PELP1/MNAR和Ki67在子宫内膜癌中的表达及临床意义
|
摘要
子宫内膜癌为女性生殖道最常见的恶性肿瘤之一,占女性生殖道恶性肿瘤的20%-30%。发达国家中子宫内膜癌发病率居女性生殖道恶性肿瘤首位,死亡率居第二位。临床上,早期(Ⅰ-Ⅱ期)子宫内膜癌患者预后较好,5年生存率接近90%,而晚期病人(Ⅲ-Ⅳ期)的生存率仅15%。因此,准确识别高危子宫内膜癌患者、正确判断子宫内膜癌的生物学行为及预后、寻找新的个体化治疗靶点意义重大,可能大大提高子宫内膜癌的治愈率、降低死亡率。PELP1/MNAR是一个新的ER共激活因子,有调节ER的基因组和非基因组途径的作用,它可以通过激活Src/MAPK通路而促进细胞的增殖,激活PI3K/Akt通路而抑制细胞的凋亡。研究发现,PELP1/MNAR在子宫内膜癌中过表达,有望成为子宫内膜癌新的肿瘤标记物。Ki67是一种细胞核相关抗原,是目前临床上广泛应用的检测细胞增殖的标志。本实验主要检测PELP1/MNAR和Ki67蛋白在子宫内膜癌中的表达情况,分析PELP1/MNAR与Ki67之间的相关性,结合临床资料进一步探讨PELP1/MNAR、Ki67与子宫内膜癌疾病发生发展和转移等临床病理因素的关系,为子宫内膜癌的预后判断和个体化治疗提供依据。
方法
1.收集1999年7月至2009年4月经汕头大学医学院附属肿瘤医院妇瘤科开腹手术的76例子宫内膜癌的组织蜡块及相关临床病理资料。
2.采用免疫组织化学Envision二步法检测PELP1/MNAR和Ki67蛋白在子宫内膜癌中的表达情况。
3.采用统计学软件(SPSS17.0)分析子宫内膜癌中PELP1/MNAR和Ki67蛋白的相互关系以及子宫内膜癌中PELP1/MNAR和Ki67蛋白的表达与肿瘤的临床病理分期、病理组织学分级、肌层浸润、淋巴结转移等临床病理因素的关系。
结果
1. PELP1/MNAR蛋白和Ki67蛋白在子宫内膜癌中的表达阳性率分别是100%(76/76)和68.4%(52/76)。定位于子宫内膜癌细胞的细胞核。
2.在子宫内膜癌中,PELP1/MNAR与Ki67蛋白的表达水平呈正相关,P = 0.036,r=0.322。
3. PELP1/MNAR蛋白的表达与子宫内膜癌各临床病理因素的关系:在晚期(Ⅲ、Ⅳ期)子宫内膜癌中PELP1/MNAR蛋白的表达水平,明显高于早期(Ⅰ、Ⅱ期)子宫内膜癌,(P=0.000);在中、低分化(G2、3)子宫内膜癌中PELP1/MNAR蛋白的表达水平明显高于高分化(G1)组(P=0.027、P=0.008);在深肌层浸润子宫内膜癌中PELP1/MNAR蛋白的表达水平明显高于浅肌层浸润者(P=0.000);腹膜后淋巴结转移的子宫内膜癌中,PELP1/MNAR蛋白的表达水平高于无淋巴结转移者(P=0.015);腹水涂片有癌细胞的子宫内膜癌组织中PELP1/MNAR蛋白的表达高于腹水涂片无癌细胞的子宫内膜癌组织(P=0.000);双附件有转移的子宫内膜癌组织中PELP1/MNAR的表达高于双附件无转移的子宫内膜癌组织(P=0.000);但PELP1/MNAR蛋白的表达与是否绝经、ER、PR的表达之间均无关(P>0.05)。
4. Ki67蛋白的表达与子宫内膜癌各临床病理因素的关系:Ki67蛋白的表达水平与子宫内膜癌的组织分化程度有关(P<0.05);Ki67蛋白的表达水平还与子宫内膜癌的手术-病理分期和是否有淋巴结转移有关(P<0.01);但其表达水平与肌层浸润深度及有无腹膜后淋巴结转移无关(P>0.05)。
结论
1. PELP1/MNAR有望成为判断子宫内膜癌进展的新的肿瘤标记物。
2. PELP1/MNAR蛋白和Ki67蛋白在子宫内膜癌中的的表达水平呈正相关,提示两者在子宫内膜癌的发生发展中可能具有协同作用。
3. PELP1/MNAR蛋白和Ki67蛋白的表达的表达水平与子宫内膜癌的手术-病理分期有关,提示PELP1/MNAR和Ki67可能影响子宫内膜癌疾病的进展。
4. PELP1/MNAR蛋白和Ki67蛋白的表达与子宫内膜癌的恶性程度和转移有关,对于判断肿瘤的生物学行为及预后具有重要的意义,可以用于筛选高危组患者,为子宫内膜癌的个体化治疗提供依据。
Endometrial cancer (cancer of the uterine corpus) is one of the common malignant tumor of the female genital tract, accounted for 20% to 30% of the female genital tract malignant tumors.In developed countries, incidence rates for EMC ranks first in all malignant tumor of the female genital tract, mortality ranks second. Clinically, prognosis of early stage(stageⅠ-Ⅱ) patients with EMC is good, the 5-year survival rate is close to 90%, and terminally stage patients(stageⅢ-Ⅳ) is only 15%. Therefore, accurately identifying high-risk EMC patients, judging correctly biological actions and prognosis, and looking for new individualized therapeutic targets are particularly important, which can greatly improve the EMC cure rate and reduce mortality. PELP1 / MNAR is a novel ER coactivator, can regulate the biological actions of ERs resulting from genomic and non-genomic signaling. It can promote cell proliferation through activating the Src/MAPK pathways and inhibits cell apoptosis via activating PI3K/Akt pathways. The study found that PELP1/MNAR overexpressed in EMC, is expected to become new tumor markers of EMC.Ki67 is a nuclei related antigen, which is widely used for detecting cell proliferation as a marker currently. This study was designed to evaluate the expression of PELP1/MNAR and Ki67 proteins in EMC,analys the relationship between PELP1/MNAR and Ki67, explore the relation of PELP1/MNAR and Ki67 expression with clinical pathology factor,including disease occurrence,development and metastasis etc, which provide the basis for deciding prognostic and individualized treatments.
