乳腺癌组织中mTOR、eIF4E、4EBPS蛋白的表达及意义
摘要
乳腺癌是妇女最为常见的恶性肿瘤之一,严重威胁着女性的身体健康。在欧美国家发病率最高,2007年美国乳腺癌新发178480例,占新发肿瘤病例总数的26%,死亡率在支气管肺癌之后居第二位；相对于欧美地区,亚洲地区的乳腺癌发病率虽然稍低,但近几年来也呈明显上升趋势。在国内某些沿海城市,乳腺癌的发生在过去20年内不断上升,并且有进一步加速的趋势。许多地区的乳腺癌已占女性恶性肿瘤的首位。流行病学、遗传学和化学致癌动物模型以及分子遗传学的研究证明,恶性肿瘤的发生是一个长期的多因素参与且呈多阶段发展的过程。研究表明,在诸多致病因素中,细胞信号传导异常与肿瘤的关系密切,在诸多信号转导通路上,某些蛋白发生异常,导致肿瘤细胞合成大量的促生长因子,最终导致细胞增殖失控。
哺乳动物雷帕霉素蛋白(mammlalian target of rapamycin, mTOR)是雷帕霉素在哺乳动物内作用的蛋白激酶,是一种非典型的丝氨酸/苏氨酸蛋白激酶,其蛋白分子量为289kDa,含2549个氨基酸。mTOR信号通路对细胞的分化、生长、增殖、凋亡起着非常重要的调节作用,在哺乳类动物体内,mTOR的主要功能是对翻译过程进行调节。真核细胞翻译启动因子4E (eukaryotic translation initiation factor 4E, eIF4E)是mTOR信号通路的下游位点,是真核细胞mRNA翻译的最有效的限速调节因子,在蛋白质合成的起始阶段起重要的调节作用。eIF4E是新近发现的一个原癌基因,其编码蛋白是存在于细胞质的一个帽子结合磷蛋白,与eIF4G和eIF4A结合为翻译起始复合物eIF4F后,可将真核细胞核糖体的40S亚基和mRNA联系起来,从而起始翻译过程。真核细胞翻译起始因子4E结合蛋白(eIF4E binding proteins,4EBPS)包含三个有关的多肽家族：4EBPI、4EBP2、4EBP3,三者均可与eIF4E结合,抑制eIF4E与帽子结合。当4EBPS磷酸化时,可释放eIF4E,使之与eIF4G和eIF4A结合形成翻译起始复合物,提高蛋白质的翻译效率。当4EBPS低磷酸化时,与eIF4E结合,从而限制帽依赖翻译的起始。因此,mTOR信号通路的下游位点和下游底物eIF4E、4EBPS分别对细胞的生长起重要调节作用。恶性肿瘤的主要生物学特性是细胞的异常生长和无限制的增殖,mTOR所介导的信号通路异常与人体的多种恶性肿瘤的发生密切相关,但有关乳腺癌中mTOR、eIF4E、4EBPS蛋白的表达情况及其与乳腺癌的发生发展关系和浸润转移情况的研究迄今尚未见文献报道。
本研究采用免疫组织化学SP方法检测mTOR、eIF4E、4EBPS在乳腺癌组织和手术切缘正常乳腺组织中mTOR、白表达情况,探讨mTOR、eIF4E、4EBPS在乳腺癌组织中的表达及临床eIF4E、4EBPS的蛋病理意义。
材料与方法
1.采用免疫组织化学SP法检测45例乳腺癌组织和45例手术切缘正常乳腺组织及相应淋巴结中mTOR、eIF4E、4EBPS的蛋白表达情况。
2.统计处理：所有数据均经SPSS13.0软件进行统计分析。阳性率之间的比较采用X2检验,阳性率间相关性采用spearman相关分析检验,检验标准以a=0.05为显著性检验水准。
结果
1.mTOR在正常乳腺组织中的的阳性表达率为20.00%,在乳腺癌组织中的阳性表达率为75.56%,其在乳腺癌中表达明显高于正常组织(P<0.05)。在淋巴结转移乳腺癌组织中的阳性表达率为93.33%,在无淋巴结转移乳腺癌组织中的阳性表达率为66.67%。mTOR的蛋白表达与乳腺癌的淋巴结转移有明显相关性(P<0.05)。
2.eIF4E在正常乳腺组织中的阳性表达率为22.22%,在乳腺癌组织中阳性表达率为84.44%,其在乳腺癌组织中的表达明显高于正常乳腺组织(P<0.05)。在淋巴结转移乳腺癌组织中的阳性表达率为100.00%,在无淋巴结转移乳腺癌组织的阳性率为76.67%,eIF4E的蛋白表达与乳腺癌的淋巴结转移有显著关系(P<0.05)。
3.4EBPS在正常乳腺组织的阳性表达率为95.60%,在乳腺癌组织的阳性率为31.10%,在乳腺癌组织中的表达明显低于正常乳腺组织(P<0.05)。在淋巴结转移乳腺癌组织的阳性率为20.00%,在无淋巴结转移乳腺癌组织中的表达阳性率为36.66%,组间比无显著性差异。4EBPS的表达与乳腺癌有无淋巴结转移无明显关系(P>0.05)。
4.mTOR蛋白表达与eIF4E蛋白表达呈正相关关系(P<0.05)。
5.mTOR的蛋白表达与4EBPS蛋白表达呈负相关关系(P<0.05)。
6.4EBPS蛋白表达与eIF4E蛋白表达呈负相关关系(P<0.05)。
结论
1.mTOR和eIF4E在乳腺癌组织中的阳性表达率高于正常乳腺组织,4EBPS蛋白在乳腺癌组织中的阳性表达率明显低于正常乳腺组织。提示三者的异常表达可能与乳腺癌的发生有关。
2.有淋巴结转移的乳腺癌组织中eIF4E及mTOR蛋白的阳性表达率高于无淋巴结转移的乳腺癌组织,提示两者的异常表达可能与乳腺癌的转移有关。
3.mTOR、eIF4E和4EBPS蛋白在乳腺癌组织中的阳性表达率均具有相关性,提示三者在乳腺癌的发生发展过程中存在内在的联系。
Breast cancer, a serious threat to women's health, is one of the most common malignant tumors that women have got. It has the highest incidence in European and American. In 2007, there are 178,480 new-added breast cancer patients, accounting for 26% of the total number of the tumour cases. The mortality rate of this cancer is in the second place, just behind bronchogenic carcinoma. Although breast cancer in Asia is slightly lower compared with Europe and America, in recent years, it also shows a clearly increasing trend. In China, in the past 20 years, the incidence of breast cancer is rising, and there seems to be an accelerating trend. In many areas, breast cancer has been in the first place of the female malignant tumors. Studies on epidemiology, genetics and animal model of chemical carcinogen, as well as molecular genetics show that the incidence of malignant tumors is a long-term, multi-factor participating in and multistage process. Studies show that in many pathogenic factors, the cell signaling abnormity keeps a close relationship with tumor. In many signaling pathways, some abnormal proteins cause tumor cell synthesize a large number of somatomedins, which finally result in the lose control of cell proliferation.
