth arrest is RB dependent. Proc Natl Acad Sci USA. 1999, 96:11866-71.
91. Kerangueven F, Essioux L, Dib A et al. Loss of heterozygosity and linkage analysis in breast carcinoma: indication for a putative third susceptibility gene on the short arm of chromosome 8. Oncogene. 1995, 10:1023–1026.
92. Rocco JW, Sidransky D. Exp. p16 (MTS-1/CDKN2/INK4a) in cancer progression. Cell Res. 2001, 264:42–55.
93. Sherr CJ, McCormick F. The RB and p53 pathways in cancer. Cancer Cell. 2002,2:103–112.
94. McDermott KM, Zhang J, Holst CR et al. p16 (INK4a) prevents centrosome dysfunction and genomic instability in primary cells. PLoS Biol. 2006, 4:e51.
95. Xu L, Sgroi D, Sterner CJ et al. Mutational analysis of CDKN2 (MTS1/p16ink4) in human breast carcinomas. Cancer Res. 1994, 54: 5262–4.
96. Kamb A, Gruis NA, Weaver-Feldhaus J et al. A cell cycle regulator potentially involved in genesis of many tumor types. Science. 1994, 264:436–40.
97. Silva J, Silva JM, Dominguez G et al. Concomitant expression of p16INK4a and p14ARF in primary breast cancer and analysis of inactivation mechanisms. J Pathol. 2003, 199:289–97.
98. Jones PA, Laird PW. Cancer epigenetics comes of age. Nat Genet. 1999, 21:163–7.
99. Lehmann U, Langer F, Feist H et al. Quantitative assessment of promoter hypermethylation during breast cancer development. Am J Pathol. 2002, 160:605–12.
100. Sheng S. The promise and challenge toward the clinical application of maspin in cancer. Front Biosci. 2004,9:2733-45.
101. Pemberton PA, Tipton AR, Pavloff N et al. Maspin is an intracellular serpin that partitions into secretory vesicles and is present at the cell surface. J Histochem Cytochem. 1997, 45:697-1706.
102. Katz AB and Taichman LB. A partial catalog of proteins secreted by epidermal keratinocytes in culture. J Invest Dermatol. 1999, 112:818-821.
103. Zou Z, Anisowicz A, HendrixMJC, et al.Maspin, a serpin with tumor-suppressing activity in human mammary epithelial cells.Science. 1994, 263: 526–9.
104. Maass N, Nagasaki K, Ziebart M et al. Expression and regulation of tumor suppressor gene maspin in breast cancer. Clin Breast Cancer. 2002, 3(4):281-7.
105. Maass N, Hojo T, Ueding M et al. Expression of the tumor suppressor gene Maspin in human pancreatic cancers. Clin Cancer Res. 2001, 7:812-817.
106. Umekita Y, Hiipakka RA and Liao S. Rat and human maspins: structures, metastatic suppressor activity and mutation in prostate cancer cells. Cancer Lett. 1997, 113:87-93.
107. Boltze C, Schneider-Stock R, and Meyer F et al. Roessner: Maspin in thyroid cancer: its relationship with p53 and clinical outcome. Oncol Rep. 2003, 10; 1783-1787.
108. Heighway J, Knapp T, Boyce L et al. Lasek and P. Rickert: Expression profiling ofprimary non-small cell lung cancer for target identification. Oncogene. 2002, 21:7749-7763.
109. Sood AK, Fletcher MS, Gruman LM et al. The paradoxical expression of maspin in ovarian carcinoma. Clin Cancer Res. 2002, 8:2924-2932.
110. Matsuda S, Rouault J, Magaud J, Berthet C. In search of a function for the TIS21/PC3/BTG1/TOB family. FEBS Lett. 2001; 497(2-3):67-72.
111. Matsuda S, Kawamura-Tsuzuku J, Ohsugi M et al. Tob, a novel protein that interacts with p185erbB2, is associated with anti-proliferative activity. Oncogene. 1996, 12: 705-13.
112. Yoshida Y, Von Bubnoff A, Ikematsu N et al. Tob proteins enhance inhibitory Smad-receptor interactions to repress BMP signaling. Mech Dev. 2003, 120(5): 629- 37.
113. Yoshida Y, Nakamura T, Komoda M et al. Mice lacking a transcriptional corepressor Tob are predisposed to cancer. Genes Dev. 2003; 17(10):1201-6.
114. Ito Y, Suzuki T, Yoshida H, Tomoda C, Uruno T, Takamura Y, et al. Phosphorylation and inactivation of Tob contributes to the progression of papillary carcinoma of the thyroid. Cancer Lett 2005; 220: 237-42.
115. Yanagie H, Sumimoto H, Nonaka Y, Matsuda S, Hirose I, Hanada S, et al. Inhibition of human pancreatic cancer growth by the adenovirus-mediated introduction of a novel growth suppressing gene, tob, in vitro. Adv Exp Med Biol 1998; 451: 91-6.
116. Jiao Y, Ge C, Meng Q, Cao J, Tong J, Fan S. Adenovirus-Mediated Expression of Tob1 Sensitizes Breast Cancer Cells to Ionizing Radiation. Acta Pharmacologica Sinica. 2007(In press)