Methods
1. A total of 76 paraffin-embedded endometrial cancer tissue blocks were obtained from the Department of Gynecologic Oncology at the Cancer Affiliated Hospital of Shantou University Medical College in the period between July 1999 and April 2009, and clinical data of these patients was collected.
2. The immunohistochemical detection system was used to detect the expression of PELP1/MNAR protein and Ki67 in endometrial cancer.
3. SPSS Statistics 17.0 software was used to analyze the relationship between the expression of PELP1/MNAR、Ki67 in EMC with clinical stage, histological grade, myometrial invasion and lymph node metastasis, as well as the relationship between PELP1/MNAR and Ki67.
Results
1. The positive rate of PELP1/MNAR protein and Ki67 in EMC were 100% and 68.4%.The patterns of PELP1/MNAR and Ki67 expression in the tumor cells were nuclear staining.
2. The expression of PELP1/MNAR protein is positively correlated with the expression of Ki67 in EMC, P = 0.036,r=0.322.
3. The relationship between PELP1/MNAR protein expression intensity and the clinicopathological significance of EMC:The intensity of PELP1 protein expression in advanced endometrial cancer (Ⅲ-Ⅳstage), was significantly higher than that in early ovarian cancer (Ⅰ-Ⅱstage), P = 0.000.In moderately and poorly differentiated endometrial cancer (G2、G3),the intensity of PELP1 protein expression, was significantly higher than that in well differentiated endometrial cancer (G1), P = 0.027、P = 0.008. PELP1 protein expression intensity of endometrial cancer with deep myometrial invasion, was significantly higher than that in the superficial myometrial invasion ones, P = 0.000.In retroperitoneal lymph node positive endometrial cancer,the intensity of PELP1 expression was higher than the retroperitoneal lymph node negative ones,P=0.015.The intensity of PELP1 protein expression in endometrial cancer,which showed positive cancer cells in ascites or peritoneal washing liquid,was obviously higher than negative ones.P=0.000. The intensity of PELP1 protein expression in adnexa metastasis endometrial cancer was higher than opposite ones.P=0.000. However, the intensity of PELP1 protein expression in EMC was not related with the expression of ER, PR and menopause cases (P> 0.05).
4. The relationship between Ki67 protein expression intensity and the clinicopathological significance of EMC: The level of Ki67 expression was related with tumor grade, clinical stage and clinical stage (P <0.05). However, the Ki67 expression levels in EMC was not related with myometrial invasion and retroperitoneal lymph node metastasis (P> 0.05).
Conclusions
1. PELP1/MNAR is expected as a marker of endometrial tumor progression.
2. The intensity of PELP1/MNAR is positively correlated with the level of Ki67 in EMC, which suggest they may have a synergistic effect in the occurrence and development of endometrial cancer.
3. The intensity of PELP1/MNAR and the levels of Ki67 expression were positively correlated with clinical stage of EMC. Suggest PELP1/MNAR and Ki67 may affect the progression of EMC.
4. PELP1/MNAR and Ki67 were significantly related to malignant degree and metastasis in EMC,which was important to determining tumor biological behavior and prognosis. Detecting the two indicators can be used for screening high-risk group and offering reference for individualized therapy.