Mammlalian target of rapamycin, mTOR is a protein kinase which is generated by rapamycin in mammals. Also it is an atypical serine/threonine and its protein molecular weight is 289kDa, including 2549 amino acid. mTOR signaling pathways play a very important role in regulating cell's differentiation, growth, proliferation and apoptosis. In the bodies of mammals, the main function of mTOR is to regulate the translation process. Eukaryotic translation initiation factor 4E, eIF4E is a downstream site of mTOR's signaling pathways and the most effective adjustment factor to limit speed in the process of translation of mRNA. It plays an important role of regulation in the initial stage of protein synthesis. EIF4E is one of the newly discovered proto-oncogenes. Its encoded protein is a cap binding phosphoprotein existing in cytoplasm and can be combined with eIF4G and eIF4A to form a translation initiation complex. It also can be connected with 40S subunit of eukaryotic cell ribosome to start the process of translation. Eukaryotic initiation factor 4E binding proteins (eIF4E 4E proteins,4EBPS) contain three related polypeptide families:4EBPI,4EBP2,4EBP3. Each can combine with eIF4E and restrain the combination between eIF4E and the cap. When 4EBPS become phosphorylation, it can release eIF4E and can combine with eIF4G and eIF4A to form translation initiation complex so as to improve protein's translation efficiency. When 4EBPS becomes hypophosphorylation, it can combine with eIF4E to restrain the dependence of the cap on initial translation. Therefore, mTOR signaling pathways of downstream sites and downstream substrates---eIF4E and 4EBPS, respectively play an important adjustment function for the growth of cells. The main biological characteristics of malignant tumors are abnormal growth and unlimited proliferation of cells. The abnormity of signaling pathways mediated by mTOR is closely related with the incident of many malignant tumors. However, as to mTOR, eIF4E and 4EBPS's protein expression and their relationship with the breast cancer, as well as the study on metastasis, reports have not yet been seen in literatures.
This study adopts immunohistochemical SP method to detect eIF4E, mTOR and 4EBPS's protein expression in breast cancer tissue and surgical margin of normal breast tissue and to discuss the expression and the clinicopathological significance of eIF4E mTOR 4EBPS in breast cancer tissue.
Materials and methods:
1. SP immunohistochemical method is adopted to detect the protein expression of eIF4E, mTOR, and 4EBPS in 45 cases of breast cancer tissue,45 cases of surgical margin of normal breast tissue and corresponging lymph node.
2. Statistical processing:All data has been analyzed through statistic software SPSS13.0. X2 is used to compare positive rates, while spearman related inspection and analysis are used for the detection of correlation between positive rates. When a=0.05, it is believed to be significant inspection.
Results:
1. The positive rate of expression of mTOR in normal breast tissue is 20.00% while it is 75.56% in breast cancer, which is significantly higher than normal tissue (P<0.05). The positive rate of expression in the lymph node metastasis from breast cancer tissue is 93.33%, while the positive rate of expression without the lymph node metastasis is 66.67%. The expression of mTOR has clear correlations with infiltrating degree of breast cancer and lymph node metastasis (P 2. The positive rate of expression of eIF4E in normal breast tissue is 22.22% while the rate can reach 84.44% in breast cancer tissue, which is significantly higher than normal tissue (P<0.05). The positive rate of expression in the lymph node metastasis from breast cancer tissue is 100.00%, while the positive rate of expression without the lymph node metastasis is 76.67%. The expression of eIF4E has clear correlations with infiltrating degree of breast cancer and lymph node metastasis (P< 0.05).
3. The positive rate of expression of 4EBPS in normal breast tissue is 95.60% while the rate is 31.10% in breast cancer tissue, which is significantly lower than normal tissue (P< 0.05). The positive rate of expression in the lymph node metastasis from breast cancer tissue is 20.00%, while the positive rate of expression without the lymph node metastasis is 36.66%. The expression of 4EBPS has no clear correlations with infiltrating degree of breast cancer and lymph node metastasis (P>0.05).
4. mTOR protein expression and eIF4E protein expression are positively related (P <0.05).
5. The mTOR protein expression and 4EBPS protein expression is inversely related (P<0.05).
6.4EBPS protein expression and eIF4E. protein expression is inversely related (P< 0.05).
Conclusion:
1. The positive expression rates of mTOR and eIF4E in the breast cancer tissue are higher than those in the normal breast tissue. The positive rate of 4EBPS protein in the breast cancer tissue is obviously lower than that in the normal breast tissue. All those show that the abnormal expression of these three proteins may relate with the incidence of breast cancer.
2. The positive rate of expression of eIF4E and mTOR in the lymph node metastasis from breast cancer tissue is higher than those without the lymph node metastasis from breast cancer tissue. There is no clear differentiation of the positive rate of expression of 4EBPS protein between with and without lymph node metastasis. All those show that the abnormal expression of these three proteins may relate with the metastasis of breast cancer.
3. The positive rates of expression of eIF4E,4EBPS and mTOR are all related with each other, which show that there is an internal relation among these three proteins in the process of incidence of breast cancer.
哺乳动物雷帕霉素蛋白(mammlalian target of rapamycin, mTOR)是雷帕霉素在哺乳动物内作用的蛋白激酶,是一种非典型的丝氨酸/苏氨酸蛋白激酶,其蛋白分子量为289kDa,含2549个氨基酸。mTOR信号通路对细胞的分化、生长、增殖、凋亡起着非常重要的调节作用,在哺乳类动物体内,mTOR的主要功能是对翻译过程进行调节。真核细胞翻译启动因子4E (eukaryotic translation initiation factor 4E, eIF4E)是mTOR信号通路的下游位点,是真核细胞mRNA翻译的最有效的限速调节因子,在蛋白质合成的起始阶段起重要的调节作用。eIF4E是新近发现的一个原癌基因,其编码蛋白是存在于细胞质的一个帽子结合磷蛋白,与eIF4G和eIF4A结合为翻译起始复合物eIF4F后,可将真核细胞核糖体的40S亚基和mRNA联系起来,从而起始翻译过程。真核细胞翻译起始因子4E结合蛋白(eIF4E binding proteins,4EBPS)包含三个有关的多肽家族：4EBPI、4EBP2、4EBP3,三者均可与eIF4E结合,抑制eIF4E与帽子结合。当4EBPS磷酸化时,可释放eIF4E,使之与eIF4G和eIF4A结合形成翻译起始复合物,提高蛋白质的翻译效率。当4EBPS低磷酸化时,与eIF4E结合,从而限制帽依赖翻译的起始。因此,mTOR信号通路的下游位点和下游底物eIF4E、4EBPS分别对细胞的生长起重要调节作用。恶性肿瘤的主要生物学特性是细胞的异常生长和无限制的增殖,mTOR所介导的信号通路异常与人体的多种恶性肿瘤的发生密切相关,但有关乳腺癌中mTOR、eIF4E、4EBPS蛋白的表达情况及其与乳腺癌的发生发展关系和浸润转移情况的研究迄今尚未见文献报道。
本研究采用免疫组织化学SP方法检测mTOR、eIF4E、4EBPS在乳腺癌组织和手术切缘正常乳腺组织中mTOR、白表达情况,探讨mTOR、eIF4E、4EBPS在乳腺癌组织中的表达及临床eIF4E、4EBPS的蛋病理意义。
材料与方法
1.采用免疫组织化学SP法检测45例乳腺癌组织和45例手术切缘正常乳腺组织及相应淋巴结中mTOR、eIF4E、4EBPS的蛋白表达情况。
2.统计处理：所有数据均经SPSS13.0软件进行统计分析。阳性率之间的比较采用X2检验,阳性率间相关性采用spearman相关分析检验,检验标准以a=0.05为显著性检验水准。
结果
1.mTOR在正常乳腺组织中的的阳性表达率为20.00%,在乳腺癌组织中的阳性表达率为75.56%,其在乳腺癌中表达明显高于正常组织(P<0.05)。在淋巴结转移乳腺癌组织中的阳性表达率为93.33%,在无淋巴结转移乳腺癌组织中的阳性表达率为66.67%。mTOR的蛋白表达与乳腺癌的淋巴结转移有明显相关性(P<0.05)。
2.eIF4E在正常乳腺组织中的阳性表达率为22.22%,在乳腺癌组织中阳性表达率为84.44%,其在乳腺癌组织中的表达明显高于正常乳腺组织(P<0.05)。在淋巴结转移乳腺癌组织中的阳性表达率为100.00%,在无淋巴结转移乳腺癌组织的阳性率为76.67%,eIF4E的蛋白表达与乳腺癌的淋巴结转移有显著关系(P<0.05)。
3.4EBPS在正常乳腺组织的阳性表达率为95.60%,在乳腺癌组织的阳性率为31.10%,在乳腺癌组织中的表达明显低于正常乳腺组织(P<0.05)。在淋巴结转移乳腺癌组织的阳性率为20.00%,在无淋巴结转移乳腺癌组织中的表达阳性率为36.66%,组间比无显著性差异。4EBPS的表达与乳腺癌有无淋巴结转移无明显关系(P>0.05)。
4.mTOR蛋白表达与eIF4E蛋白表达呈正相关关系(P<0.05)。
5.mTOR的蛋白表达与4EBPS蛋白表达呈负相关关系(P<0.05)。
6.4EBPS蛋白表达与eIF4E蛋白表达呈负相关关系(P<0.05)。
结论
1.mTOR和eIF4E在乳腺癌组织中的阳性表达率高于正常乳腺组织,4EBPS蛋白在乳腺癌组织中的阳性表达率明显低于正常乳腺组织。提示三者的异常表达可能与乳腺癌的发生有关。
2.有淋巴结转移的乳腺癌组织中eIF4E及mTOR蛋白的阳性表达率高于无淋巴结转移的乳腺癌组织,提示两者的异常表达可能与乳腺癌的转移有关。
3.mTOR、eIF4E和4EBPS蛋白在乳腺癌组织中的阳性表达率均具有相关性,提示三者在乳腺癌的发生发展过程中存在内在的联系。
Breast cancer, a serious threat to women's health, is one of the most common malignant tumors that women have got. It has the highest incidence in European and American. In 2007, there are 178,480 new-added breast cancer patients, accounting for 26% of the total number of the tumour cases. The mortality rate of this cancer is in the second place, just behind bronchogenic carcinoma. Although breast cancer in Asia is slightly lower compared with Europe and America, in recent years, it also shows a clearly increasing trend. In China, in the past 20 years, the incidence of breast cancer is rising, and there seems to be an accelerating trend. In many areas, breast cancer has been in the first place of the female malignant tumors. Studies on epidemiology, genetics and animal model of chemical carcinogen, as well as molecular genetics show that the incidence of malignant tumors is a long-term, multi-factor participating in and multistage process. Studies show that in many pathogenic factors, the cell signaling abnormity keeps a close relationship with tumor. In many signaling pathways, some abnormal proteins cause tumor cell synthesize a large number of somatomedins, which finally result in the lose control of cell proliferation.
Mammlalian target of rapamycin, mTOR is a protein kinase which is generated by rapamycin in mammals. Also it is an atypical serine/threonine and its protein molecular weight is 289kDa, including 2549 amino acid. mTOR signaling pathways play a very important role in regulating cell's differentiation, growth, proliferation and apoptosis. In the bodies of mammals, the main function of mTOR is to regulate the translation process. Eukaryotic translation initiation factor 4E, eIF4E is a downstream site of mTOR's signaling pathways and the most effective adjustment factor to limit speed in the process of translation of mRNA. It plays an important role of regulation in the initial stage of protein synthesis. EIF4E is one of the newly discovered proto-oncogenes. Its encoded protein is a cap binding phosphoprotein existing in cytoplasm and can be combined with eIF4G and eIF4A to form a translation initiation complex. It also can be connected with 40S subunit of eukaryotic cell ribosome to start the process of translation. Eukaryotic initiation factor 4E binding proteins (eIF4E 4E proteins,4EBPS) contain three related polypeptide families:4EBPI,4EBP2,4EBP3. Each can combine with eIF4E and restrain the combination between eIF4E and the cap. When 4EBPS become phosphorylation, it can release eIF4E and can combine with eIF4G and eIF4A to form translation initiation complex so as to improve protein's translation efficiency. When 4EBPS becomes hypophosphorylation, it can combine with eIF4E to restrain the dependence of the cap on initial translation. Therefore, mTOR signaling pathways of downstream sites and downstream substrates---eIF4E and 4EBPS, respectively play an important adjustment function for the growth of cells. The main biological characteristics of malignant tumors are abnormal growth and unlimited proliferation of cells. The abnormity of signaling pathways mediated by mTOR is closely related with the incident of many malignant tumors. However, as to mTOR, eIF4E and 4EBPS's protein expression and their relationship with the breast cancer, as well as the study on metastasis, reports have not yet been seen in literatures.
This study adopts immunohistochemical SP method to detect eIF4E, mTOR and 4EBPS's protein expression in breast cancer tissue and surgical margin of normal breast tissue and to discuss the expression and the clinicopathological significance of eIF4E mTOR 4EBPS in breast cancer tissue.
Materials and methods:
1. SP immunohistochemical method is adopted to detect the protein expression of eIF4E, mTOR, and 4EBPS in 45 cases of breast cancer tissue,45 cases of surgical margin of normal breast tissue and corresponging lymph node.
2. Statistical processing:All data has been analyzed through statistic software SPSS13.0. X2 is used to compare positive rates, while spearman related inspection and analysis are used for the detection of correlation between positive rates. When a=0.05, it is believed to be significant inspection.
Results:
1. The positive rate of expression of mTOR in normal breast tissue is 20.00% while it is 75.56% in breast cancer, which is significantly higher than normal tissue (P<0.05). The positive rate of expression in the lymph node metastasis from breast cancer tissue is 93.33%, while the positive rate of expression without the lymph node metastasis is 66.67%. The expression of mTOR has clear correlations with infiltrating degree of breast cancer and lymph node metastasis (P
3. The positive rate of expression of 4EBPS in normal breast tissue is 95.60% while the rate is 31.10% in breast cancer tissue, which is significantly lower than normal tissue (P< 0.05). The positive rate of expression in the lymph node metastasis from breast cancer tissue is 20.00%, while the positive rate of expression without the lymph node metastasis is 36.66%. The expression of 4EBPS has no clear correlations with infiltrating degree of breast cancer and lymph node metastasis (P>0.05).
4. mTOR protein expression and eIF4E protein expression are positively related (P <0.05).
5. The mTOR protein expression and 4EBPS protein expression is inversely related (P<0.05).
6.4EBPS protein expression and eIF4E. protein expression is inversely related (P< 0.05).
Conclusion:
1. The positive expression rates of mTOR and eIF4E in the breast cancer tissue are higher than those in the normal breast tissue. The positive rate of 4EBPS protein in the breast cancer tissue is obviously lower than that in the normal breast tissue. All those show that the abnormal expression of these three proteins may relate with the incidence of breast cancer.
2. The positive rate of expression of eIF4E and mTOR in the lymph node metastasis from breast cancer tissue is higher than those without the lymph node metastasis from breast cancer tissue. There is no clear differentiation of the positive rate of expression of 4EBPS protein between with and without lymph node metastasis. All those show that the abnormal expression of these three proteins may relate with the metastasis of breast cancer.