方法
1.收集1999年7月至2009年4月经汕头大学医学院附属肿瘤医院妇瘤科开腹手术的76例子宫内膜癌的组织蜡块及相关临床病理资料。
2.采用免疫组织化学Envision二步法检测PELP1/MNAR和Ki67蛋白在子宫内膜癌中的表达情况。
3.采用统计学软件(SPSS17.0)分析子宫内膜癌中PELP1/MNAR和Ki67蛋白的相互关系以及子宫内膜癌中PELP1/MNAR和Ki67蛋白的表达与肿瘤的临床病理分期、病理组织学分级、肌层浸润、淋巴结转移等临床病理因素的关系。
结果
1. PELP1/MNAR蛋白和Ki67蛋白在子宫内膜癌中的表达阳性率分别是100%(76/76)和68.4%(52/76)。定位于子宫内膜癌细胞的细胞核。
2.在子宫内膜癌中,PELP1/MNAR与Ki67蛋白的表达水平呈正相关,P = 0.036,r=0.322。
3. PELP1/MNAR蛋白的表达与子宫内膜癌各临床病理因素的关系:在晚期(Ⅲ、Ⅳ期)子宫内膜癌中PELP1/MNAR蛋白的表达水平,明显高于早期(Ⅰ、Ⅱ期)子宫内膜癌,(P=0.000);在中、低分化(G2、3)子宫内膜癌中PELP1/MNAR蛋白的表达水平明显高于高分化(G1)组(P=0.027、P=0.008);在深肌层浸润子宫内膜癌中PELP1/MNAR蛋白的表达水平明显高于浅肌层浸润者(P=0.000);腹膜后淋巴结转移的子宫内膜癌中,PELP1/MNAR蛋白的表达水平高于无淋巴结转移者(P=0.015);腹水涂片有癌细胞的子宫内膜癌组织中PELP1/MNAR蛋白的表达高于腹水涂片无癌细胞的子宫内膜癌组织(P=0.000);双附件有转移的子宫内膜癌组织中PELP1/MNAR的表达高于双附件无转移的子宫内膜癌组织(P=0.000);但PELP1/MNAR蛋白的表达与是否绝经、ER、PR的表达之间均无关(P>0.05)。
4. Ki67蛋白的表达与子宫内膜癌各临床病理因素的关系:Ki67蛋白的表达水平与子宫内膜癌的组织分化程度有关(P<0.05);Ki67蛋白的表达水平还与子宫内膜癌的手术-病理分期和是否有淋巴结转移有关(P<0.01);但其表达水平与肌层浸润深度及有无腹膜后淋巴结转移无关(P>0.05)。
结论
1. PELP1/MNAR有望成为判断子宫内膜癌进展的新的肿瘤标记物。
2. PELP1/MNAR蛋白和Ki67蛋白在子宫内膜癌中的的表达水平呈正相关,提示两者在子宫内膜癌的发生发展中可能具有协同作用。
3. PELP1/MNAR蛋白和Ki67蛋白的表达的表达水平与子宫内膜癌的手术-病理分期有关,提示PELP1/MNAR和Ki67可能影响子宫内膜癌疾病的进展。
4. PELP1/MNAR蛋白和Ki67蛋白的表达与子宫内膜癌的恶性程度和转移有关,对于判断肿瘤的生物学行为及预后具有重要的意义,可以用于筛选高危组患者,为子宫内膜癌的个体化治疗提供依据。
Endometrial cancer (cancer of the uterine corpus) is one of the common malignant tumor of the female genital tract, accounted for 20% to 30% of the female genital tract malignant tumors.In developed countries, incidence rates for EMC ranks first in all malignant tumor of the female genital tract, mortality ranks second. Clinically, prognosis of early stage(stageⅠ-Ⅱ) patients with EMC is good, the 5-year survival rate is close to 90%, and terminally stage patients(stageⅢ-Ⅳ) is only 15%. Therefore, accurately identifying high-risk EMC patients, judging correctly biological actions and prognosis, and looking for new individualized therapeutic targets are particularly important, which can greatly improve the EMC cure rate and reduce mortality. PELP1 / MNAR is a novel ER coactivator, can regulate the biological actions of ERs resulting from genomic and non-genomic signaling. It can promote cell proliferation through activating the Src/MAPK pathways and inhibits cell apoptosis via activating PI3K/Akt pathways. The study found that PELP1/MNAR overexpressed in EMC, is expected to become new tumor markers of EMC.Ki67 is a nuclei related antigen, which is widely used for detecting cell proliferation as a marker currently. This study was designed to evaluate the expression of PELP1/MNAR and Ki67 proteins in EMC,analys the relationship between PELP1/MNAR and Ki67, explore the relation of PELP1/MNAR and Ki67 expression with clinical pathology factor,including disease occurrence,development and metastasis etc, which provide the basis for deciding prognostic and individualized treatments.
Methods
1. A total of 76 paraffin-embedded endometrial cancer tissue blocks were obtained from the Department of Gynecologic Oncology at the Cancer Affiliated Hospital of Shantou University Medical College in the period between July 1999 and April 2009, and clinical data of these patients was collected.
2. The immunohistochemical detection system was used to detect the expression of PELP1/MNAR protein and Ki67 in endometrial cancer.
3. SPSS Statistics 17.0 software was used to analyze the relationship between the expression of PELP1/MNAR、Ki67 in EMC with clinical stage, histological grade, myometrial invasion and lymph node metastasis, as well as the relationship between PELP1/MNAR and Ki67.
Results
1. The positive rate of PELP1/MNAR protein and Ki67 in EMC were 100% and 68.4%.The patterns of PELP1/MNAR and Ki67 expression in the tumor cells were nuclear staining.
2. The expression of PELP1/MNAR protein is positively correlated with the expression of Ki67 in EMC, P = 0.036,r=0.322.
3. The relationship between PELP1/MNAR protein expression intensity and the clinicopathological significance of EMC:The intensity of PELP1 protein expression in advanced endometrial cancer (Ⅲ-Ⅳstage), was significantly higher than that in early ovarian cancer (Ⅰ-Ⅱstage), P = 0.000.In moderately and poorly differentiated endometrial cancer (G2、G3),the intensity of PELP1 protein expression, was significantly higher than that in well differentiated endometrial cancer (G1), P = 0.027、P = 0.008. PELP1 protein expression intensity of endometrial cancer with deep myometrial invasion, was significantly higher than that in the superficial myometrial invasion ones, P = 0.000.In retroperitoneal lymph node positive endometrial cancer,the intensity of PELP1 expression was higher than the retroperitoneal lymph node negative ones,P=0.015.The intensity of PELP1 protein expression in endometrial cancer,which showed positive cancer cells in ascites or peritoneal washing liquid,was obviously higher than negative ones.P=0.000. The intensity of PELP1 protein expression in adnexa metastasis endometrial cancer was higher than opposite ones.P=0.000. However, the intensity of PELP1 protein expression in EMC was not related with the expression of ER, PR and menopause cases (P> 0.05).