3. The positive rates of expression of eIF4E,4EBPS and mTOR are all related with each other, which show that there is an internal relation among these three proteins in the process of incidence of breast cancer.
引文
[1]Jensen MD, Esteve J, Moller H. Cancer in the European commnity and its member states [J]. Eur J cancer,1990,26 (11-12):1167-1256
[2]Jemal A, Siegel R, ward E,et al,cancer statistics,2007. CA Cancer J Clin,2007,57(1): 43-66
[3]Yang L, Li LD, Chen Yd, et al. Time trends, estimates and projects for breast cancer incidence and mortality in China. Zhong Hua Zhong Liu Za Zhi,2006,28 (6):438-440
[4]陈杰,李甘地主编.病理学·第一版·北京：人民卫生出版社,2005,149-158
[5]Huang S, Houghton PJ, Targeting mTOR signaling for cancer therapy [J]. Curr opin pharmcol,2003,3(4):3717
[6]Shaw RJ, Cantley LC. Ras PI3K and mTOR Ssignaling controls tumour cell growth. Nature,2006,441 (7092):424-430
[7]Sabatin DM, mTOR and cancer insights into a complex relationship. Nat Rev cancer,2006, 6(9):729-734
[8]Nathan CA, Amirghahari N, AbreoF, et al. Overexpressed eIF4E is functionally active in surgical margins of head and neck cance patients via activation of the Akt/manmalian target of rapamycin. Clin Cancer Res,2004,10 (17):5820---5827
[9]潘智,张令强,蒋继志,等mTOR的研究进展[J].细胞生物学杂志,2006,28：3958
[10]Bjormsti MA, Honghton PJ. The TOR pathway:a target for cancer therapy [J]. Nat Rew Cancer,2004,4 (5):33548
[11]Sonenberg N. mRNA5'Cap-binding protein eIF4E and control of growth [M]. In:Hershey J, Mathews M, Sonenberg N, eds.Translational control, New York:Cold Spring Harbor Laboratory Press,1996.245-270
[12]De Bendetti A, Graff JR. eIF4E expression and its role in malignancies and metastasis Oncogene,2004,23 (18):3189-3199.
[13]Ribatti D, Vacca A, presta M. The discoery of angiogenic factors:a historical review [J]. Gen Pharmacol.2000,35 (5):227-231
[14]Rosenwaid IB, Chen JJ, Wang S, et al. Upregulation of protein synthesis initiation factor eIF4E is an early event during colon Carcinogenrsis. Oncogene,1999,18(15):2507-2517
[15]Roussean D, Ginras AC, Pause A, et al. The eIF4E binding proteins 1 and 2 are negative regulators of cell growth. Oncogene,1996,13 (11):2415-2420
[16]Yang YJ, zhang YL, Lix, et al.Contribution of eIF4E inhibition to the expression and activity of heparanase in human colon adenocarcinoma cell line:LS 174 T [J]. World J Gastroenterol,2003; 9 (8):170712
[17]Khaleghpour K, Pyronnets, Gingras AC, et al. Translational homeoslasis:eukaryotic translation factor 4E control of 4E bingding protein 1 and P70S6 Kinase activities [J]. Mlol Cell Biol.1999; 19 (6):430210
[18]Schmelzle T, Hall MN. TOR, a central controller of cell growth [J]. Cell,2000; 103:25362
[19]Thomas GV mTOR and cancer:reason for dancing at the Crossroads [J]. Gen Dev, 2006; 16:7884
[20]Sonerberg N, Gingras AC. The mRNA 51 capbinding protein eIF4E and control of cell growth [J]. Curr Opin Cell Biol,1998; 10:26875
[21]Memmott RM, Dennis PA. Aktdependent and independent mechanisms of mTOR regulation in cancer [J]. Cell signal.2009; 21:65664
[22]Naoki Fjise,Atsushi Nanashima,yashitaka Taniguchi, et al. prognostic impact of CathepsinB and matrimetalloproteinase-q in pulmonary adenocarcinomas by immunhistochemical study, lung cancer,2000 Jau,27 (1):19-26
[23]Gingras AC. Regulation of translation initiation by FRAP/mTOR Genes Dev,2001,15 (7): 807-826
[24]Jacinto E. TOR Signaling in bugs brain and brawn, Nat Rew Mol Cell Biod,2003,4: 117-126
[25]Asnaghi L, Bruno P, Ulla M, et al. mTOR:a protein kinase switching between life and death. Pharmacol Res,2004,50 (6):545-549
[26]Schalm SS, Fingar DC, Sabatinin DM, et al. TOS motif-mediated raptor binding regulates 4E-BP1 muhisite phosphorylation and function. Curt Biol,2003,13 (10):793-806
[27]Xu G, Zhang W, Bertram P, et al. Pharmacogenomic profiling of the PI3K/PTEN-Akt-mTOR pathway in common human tumors.Int J Oncol,2004,24 (10):893-900
[28]Zhou X,Tan M, Stone Hawthome V, et al Actination of the Akt/m ammalian target of Rapamycin/4E-BP1 pathway by E-erB-2 overexpression predicts tumor progression in breat cancel [J] Clin Cancer Res 2004,10 6779-6788
[29]Graff JR, Zimmer SG. Translational control and metastatic progression:enhanced activity of the mRNA Cap-binding protein eIF4E selectively enhances translation of metastasis related mRNA [J].Clin Exp Metastasis,2003,20 (3):165-273
[30]Martin ME, Perez MI, Redondo C.4E binding protein/expression is inversely correlated to the progression of gastrointestinal cancer [J]. Int J Biochem Cell Biol,2000,32 (6):633-642
[31]Derek R, McClusky MD, Ouyen Chu MD, et al. A prospective trial on initiation factor 4E overexpression and cancer recurrence in node positive breast cancer [J]. Ann surg,2005, 242 (1):584-592
[32]Kerekatte V, Smiley K, Hu B, et al. The protooncogene/translation factor eIF4E:a survey of its expression in breast carcinomas [J] Int J Cancer,1995,64 (1):27-31
[33]Li BD, McDonald JC, Nassar R, et al. Clinical outcome in stage Ⅰ To Ⅲ breast carcinoma and eIF4E overexpression [J]. Ann Surg.1998,277 (5):756-763
[34]De Benedetti A, Hurris A I. eIF4E expression in tumors; its possible role in progression of malignamcies [J] Int J Biochem Cell Biol,1999,31 (1):59-72
[35]Hannan K. M, Y. Brandenburger, A Jenkina, et al. mTOR-dependent of ribosomal gene transcripition requires S6K1 is mediated by phosphhoryation of the carboy/-terminal activation domain of the mucleolar transcription factor UBF. Mol Cell Boil,2003,23 (23): 8862-8877
[36]Mayer.C, J.Zhao, X.Yuan, et al. mTOR-dependent activation of the transcription factor TIF-1A links rRNA synthesis to nutrient availability.Genes Dev,2004,181 (4):423-434
[37]陈振东,秦凤展,秦叔逵,主编·肿瘤学概论·人民卫生出版社,北京,2006,1(1)：37-38
[38]Gera JF, Mellinghoff IK, Shi Y, et al.AKT activity determines Sensitivity to Mammalian target of rapamycin (mTOR) inhibitions by regulating cyclinD1 and c-myc expression. J Biol chen,2004,279 (4):2737-2746
[39]Dilling Mb, Germain GS, Dudkin I, et al.4E-bingdig proteins, the suppressors of eukaryotic initintion factor 4E are down-regulated in cells with acquired or initinsic resistance to mpamycin. J Bid Chem.2002,277 (16):13907-13917
[40]Rosnwald IB. The role of translation in neoplastic transformation from a pathologists piont of view. Oncogene,2004,23 (18):3230-3247
[41]Schoppmann SF, Fenzl A, Nagy K, et al. VEGF 2 C expressing tumor2associated macrophages in lymph node positive breast cancer:impact on lymphangiogenesis and survival [J]1 Surgery,2006,139 (6):839-8461
[42]Li YS, Kaneko M, Amatya VJ, et al. Expression of vascular endot helial growt h factor2C and it s receptor in invasive micropapillary carcinoma of t he breast [J]1 Pat hol Int,2006, 56(5):256-2611
[43]Byrnes K, White S, Chu Q, et al 1 High elF 4 E, VEGF, and microvessel density in stage Ⅰ to Ⅲ breast cancer [J] 1 Ann Surg,2006,243 (5):684-690
[44]Nobukuni T, Joaquin M, Roccio M, et al. Amino acids mediate mTOR/raptor signaling through activation of class 3 phosphatidylinositol 3OH-kinase. Proc Natl Acad Sci,2005, 102 (40):14238-14243.
[45]Liu LZ, Zhou XD, Qian GS, et al. A KT1 amplif ication regulates cisplatin resistance in huma n lung ca ncer cells t hrough t he mammalia n ta rget of rapamycin/p70s6k1 pat hway [J]. Cancer Res,2007,67:6325-6332.
[46]Lu Ch, Wys Zomi Ers KI SL, Tsen G LM, et al. Preclinical testing of clinically applicable st rateies for overcoming t rastu2 zumab resista nce caused by PTEN deficiency [J]. Clin Ca ncer Res,2007,13:5883-5888.
[47]Connolly E, Braunstein S, Formenti S, et al. Hypoxia inhibits p rotein synthesis through a 4E-BP1 and elongation factor 2 kinase pathway controlled bymTOR and uncoup led in breast cancer cells. Mol CellBi2 ol,2006,26 (10):3955～3965.
[48]Martin JL, Baxter RC. Exp ression of insulin-like growth factor bind2 ing p rotein-2 byMCF-7 breast cancer cells is regulated through the phosphatidylinositol 3-kinase/AKT/ mammalian target of rapamycin pathway. Endocrinology,2007,148 (5):2532～2541.
[49]Shap iraM, Kakiashvili E, Rosenberg T, et al. The mTOR inhibitor ra2 pamycin down-regulates the exp ression of the ubiquitin ligase subunit Skp2 in breast cancer cells. Breast Cancer Res,2006,8 (4):46.
[50]Ito D, Fujimoto K, Mori T, et al. In vivo antitumor effect of t he mTOR inhibitor CCI2779 and gemcitabine in xenograft mod2 els of human pancreatic cancer [J]. Int J Cancer,2006, 118 (9):2337-2343.
[51]Stephan W, Robbie L, Michael N. TOR Signaling in Growth and Metabolism [J]. Cell, 2006,124:474-482.
[52]张涛,张保宁,张宏图等.乳腺癌前哨淋巴结微小转移的检测.中华肿瘤杂志,2007,29(2),116-118.
[53]章俊,张维元.eIF-4E、HER-2癌基因在鼻咽癌中表达的意义及其与PCNA和LMP-1的关系.诊断病理学杂志,2005,12(3)：211-213.
[54]于宝华,周晓燕.PI3K/Akt/mTOR的信号传导通路在恶性肿瘤中的研究进展.中华病理学杂志,2005,34(17)：674-676
[55]李孟圈,刘娟娟,李靖若等,mTOR在乳腺癌发生发展中的作用及其与C-erbB-2的关系.山东医药,2009,49(13)：59-61
[56]李金鸽,杨志宏.哺乳动物雷帕霉素靶蛋白信号通路与肿瘤的研究进展.医学综述,2007,13(23)：1766-1768
[57]Nancy E. Hynes, Anne Boulay. The mTOR Pathway in Breast Cancer. Journal of Mammary Gland Biology and Neoplasia.2006,1:53-61
[58]Wieslawa H. Dragowska, Maite Verreault, Donald T. T. Yapp,et al. Decreased levels of hypoxic cells in gefitinib treated ER+HER-2 overexpressing MCF-7 breast cancer tumors are associated with hyperactivation of the mTOR pathway:therapeutic implications for combination therapy with rapamycin. Breast Cancer Research and Treatment,2007, 12:319-331
[59]陈棵,张红锋.mTOR信号通路与癌症治疗.生命的化学,2005,25(2)：127-128
[1]ZhengJie, mTOR signaling pathway and cancer. Chinese Bulletin of life Sciences,2006, 18(3):261-265
[2]Asnaghil et al. Bruno P, Priulla M et al mTOR:a protein kinase swietching between life and death. Pharmacol Res 2004,50:545-549
[3]Sarbassow D D, Gmertin D A, Ali SM,et al. phosphorylation and regulation of Akt/PKB by the rictor mTOR complex Science,2005,307 (5712):1098-1101
[4]Huanys, Bjornsti MA, Houghton PJ-Papamy-cins:mechanisis of actor and cellular resistance[J].Cancer Biol Ther,2003,2(3):222-232
[5]Khaleghpour K, Pyronnet S, Gingras AC, et al. Translational homeostasis:eukaryotic translation initiation factor 4E control of 4E binding protein 1 and P70S6 Kinase activities. Mol cell Biol.1999,19(6):4302-4310
[6]Huang S, Hougheon PJ.Targeting mTOR signaling for cancer therapy opin pharmacol. 2003,3(4):371-377.