4. The relationship between Ki67 protein expression intensity and the clinicopathological significance of EMC: The level of Ki67 expression was related with tumor grade, clinical stage and clinical stage (P <0.05). However, the Ki67 expression levels in EMC was not related with myometrial invasion and retroperitoneal lymph node metastasis (P> 0.05).
Conclusions
1. PELP1/MNAR is expected as a marker of endometrial tumor progression.
2. The intensity of PELP1/MNAR is positively correlated with the level of Ki67 in EMC, which suggest they may have a synergistic effect in the occurrence and development of endometrial cancer.
3. The intensity of PELP1/MNAR and the levels of Ki67 expression were positively correlated with clinical stage of EMC. Suggest PELP1/MNAR and Ki67 may affect the progression of EMC.
4. PELP1/MNAR and Ki67 were significantly related to malignant degree and metastasis in EMC,which was important to determining tumor biological behavior and prognosis. Detecting the two indicators can be used for screening high-risk group and offering reference for individualized therapy.
引文
[1]. Chaudhry P, Asselin E. Resistance to chemotherapy and hormone therapy in endometrial cancer. Endocr Relat Cancer. 2009 Jun;16(2):363-80.
[2]. Joung I,Strominger, et al . Molecular cloning of a phosphotyrosine-independent ligand of the p56lck SH2 domain. Proc. Natl. Acad. Sci. U.S.A. 1996.93,5991–5995.
[3]. Vadlamudi RK, Wang RA, et al. Molecular cloning characterization of PELP1/MNAR, a novel human coregulator of estrogen receptor alpha.J Biol Chem, 2001,276(41):38272-38279.
[4]. Brann DW, Zhang QG, Wang RM, et al. PELP1/MNAR--a novel estrogen receptor-interacting protein. Mol Cell Endocrinol.2008,290(1-2):2-7.
[5]. Vadlamudi RK, Balasenthil S, Sahin AA, et al. Novel estrogen receptor coactivator PELP1/MNAR gene and ERbeta expression in salivary duct adenocarcinoma: potential therapeutic targets. Hum Pathol, 2005,36(6):670-675.
[6]. Vadlamudi RK, Manavathi B, Balasenthil S, et al. Functional implications of altered subcellular localization of PELP1/MNAR in breast cancer cells. Cancer Res.2005;65:7724–7732.
[7]. Habashy HO, Powe DG, Rakha EA, et al. The prognostic significance of PELP1/MNAR expression in invasive breast cancer with emphasis on the ER-positive luminal-like subtype. Breast Cancer Res. Treat. 2009 E publication ahead of print.
[8]. Kumar R, Zhang H, Holm C, et al. Extranuclear coactivator signaling confers insensitivity to tamoxifen. Clin. Cancer Res 2009;15:4123–4130.
[9]. Dimple C, Nair SS, Rajhans R, et al. Role of PELP1/MNAR signaling in ovarian tumorigenesis. Cancer Res 2008;68:4902–4909.
[10]. Nair SS, Guo Z, Mueller JM, et al. PELP1/MNAR enhances androgen receptor functions through LIM-only coactivator FHL2. Mol Endocrinol 2007;21:613–624.
[11]. Rajhans R, Nair S, Holden AH, et al. Oncogenic Potential of the Nuclear Receptor Coregulator Proline-, Glutamic Acid-, Leucine-Rich Protein 1/Modulator of the Nongenomic Actions of the Estrogen Receptor. Cancer Res 2007;67:5505–5512.
[12]. Grivas PD, Tzelepi V, Sotiropoulou-Bonikou G, et al.Expression of ERalpha, ERbeta and co-regulator PELP1/MNAR in colorectal cancer: prognostic significance andclinicopathologic correlations. Cell Oncol 2009;31:235–247.
[13]. Marquez-Garban DC, Chen HW, Fishbein MC, et al. Estrogen receptor signaling pathways in human non-small cell lung cancer. Steroids 2007;72:135–143.
[14]. Vadlamudi RK, Balasenthil S, Broaddus RR, et al. Deregulation of Estrogen Receptor Coactivator Proline-, Glutamic Acid-, and Leucine-Rich Protein-1/Modulator of Nongenomic Activity of Estrogen Receptor in Human Endometrial Tumors.J Clin Endocrinol Metab. 2004,89(12):6130-6138.
[15]. Mertens HJ, Heineman MJ, Evers JL.The expression of apoptosis-related proteins Bcl-2 and Ki67 in endometrium of ovulatory menstrual cycles. Gynecol Obstet Invest. 2002;53(4):224-30.
[16]. Zhu C, Luo J, Shi H, et al. Expression of tubulin, p53, ki67, receptors for estrogen, and progesterone in endometrial cancer Eur J Gynaecol Oncol. 2009;30(5):514-7.
[17]. Morsi HM, Leers MP, J?ger W, The patterns of expression of an apoptosis-related CK18 neoepitope, the bcl-2 proto-oncogene, and the Ki67 proliferation marker in normal, hyperplastic, and malignant endometrium. Int J Gynecol Pathol. 2000 Apr;19(2):118-26.