[7]Yang YJ, Zhang YL, LiX,et al. Contribution of eIF4E inhibton to the express and activity of heparanase in human colon adenocarcinoma cell line:LS-174T. World J Gastroentrol. 2003,9(8):1707-1712
[8]West MG, Stoneley M, willis AE. Translation induction of the c-myc oncogene via activation of the FRAP/TOR signaling pathway. Oncogene.1998,17(6):769-780
[9]Cao N,Zhang Z,Jiang BH,et al.G1 cell cycle progression and the expression of G1 cyclins are regulated by PI3K/AKT/mTOR/P70s6k1 signaling in human ovarin cancer cells.Am J Physiol cell Physiol,2004,287:c281-c291
[10]Jacinto E TOR signaling in buys brain and brawn, Nat Rew Mol cell Biol.2003,4(2): 117-126
[11]Pene F, Claessens YE, Muller O, et al. Role of the phosphatidylinositol 3-kinase/Akt and mTOR/P70S6-kinase pathways in the proliferation and apoptosis in multiple myeloma. Oncogene,2002,21:6578-6589
[12]Hill MM, Hemmings BA.Inhibition of protein kinase B/Akt. implications for cancer therapy. Pharmacol Ther,2002,93:243-251
[13]Zhoax, TanM, Stone Hawthome V, et al. Activation of the Akt/mammalian target of Rapamycin/4E-BP 1 Pathway by ErbB2 overexpression predicts tumor progression in breast cancers. clin cancer Res,2004 10:6779-6788
[14]Schalm SS, Fingar DC, Sabatinin DM, et al. TOS motif-mediated raptor binding regulates 4E.BP1 multisite Phosphorylation and function.Curr Biol,2003,13:793-806
[15]Xu G,Zhang W,Bertram P,et al.Pharmacogenomic profiling of the P13k/PTEN-Akt-mTOR pathway in common human tumors. Int J Oncol,2004,24:893-900
[16]Potter CJ pedraza LG, Xu T. Akt regulates growth by directly phosphory biting TSC2 [J]. Nat Cell Biol 2002,(4)9:658-665
[17]Corradetti M.N, K. Inoki, N. bardeesy, et al. Regulation of the TSC pathway by LKB.1: evidence of a olecular link between tubers sclerosis complex and Peutzjepbers syndrome. Gens Dev.2004.18(13):1533-1538
[18]Wullschleger S, Loewith R, Hall MN. TOR singaling in growth and metabolism Cell,2006, 124(3):471-484
[19]Beck,T,M.N.Hall.The TOR signaling pathway controls nuclear calization of nutrient regulated transcription factors.Nature,1999,402 (6762):689-692
[20]Gao X, Zhang Y, Arrazola P, et al. Tsc tumour proteins antagonaize amino-acid-TOR signaling. Nat Cell Biol,2002,4(9):699-704
[21]Smith EM Finn SG, Tee AR, et al. The tuberous sclerosis proteins TSC2 is not required for the regulation of the mammalian target of rapamycin by amino acids and certain stresess [J], J Boil Chem.2005,280(19):18717-18727
[22]Byfield MP, Murray JT. Bocker JM. Hvps34 is a mutrient-regulated lipid kinase required for activation of p70S6 kinase [J] J Boil Chem.,2005,280(38):33076-33082
[23]Yokogami, K, S Wakisaka, J, Avruch, and S.A. Reeves.serine phosphorylation and maxmal activation of STAT3 during CNTF signaling is mediated by the rapamycin target Mtor. curr Biol,2000,10(1):47-50
[24]Mayer. C, J. zhao,X. Yuan, et al. mTOR-dependont actibation of the transcription factor TIF-1A Links rRNA synthesis to nutrient availability, Dev,2004,18(4):423-434
[25]HannaK. M, Y. Brandenburger, A. Jenkina, et al, mTOM-deperdent, of ribosomal genetranscripition requires s6k1 is mediated by phosphhorylation of the carboylterminal activation domain of the mucleolar thanscription fachor UBF. Mol cell Boil,2003,23(23): 8862-8877
[26]Avruch. J, G. Belham, a, weng, K. Hara, and K.Yonezawa. The P70S6K kisnase integrates nutrient and growth signals to control translational capacity. ProgMol subcell Biol,2001, 26(1):115-154
[27]Wong Y C, Wang YZ. Growth factors and epithelial-stromal interactions in prostate cancer development. Int Rew cytol,2000,199:65-116
[28]Murillo H, Huang H, Schmidt LJ, et al. Role of PI3K Signaling in survival and Progression of LNCap prostate cancer cells to the androgen refractory state. Endocrinology,2001,142: 4795-4805
[29]Parsons R. Human cancer, PTEN and PI3 kinase pathway. Semin Cell Dev Biol,2004,15: 171-176
[30]Gupta Ak, Gerniglia GJ, Mick K, et al. R adiation sensitization of human cancer cells in vivo by inhibiting the activity of PI3K using Ly294002. Int J Radiat Oncol Biol Phy3, 2003,56:846-853
[31]Neshat MS, Mellinghoff IK, Tranc C, et al. Enhanced sensitivity of PIEN-deficient tumors to inhibition of FRAP/mTOR. Proc Natl Acad Sci U S A,2001,98:10314-10319
[32]Simith PG, Wang F, Wickinson KN, et al, The phosphodiesterase PDE4B limits CAMP-associated PI3K/Akt-dependent apoptosis in diffuse large B cell Lymphoma-blood,2005, 105:308-316
[33]Wang L, Fortney JE, Gibson LF-Stromal cell protection of B-lineage acute lymphoblastic cells during chemotherapy requires active Akt.Leuk Res,2004,28:733-742
[34]Grewe M, Gansauge F, Schmid RM, et al. Regulation of cell growth and cyclin D, expression by the constitutively active FRAP-P70S6K pathway in human pancreatic cancer cells. Cancer Res,1999,59:3581-3587
[35]Proud CG. The multifaceted role of mTOR in cellular stress responses. DNA Repair (Amst),2004,3:927-934
[36]Wendel HG, De Stanchina E, Fridman J S,et al. Survival signalling by Akt and eIF4E in oncongenesis and cancer therapy. Nature,2004,428:332-337
[37]KnuefermannC, Luy, Liu B, et al. HER2/PI-3K/Akt activation leads to a multidrug resistance in human breast adenocarcinoma cells. Oncogene,2003,22:3205-3212
[38]Brognad J.Clark AS,Niy,et al. Akt/protein kinase B is constitu tively active in non-small cell lung cancer cells and promotes cellular survival and resistance to chemotherapy and radiation. Cancer Res,2001,61:3986-3997
[39]Langher E, Taghavi P, Chiles K, et al. HER2 (neu) signaling increases the rate of hypoxia-inducible factor 1 alpha (HIF-1 alpha) Synthesis:novel mechanism for HIF-1-madiated vascular edothelial growth factor expression. Mol Cell Biol,2001,21:3995-4004
[40]Gao N, Nester RA, Sarkar MA.4-Hydroxy estradiol but not 2-hydroxy estradiol induces expression of hypoxia-induible factor 1 alpha and vascular endithelial growth factor A through phosphatidylinositol 3-kinase/Akt/FBAP pathway in OVCAR-3 and A 2780-CP70 human ovarian carcinoma cells. Toxicol Appl Pharmaol,2004,196:124-135
[41]Tuck AB, Hotac, Wilsons M, et al. Osteopontin-indued migration of human mammary epithelial cells involves activation of EGF receptor and multiple signal transduction pathways. Oncogene,2003,22:1198-1205
[42]Gotoh M, Sakamoto M, kanetaka K, et al. Overexpression of osteopontin in hepatocellular carinoma. Pathol Int,2002,52:19-24.
[43]Chen J, Fang Y.A novel pathway requlating the mammalian target of Rapamycin (mTOR) singaling. Biochem Pharmacol,2002,64:1071-1077
[44]Rowinsky Ek.Targeting the molecular target of rapamycin (mTOR) Curr Opin Oncol,2004, 16(6):564-575
[45]Gera J F Mellinghoff I K.Shi y. et al. Akt activity getermines mins seneitivity to mammalian target of Rapamycin (mTOR) inhibitors by regulating cyclin D1 and c-myc expessionJ Bion Chem.2004,279(4):2737-2746
[46]BrianK.LawRapamycin:Ananti-cancerimmunosuppressant[J]oncology-huematolo-gy,2005, 56(1):47-60
[47]Schoppmann SF, Fenzl A, Nagy K, et al. VEGF 2C expressing tumor2associated macrophages in lymph node positive breast cancer:impact on lymphangiogenesis and survival [J]1 Surgery,2006,139 (6):839-8461
[48]Li YS, Kaneko M, Amatya VJ, et al. Expression of vascular endot helial growt h factor2C and it s receptor in invasive micropapillary carcinoma of t he breast [J] 1 Pat hol Int,2006, 56(5):256-2611
[49]Byrnes K, White S, Chu Q, et al. High eIF 4 E, VEGF, and microvessel density in stage Ⅰ to Ⅲ breast cancer [J]1Ann Surg,2006,243 (5):684-690
[50]Sancak Y, Thoreen CC, Peterson TR, et al. PRAS40 is an insulin-regulated inhibitor of the mTORC1 protein kinase. Mol Cell,2007,25 (6):903-915.
[51]Nobukuni T, Joaquin M, Roccio M, et al. Amino acids mediate mTOR/raptor signaling through activation of class 3 phosphatidylinositol 3OH-kinase. Proc Natl Acad Sci,2005, 102 (40):14238-14243.
[52]苑红,牛燕媚,刘彦辉,等.mTOR/S6K1信号通路与有氧运动改善小鼠高脂饮食诱导胰岛素抵抗间的关系.中国康复医学杂志,2009,24(4)：297-302.
[53]牛燕媚,苑红,刘彦辉,等.有氧运动对胰岛素抵抗小鼠骨骼肌球形脂联素及腺苷酸活化蛋白激酶的响.中国运动医学杂志,2009,28(1)：36-40.
[54]Dreyer HC, Fujita S, Cadenas JG, et al. Resistance exercise increases AMPK activity and reduces 4E-BP1 phosphorylation and protein synthesis in human skeletal muscle. J Physiol,2006,576 (2):613-624.
[55]O'Neil TK, Duffy LR, Frey JW, et al. The role of phosphoinositide 3-kinase and phosphatidic acid in the regulation of mTOR following eccentric contractions. J Physiol, 2009,587 (Pt 14):3691-701.
[56]Carriere A, Cargnello M, Julien LA, et al. Oncogenic MAPK Signaling stimulates mTORC 1 activity by promoting RSK-mediated raptor phosphorylation. Current Biol 2008, 18 (17):1269-1277.
[57]Bose S, Chandran S, Mirocha JM, et al. The Akt pat h2 way in huma n breast ca ncer:a tissue2ar ray2based analysis [J]. Mod Pat hol,2006,19:238-245.
[58]Faivr RE S, Kroemer G, Raumond E. Cur rent develop2 ment of mTOR inhibitors as anticancer agents [J]. Nat Rev Drug Discov,2006,5:671-688.
[59]Mirsha HI P, Topra K S K, Faussa T AM, et al. Malignant hematop oietic cells induce a n increased exp ression of V EGFR21 a nd V EGFR23 on bone mar row endot helial cells via A KT a nd mTOR signalling pat hways [J]. Biochem Biop hys Res Com2 mun,2006,349 (3):1003-1010.
[60]Weppl ER SA, Krause M, Z Yroms KA A, et al. Resp onse of U87 glioma xenograf ts t reated wit hconcurrent rapamycin and fractionated radiot herapy:possible role f or t hrombosis [J]. Radiot her Oncol,2007,82 (1):96-104.
[61]Ama TO RJ, Misella TI A, Khan M, et al. A p hase Ⅱt rial of RAD001 in patients wit h metastatic renal cell ca rcinoma (MRCC) [J]. J Clin Oncol,2006,24:4530.
[62]Jo Hnston PB, Ansell SM, Col Gan J P, et al. Phase Ⅱ trial of the oral mTOR inhibitor everolimus (RAD001) for pa2 tients wit h relapsed or ref ractory lymp homa [J]. J Clin Oncol,2007,25:8055.
[63]Liu LZ, Zhou XD, Qian GS, et al. A KT1 amplif ication regulates cisplatin resistance in huma n lung ca ncer cells through the mammalia n ta rget of rapamycin/p70s6k1 pat hway [J]. Cancer Res,2007,67:6325-6332.
[64]Lu Ch, Wys Zomi Ers KI SL, Tsen G LM, et al. Preclinical testing of clinically applicable st rateies for overcoming t rastu2 zumab resista nce caused by PTEN def iciency [J]. Clin Cancer Res,2007,13:5883-5888.
[65]Connolly E, Braunstein S, Formenti S, et al. Hypoxia inhibits p rotein synthesis through a 4E-BP1 and elongation factor 2 kinase pathway controlled bymTOR and uncoup led in breast cancer cells. Mol CellBi2 ol,2006,26 (10):3955-3965.
[66]Martin JL, Baxter RC. Exp ression of insulin-like growth factor bind2 ing p rotein-2 byMCF-7 breast cancer cells is regulated through the phosphatidylinositol 3-kinase /AKT/mammalian target of rapamycin pathway. Endocrinology,2007,148 (5):2532～ 2541.
[67]Shap iraM, Kakiashvili E, Rosenberg T, et al. The mTOR inhibitor ra2 pamycin down-regulates the exp ression of the ubiquitin ligase subunit Skp2 in breast cancer cells. Breast Cancer Res,2006,8 (4):46.
[68]Ito D, Fujimoto K, Mori T, et al. In vivo antitumor effect of t he mTOR inhibitor CCI2779 and gemcitabine in xenograft mod2 els of human pancreatic cancer [J]. Int J Cancer,2006, 118 (9):2337-2343.
[69]Sabatini D M. mTOR and cancer:insights into a complex relationship [J]. Nat Rev Cancer, 2006,6(9):729-734.
[70]Stephan W, Robbie L, Michael N. TOR Signaling in Growth and Metabolism [J]. Cell, 2006,124:474-482.
[71]Ruvinsky I, Meyuhas O. Ribosomal protein S6 phosphorylation:from protein synthesis to cell size [J]. Trend Biochem Sci,2006,31(6):342-348.
[72]Cota D, Proulx K, Smith K A, et al.Hypothalamic mTOR signaling regulates food intake [J]. Science,2006,312(5775):861-864.
[73]张涛,张保宁,张宏图等.乳腺癌前哨淋巴结微小转移的检测.中华肿瘤杂志,2007,29(2),116-118.
[74]Abdul-Rasool S, Kidson SH, Panieri E, et al. An evaluation of molecular markers for improved detection of breast cancer metastases in sentinel nodes. J Clin Pathol,2006, 59(3):289-297.
[75]章俊,张维元.eIF-4E、HER-2癌基因在鼻咽癌中表达的意义及其与PCNA和LMP-1的关系.诊断病理学杂志,2005,12(3)：211-213.
[76]于宝华,周晓燕.PI3K/Akt/mTOR的信号传导通路在恶性肿瘤中的研究进展.中华病理学杂志,2005,34(17)：674-676
[77]李孟圈,刘娟娟,李靖若等,mTOR在乳腺癌发生发展中的作用及其与C-erbB-2的 关系.山东医药,2009,49(13)：59-61
[78]李金鸽,杨志宏.哺乳动物雷帕霉素靶蛋白信号通路与肿瘤的研究进展.医学综述,2007,13(23)：1766-1768
[79]陈棵,张红锋.]mTOR信号通路与癌症治疗.生命的化学,2005,25(2)：127-128
[80]Nancy E. Hynes, Anne Boulay. The mTOR Pathway in Breast Cancer. Journal of Mammary Gland Biology and Neoplasia.2006,1:53-61
[81]Diana Behrens, Anne E. Lykkesfeldt, Iduna Fichtner. The mTOR pathway inhibitor RAD001 (everolimus) is highly efficacious in tamoxifen-sensitive and-resistant breast cancer xenografts. Targeted Oncology,2007,7:135-144
[82]Wieslawa H. Dragowska,Maite Verreault,Donald T. T. Yapp,et al. Decreased levels of hypoxic cells in gefitinib treated ER+HER-2 overexpressing MCF-7 breast cancer tumors are associated with hyperactivation of the mTOR pathway:therapeutic implications for combination therapy with rapamycin. Breast Cancer Research and Treatment,2007, 12:319-331
[2]Jemal A, Siegel R, ward E,et al,cancer statistics,2007. CA Cancer J Clin,2007,57(1): 43-66
[3]Yang L, Li LD, Chen Yd, et al. Time trends, estimates and projects for breast cancer incidence and mortality in China. Zhong Hua Zhong Liu Za Zhi,2006,28 (6):438-440
[4]陈杰,李甘地主编.病理学·第一版·北京：人民卫生出版社,2005,149-158
[5]Huang S, Houghton PJ, Targeting mTOR signaling for cancer therapy [J]. Curr opin pharmcol,2003,3(4):3717
[6]Shaw RJ, Cantley LC. Ras PI3K and mTOR Ssignaling controls tumour cell growth. Nature,2006,441 (7092):424-430
[7]Sabatin DM, mTOR and cancer insights into a complex relationship. Nat Rev cancer,2006, 6(9):729-734
[8]Nathan CA, Amirghahari N, AbreoF, et al. Overexpressed eIF4E is functionally active in surgical margins of head and neck cance patients via activation of the Akt/manmalian target of rapamycin. Clin Cancer Res,2004,10 (17):5820---5827
[9]潘智,张令强,蒋继志,等mTOR的研究进展[J].细胞生物学杂志,2006,28：3958
[10]Bjormsti MA, Honghton PJ. The TOR pathway:a target for cancer therapy [J]. Nat Rew Cancer,2004,4 (5):33548
[11]Sonenberg N. mRNA5'Cap-binding protein eIF4E and control of growth [M]. In:Hershey J, Mathews M, Sonenberg N, eds.Translational control, New York:Cold Spring Harbor Laboratory Press,1996.245-270
[12]De Bendetti A, Graff JR. eIF4E expression and its role in malignancies and metastasis Oncogene,2004,23 (18):3189-3199.