[18]. Vadlamudi RK, Kumar R. Functional and biological properties of the nuclear receptor coregulator PELP1/MNAR. Nuclear receptor signaling. 2007,5:e004.
[19]. Hoskins WJ, Perez CA, Young RC. Principles and Practice of Gynecologic Oncology. Philadelphia’Lippincott Williams and Wilkins; 2000. p. 1005– 7.
[1] Cheskis BJ, Greger J, Cooch N, et al. MNAR plays an important role in ERa activation of Src/MAPK and PI3K/Akt signaling pathways[J]. Steroids.,2008,73(9-10):901-905.
[2] Hall JM, McDonnell DP. Coregulators in nuclear estrogen receptor action: from concept to therapeutic targeting[J].. Mol Interv,2005,5(6):343–357.
[3] O'Malley BW. Coregulators: from whence came these "master genes"[J].. Mol Endocrinol. 2007,21(5):1009-1013.
[4]庄育红,任慕兰,魏晓滢.雌激素受体亚型ERα和ERβ在子宫内膜癌的表达研究[J]..东南大学学报, 2008, 27 (5): 361-365.
[5] Anzick SL, Kononen J, Walker RL. AIB1,a steroid receptor coactivator amplified in breast and ovarian cancer[J].. Science., 1997, 277:965–968.
[6] Kershah SM, Desouki MM, Koterba KL, et al. Expression of estrogen receptor coregulators in normal and malignant human endometrium[J].. Gynecol. Oncol, 2004,92(1):304–313.
[7] Sakaguchi H, Fujimoto J, Sun WS, et al. Clinical implications of steroid receptor coactivator (SRC)-3 in uterine endometrial cancers[J]. J Steroid Biochem Mol Biol. 2007,104(3-5):237-240.
[8] Balmer NN, Richer JK, Spoelstra NS, et al. Steroid receptor coactivator AIB1 in endometrial carcinoma, hyperplasia and normal endometrium: correlation with clinicopathologic parameters and biomarkers[J].. Mod Pathol. 2006,19(12):1593-1605.
[9]韩肖燕,张雪梅,陈悦等.AIB1蛋白在妇科肿瘤中的表达[J].四川大学学报, 2007,38(2):246-249.
[10] Kuang S, Liao L, Zhang H, et al. AIB1/SRC-3 deficiency affects insulin-like growth factor I signaling pathway and suppresses v-Ha-ras-induced breast cancer initiation and progression in mice[J].. Cancer Research. 2004,64(5):1875-1885.
[11] Vadlamudi RK, Wang RA, Mazumdar A, et al. Molecular cloning characterization of PELP1/MNAR, a novel human coregulator of estrogen receptor alpha[J].. J Biol Chem, 2001,276(41):38272-38279.
[12] Brann DW, Zhang QG, Wang RM, et al. PELP1/MNAR--a novel estrogen receptor-interacting protein[J]. 2008,290(1-2):2-7.
[13] Vadlamudi RK, Balasenthil S, Sahin AA, et al. Novel estrogen receptor coactivator PELP1/MNAR gene and ERbeta expression in salivary duct adenocarcinoma: potential therapeutic targets[J].. Hum Pathol, 2005,36(6):670-675.
[14] Mishra SK, Balasenthil S, Nguyen D, et al. Cloning and functional characterization of PELP1/MNAR promoter[J].. Gene. 2004,330:115-122.
[15] Vadlamudi RK, Kumar R. Functional and biological properties of the nuclear receptor coregulator PELP1/MNAR. Nuclear receptor signaling. 2007,5:e004.
[16] Nair S, Vadlamudi RK. Emerging significance of ER-coregulator PELP1/MNAR in cancer[J]. Histol Histopathol, 2007,22(1): 91-96.
[17] Vadlamudi RK, Balasenthil S, Broaddus RR, et al. Deregulation of Estrogen Receptor Coactivator Proline-, Glutamic Acid-, and Leucine-Rich Protein-1/Modulator of Nongenomic Activity of Estrogen Receptor in Human Endometrial Tumors[J].. J Clin Endocrinol Metab. 2004,89(12):6130-6138.
[18] Mishra SK, Mazumdar A, Vadlamudi RK, et al. MICoA, A novel metastasis-associated protein 1 (MTA1) interacting protein coactivator, regulates estrogen receptor-αtransactivation functions[J].. J Biol Chem. 2003,278(21):19209-19219.
[19] Kumar R, Zhang H, Holm C, et al. Extranuclear coactivator signaling confers insensitivity to tamoxifen[J].. Clin Cancer Res. 2009,15(12):4123-4130.
[20] Pencil SD, Toh Y, Nicolson GL. Candidate metastasis-associated genes of the rat 13762NF mammary adenocarcinoma[J].. Breast Cancer Res Treat. 1993,25 (2):165-174.
[21] Toh Y, Nicolson GL.The role of the MTA family and their encoded proteins in human cancers: molecular functions and clinical implications.. Clin Exp Metastasis. 2009;26(3):215-27.
[22] Jang KS, Paik SS, Chung H, Oh YH, Kong G. MTA1 overexpression correlates significantly with tumor grade and angiogenesis in human breast cancers. Cancer Science.2006 ;97(5):374-379.
[23] Zhang H, Stephens LC, Kumar R. Metastasis tumor antigen family protein during breast cancer progression and metastasis in a reliable mouse model for human breast cancer [J ] . Clinical Cancer Res. 2006,12 (5):1479-1486.
[24] Zhang H, Singh RR, Talukder AH, et al. Metastatic tumor antigen 3 is a direct corepressor of the Wnt4 pathway[J].. Genes & Development. 2006,20(21):2943-2948.
[25] Bui TD, Zhang L, Rees MC, Bicknell R, Harris AL.Expression and hormone regulation of Wnt2, 3, 4, 5a, 7a, 7b and 10b in normal human endometrium and endometrial carcinoma[J].. Br J Cancer.1997,75(8):1131-1136.
[26] Gururaj AE, Singh RR, Rayala SK, et al. MTA1, a transcriptional activator of breast cancer amplified sequence 3[J].. Proc Natl Acad Sci USA. 2006,103(17):6670-6675.
[27] Balasenthil S, Broaddus RR, Kumar R. Expression of metastasis-associated protein 1 (MTA1) in benign endometrium and endometrial adenocarcinomas[J]. 2006, 37(6):656-61.
[28]潘九林,韩素萍.子宫内膜癌中MTA1蛋白表达水平的研究[J].实用临床医药杂志, 2007,11(6):32-34.
[29]何秀萍,黄明莉,吴春凤.转移相关蛋白-1和E-钙黏蛋白基因与子宫内膜癌的相关性研究[J].中国全科医学, 2008,8(15):1348-1350。
[30] Webb P, Valentine C, Nguyen P, et al. ERβbinds N-CoR in the presence of estrogens via an LXXLL-like motif in the N-CoR C-terminus[J].. Nucl Recept. 2003,1 (1):4.
[31]吴秀丽,何英,杨开选. 499例子宫内膜癌预后及随访资料分析[J].华西医学, 2009 ,24 (6):1403-1407.
[32] Kershah SM, Desouki MM, Koterba KL, et al. Expression of estrogen receptor coregulators in normal and malignant human endometrium[J].. Gynecol Oncol.,2004,92(1):304-313.
[33] Kurebayashi J, Otsuki T, Kunisue H, et al. Expression levels of estrogen receptor-alpha, estrogen receptor-beta, coactivators, and corepressors in breast cancer[J].. Clin Cancer Res. 2000,6(2):512–518.
[34] Girault I, Lerebours F, Amarir S, et al. Expression analysis of estrogen receptor alpha coregulators in breast carcinoma: evidence that NCOR1 expression is predictive of the response to tamoxifen[J].. Clin Cancer Res. 2003,9(4):1259–66.
[35] Lonard DM, Lanz RB, O'Malley BW. Nuclear receptor coregulators and human disease. Endocr Rev. 2007,28(5):575-87.
[36] Zhang H, Liao L, Kuang S, et al. Spatial distribution of the messenger ribonucleic acid and protein of the nuclear receptor coactivator, amplified in breast cancer-3 ,in mice[J].. Endocrinology.2003,144(4):1435-1443.
[37] Zhang H, Kuang S,Liao L, et al. Haploid inactivation of the amplified-in-breast cancer 3 coactivator reduces the inhibitory effect of peroxisome proliferator-activated receptorγand retinoid X receptor on cell proliferation and accelerates polyoma middle-T antigen-induced mammary tumorigenesis in mice[J].. Cancer Research. 2004,64(19):7169-7177.
[38] Zhang H. Endocrine-related Cancer[M]. In Encyclopedia of Cancer 2th Edition. Ed. By Schwab M. Springer, Heidelberg, Germany, 2008: 435-439
[2]. Joung I,Strominger, et al . Molecular cloning of a phosphotyrosine-independent ligand of the p56lck SH2 domain. Proc. Natl. Acad. Sci. U.S.A. 1996.93,5991–5995.
[3]. Vadlamudi RK, Wang RA, et al. Molecular cloning characterization of PELP1/MNAR, a novel human coregulator of estrogen receptor alpha.J Biol Chem, 2001,276(41):38272-38279.
[4]. Brann DW, Zhang QG, Wang RM, et al. PELP1/MNAR--a novel estrogen receptor-interacting protein. Mol Cell Endocrinol.2008,290(1-2):2-7.
[5]. Vadlamudi RK, Balasenthil S, Sahin AA, et al. Novel estrogen receptor coactivator PELP1/MNAR gene and ERbeta expression in salivary duct adenocarcinoma: potential therapeutic targets. Hum Pathol, 2005,36(6):670-675.
[6]. Vadlamudi RK, Manavathi B, Balasenthil S, et al. Functional implications of altered subcellular localization of PELP1/MNAR in breast cancer cells. Cancer Res.2005;65:7724–7732.
[7]. Habashy HO, Powe DG, Rakha EA, et al. The prognostic significance of PELP1/MNAR expression in invasive breast cancer with emphasis on the ER-positive luminal-like subtype. Breast Cancer Res. Treat. 2009 E publication ahead of print.
[8]. Kumar R, Zhang H, Holm C, et al. Extranuclear coactivator signaling confers insensitivity to tamoxifen. Clin. Cancer Res 2009;15:4123–4130.
[9]. Dimple C, Nair SS, Rajhans R, et al. Role of PELP1/MNAR signaling in ovarian tumorigenesis. Cancer Res 2008;68:4902–4909.
[10]. Nair SS, Guo Z, Mueller JM, et al. PELP1/MNAR enhances androgen receptor functions through LIM-only coactivator FHL2. Mol Endocrinol 2007;21:613–624.
[11]. Rajhans R, Nair S, Holden AH, et al. Oncogenic Potential of the Nuclear Receptor Coregulator Proline-, Glutamic Acid-, Leucine-Rich Protein 1/Modulator of the Nongenomic Actions of the Estrogen Receptor. Cancer Res 2007;67:5505–5512.
[12]. Grivas PD, Tzelepi V, Sotiropoulou-Bonikou G, et al.Expression of ERalpha, ERbeta and co-regulator PELP1/MNAR in colorectal cancer: prognostic significance andclinicopathologic correlations. Cell Oncol 2009;31:235–247.
[13]. Marquez-Garban DC, Chen HW, Fishbein MC, et al. Estrogen receptor signaling pathways in human non-small cell lung cancer. Steroids 2007;72:135–143.
[14]. Vadlamudi RK, Balasenthil S, Broaddus RR, et al. Deregulation of Estrogen Receptor Coactivator Proline-, Glutamic Acid-, and Leucine-Rich Protein-1/Modulator of Nongenomic Activity of Estrogen Receptor in Human Endometrial Tumors.J Clin Endocrinol Metab. 2004,89(12):6130-6138.
[15]. Mertens HJ, Heineman MJ, Evers JL.The expression of apoptosis-related proteins Bcl-2 and Ki67 in endometrium of ovulatory menstrual cycles. Gynecol Obstet Invest. 2002;53(4):224-30.
[16]. Zhu C, Luo J, Shi H, et al. Expression of tubulin, p53, ki67, receptors for estrogen, and progesterone in endometrial cancer Eur J Gynaecol Oncol. 2009;30(5):514-7.
[17]. Morsi HM, Leers MP, J?ger W, The patterns of expression of an apoptosis-related CK18 neoepitope, the bcl-2 proto-oncogene, and the Ki67 proliferation marker in normal, hyperplastic, and malignant endometrium. Int J Gynecol Pathol. 2000 Apr;19(2):118-26.
[18]. Vadlamudi RK, Kumar R. Functional and biological properties of the nuclear receptor coregulator PELP1/MNAR. Nuclear receptor signaling. 2007,5:e004.
[19]. Hoskins WJ, Perez CA, Young RC. Principles and Practice of Gynecologic Oncology. Philadelphia’Lippincott Williams and Wilkins; 2000. p. 1005– 7.
[1] Cheskis BJ, Greger J, Cooch N, et al. MNAR plays an important role in ERa activation of Src/MAPK and PI3K/Akt signaling pathways[J]. Steroids.,2008,73(9-10):901-905.
[2] Hall JM, McDonnell DP. Coregulators in nuclear estrogen receptor action: from concept to therapeutic targeting[J].. Mol Interv,2005,5(6):343–357.
[3] O'Malley BW. Coregulators: from whence came these "master genes"[J].. Mol Endocrinol. 2007,21(5):1009-1013.
[4]庄育红,任慕兰,魏晓滢.雌激素受体亚型ERα和ERβ在子宫内膜癌的表达研究[J]..东南大学学报, 2008, 27 (5): 361-365.
[5] Anzick SL, Kononen J, Walker RL. AIB1,a steroid receptor coactivator amplified in breast and ovarian cancer[J].. Science., 1997, 277:965–968.
[6] Kershah SM, Desouki MM, Koterba KL, et al. Expression of estrogen receptor coregulators in normal and malignant human endometrium[J].. Gynecol. Oncol, 2004,92(1):304–313.
[7] Sakaguchi H, Fujimoto J, Sun WS, et al. Clinical implications of steroid receptor coactivator (SRC)-3 in uterine endometrial cancers[J]. J Steroid Biochem Mol Biol. 2007,104(3-5):237-240.
[8] Balmer NN, Richer JK, Spoelstra NS, et al. Steroid receptor coactivator AIB1 in endometrial carcinoma, hyperplasia and normal endometrium: correlation with clinicopathologic parameters and biomarkers[J].. Mod Pathol. 2006,19(12):1593-1605.
[9]韩肖燕,张雪梅,陈悦等.AIB1蛋白在妇科肿瘤中的表达[J].四川大学学报, 2007,38(2):246-249.
[10] Kuang S, Liao L, Zhang H, et al. AIB1/SRC-3 deficiency affects insulin-like growth factor I signaling pathway and suppresses v-Ha-ras-induced breast cancer initiation and progression in mice[J].. Cancer Research. 2004,64(5):1875-1885.
[11] Vadlamudi RK, Wang RA, Mazumdar A, et al. Molecular cloning characterization of PELP1/MNAR, a novel human coregulator of estrogen receptor alpha[J].. J Biol Chem, 2001,276(41):38272-38279.
[12] Brann DW, Zhang QG, Wang RM, et al. PELP1/MNAR--a novel estrogen receptor-interacting protein[J]. 2008,290(1-2):2-7.
[13] Vadlamudi RK, Balasenthil S, Sahin AA, et al. Novel estrogen receptor coactivator PELP1/MNAR gene and ERbeta expression in salivary duct adenocarcinoma: potential therapeutic targets[J].. Hum Pathol, 2005,36(6):670-675.
[14] Mishra SK, Balasenthil S, Nguyen D, et al. Cloning and functional characterization of PELP1/MNAR promoter[J].. Gene. 2004,330:115-122.
[15] Vadlamudi RK, Kumar R. Functional and biological properties of the nuclear receptor coregulator PELP1/MNAR. Nuclear receptor signaling. 2007,5:e004.
[16] Nair S, Vadlamudi RK. Emerging significance of ER-coregulator PELP1/MNAR in cancer[J]. Histol Histopathol, 2007,22(1): 91-96.
[17] Vadlamudi RK, Balasenthil S, Broaddus RR, et al. Deregulation of Estrogen Receptor Coactivator Proline-, Glutamic Acid-, and Leucine-Rich Protein-1/Modulator of Nongenomic Activity of Estrogen Receptor in Human Endometrial Tumors[J].. J Clin Endocrinol Metab. 2004,89(12):6130-6138.
[18] Mishra SK, Mazumdar A, Vadlamudi RK, et al. MICoA, A novel metastasis-associated protein 1 (MTA1) interacting protein coactivator, regulates estrogen receptor-αtransactivation functions[J].. J Biol Chem. 2003,278(21):19209-19219.
[19] Kumar R, Zhang H, Holm C, et al. Extranuclear coactivator signaling confers insensitivity to tamoxifen[J].. Clin Cancer Res. 2009,15(12):4123-4130.
[20] Pencil SD, Toh Y, Nicolson GL. Candidate metastasis-associated genes of the rat 13762NF mammary adenocarcinoma[J].. Breast Cancer Res Treat. 1993,25 (2):165-174.
[21] Toh Y, Nicolson GL.The role of the MTA family and their encoded proteins in human cancers: molecular functions and clinical implications.. Clin Exp Metastasis. 2009;26(3):215-27.
[22] Jang KS, Paik SS, Chung H, Oh YH, Kong G. MTA1 overexpression correlates significantly with tumor grade and angiogenesis in human breast cancers. Cancer Science.2006 ;97(5):374-379.
[23] Zhang H, Stephens LC, Kumar R. Metastasis tumor antigen family protein during breast cancer progression and metastasis in a reliable mouse model for human breast cancer [J ] . Clinical Cancer Res. 2006,12 (5):1479-1486.
[24] Zhang H, Singh RR, Talukder AH, et al. Metastatic tumor antigen 3 is a direct corepressor of the Wnt4 pathway[J].. Genes & Development. 2006,20(21):2943-2948.
[25] Bui TD, Zhang L, Rees MC, Bicknell R, Harris AL.Expression and hormone regulation of Wnt2, 3, 4, 5a, 7a, 7b and 10b in normal human endometrium and endometrial carcinoma[J].. Br J Cancer.1997,75(8):1131-1136.
[26] Gururaj AE, Singh RR, Rayala SK, et al. MTA1, a transcriptional activator of breast cancer amplified sequence 3[J].. Proc Natl Acad Sci USA. 2006,103(17):6670-6675.
[27] Balasenthil S, Broaddus RR, Kumar R. Expression of metastasis-associated protein 1 (MTA1) in benign endometrium and endometrial adenocarcinomas[J]. 2006, 37(6):656-61.
[28]潘九林,韩素萍.子宫内膜癌中MTA1蛋白表达水平的研究[J].实用临床医药杂志, 2007,11(6):32-34.
[29]何秀萍,黄明莉,吴春凤.转移相关蛋白-1和E-钙黏蛋白基因与子宫内膜癌的相关性研究[J].中国全科医学, 2008,8(15):1348-1350。
[30] Webb P, Valentine C, Nguyen P, et al. ERβbinds N-CoR in the presence of estrogens via an LXXLL-like motif in the N-CoR C-terminus[J].. Nucl Recept. 2003,1 (1):4.
[31]吴秀丽,何英,杨开选. 499例子宫内膜癌预后及随访资料分析[J].华西医学, 2009 ,24 (6):1403-1407.
[32] Kershah SM, Desouki MM, Koterba KL, et al. Expression of estrogen receptor coregulators in normal and malignant human endometrium[J].. Gynecol Oncol.,2004,92(1):304-313.
[33] Kurebayashi J, Otsuki T, Kunisue H, et al. Expression levels of estrogen receptor-alpha, estrogen receptor-beta, coactivators, and corepressors in breast cancer[J].. Clin Cancer Res. 2000,6(2):512–518.
[34] Girault I, Lerebours F, Amarir S, et al. Expression analysis of estrogen receptor alpha coregulators in breast carcinoma: evidence that NCOR1 expression is predictive of the response to tamoxifen[J].. Clin Cancer Res. 2003,9(4):1259–66.
[35] Lonard DM, Lanz RB, O'Malley BW. Nuclear receptor coregulators and human disease. Endocr Rev. 2007,28(5):575-87.
[36] Zhang H, Liao L, Kuang S, et al. Spatial distribution of the messenger ribonucleic acid and protein of the nuclear receptor coactivator, amplified in breast cancer-3 ,in mice[J].. Endocrinology.2003,144(4):1435-1443.
[37] Zhang H, Kuang S,Liao L, et al. Haploid inactivation of the amplified-in-breast cancer 3 coactivator reduces the inhibitory effect of peroxisome proliferator-activated receptorγand retinoid X receptor on cell proliferation and accelerates polyoma middle-T antigen-induced mammary tumorigenesis in mice[J].. Cancer Research. 2004,64(19):7169-7177.
[38] Zhang H. Endocrine-related Cancer[M]. In Encyclopedia of Cancer 2th Edition. Ed. By Schwab M. Springer, Heidelberg, Germany, 2008: 435-439