[13]Ribatti D, Vacca A, presta M. The discoery of angiogenic factors:a historical review [J]. Gen Pharmacol.2000,35 (5):227-231
[14]Rosenwaid IB, Chen JJ, Wang S, et al. Upregulation of protein synthesis initiation factor eIF4E is an early event during colon Carcinogenrsis. Oncogene,1999,18(15):2507-2517
[15]Roussean D, Ginras AC, Pause A, et al. The eIF4E binding proteins 1 and 2 are negative regulators of cell growth. Oncogene,1996,13 (11):2415-2420
[16]Yang YJ, zhang YL, Lix, et al.Contribution of eIF4E inhibition to the expression and activity of heparanase in human colon adenocarcinoma cell line:LS 174 T [J]. World J Gastroenterol,2003; 9 (8):170712
[17]Khaleghpour K, Pyronnets, Gingras AC, et al. Translational homeoslasis:eukaryotic translation factor 4E control of 4E bingding protein 1 and P70S6 Kinase activities [J]. Mlol Cell Biol.1999; 19 (6):430210
[18]Schmelzle T, Hall MN. TOR, a central controller of cell growth [J]. Cell,2000; 103:25362
[19]Thomas GV mTOR and cancer:reason for dancing at the Crossroads [J]. Gen Dev, 2006; 16:7884
[20]Sonerberg N, Gingras AC. The mRNA 51 capbinding protein eIF4E and control of cell growth [J]. Curr Opin Cell Biol,1998; 10:26875
[21]Memmott RM, Dennis PA. Aktdependent and independent mechanisms of mTOR regulation in cancer [J]. Cell signal.2009; 21:65664
[22]Naoki Fjise,Atsushi Nanashima,yashitaka Taniguchi, et al. prognostic impact of CathepsinB and matrimetalloproteinase-q in pulmonary adenocarcinomas by immunhistochemical study, lung cancer,2000 Jau,27 (1):19-26
[23]Gingras AC. Regulation of translation initiation by FRAP/mTOR Genes Dev,2001,15 (7): 807-826
[24]Jacinto E. TOR Signaling in bugs brain and brawn, Nat Rew Mol Cell Biod,2003,4: 117-126
[25]Asnaghi L, Bruno P, Ulla M, et al. mTOR:a protein kinase switching between life and death. Pharmacol Res,2004,50 (6):545-549
[26]Schalm SS, Fingar DC, Sabatinin DM, et al. TOS motif-mediated raptor binding regulates 4E-BP1 muhisite phosphorylation and function. Curt Biol,2003,13 (10):793-806
[27]Xu G, Zhang W, Bertram P, et al. Pharmacogenomic profiling of the PI3K/PTEN-Akt-mTOR pathway in common human tumors.Int J Oncol,2004,24 (10):893-900
[28]Zhou X,Tan M, Stone Hawthome V, et al Actination of the Akt/m ammalian target of Rapamycin/4E-BP1 pathway by E-erB-2 overexpression predicts tumor progression in breat cancel [J] Clin Cancer Res 2004,10 6779-6788
[29]Graff JR, Zimmer SG. Translational control and metastatic progression:enhanced activity of the mRNA Cap-binding protein eIF4E selectively enhances translation of metastasis related mRNA [J].Clin Exp Metastasis,2003,20 (3):165-273
[30]Martin ME, Perez MI, Redondo C.4E binding protein/expression is inversely correlated to the progression of gastrointestinal cancer [J]. Int J Biochem Cell Biol,2000,32 (6):633-642
[31]Derek R, McClusky MD, Ouyen Chu MD, et al. A prospective trial on initiation factor 4E overexpression and cancer recurrence in node positive breast cancer [J]. Ann surg,2005, 242 (1):584-592
[32]Kerekatte V, Smiley K, Hu B, et al. The protooncogene/translation factor eIF4E:a survey of its expression in breast carcinomas [J] Int J Cancer,1995,64 (1):27-31
[33]Li BD, McDonald JC, Nassar R, et al. Clinical outcome in stage Ⅰ To Ⅲ breast carcinoma and eIF4E overexpression [J]. Ann Surg.1998,277 (5):756-763
[34]De Benedetti A, Hurris A I. eIF4E expression in tumors; its possible role in progression of malignamcies [J] Int J Biochem Cell Biol,1999,31 (1):59-72
[35]Hannan K. M, Y. Brandenburger, A Jenkina, et al. mTOR-dependent of ribosomal gene transcripition requires S6K1 is mediated by phosphhoryation of the carboy/-terminal activation domain of the mucleolar transcription factor UBF. Mol Cell Boil,2003,23 (23): 8862-8877
[36]Mayer.C, J.Zhao, X.Yuan, et al. mTOR-dependent activation of the transcription factor TIF-1A links rRNA synthesis to nutrient availability.Genes Dev,2004,181 (4):423-434
[37]陈振东,秦凤展,秦叔逵,主编·肿瘤学概论·人民卫生出版社,北京,2006,1(1)：37-38
[38]Gera JF, Mellinghoff IK, Shi Y, et al.AKT activity determines Sensitivity to Mammalian target of rapamycin (mTOR) inhibitions by regulating cyclinD1 and c-myc expression. J Biol chen,2004,279 (4):2737-2746
[39]Dilling Mb, Germain GS, Dudkin I, et al.4E-bingdig proteins, the suppressors of eukaryotic initintion factor 4E are down-regulated in cells with acquired or initinsic resistance to mpamycin. J Bid Chem.2002,277 (16):13907-13917
[40]Rosnwald IB. The role of translation in neoplastic transformation from a pathologists piont of view. Oncogene,2004,23 (18):3230-3247
[41]Schoppmann SF, Fenzl A, Nagy K, et al. VEGF 2 C expressing tumor2associated macrophages in lymph node positive breast cancer:impact on lymphangiogenesis and survival [J]1 Surgery,2006,139 (6):839-8461
[42]Li YS, Kaneko M, Amatya VJ, et al. Expression of vascular endot helial growt h factor2C and it s receptor in invasive micropapillary carcinoma of t he breast [J]1 Pat hol Int,2006, 56(5):256-2611
[43]Byrnes K, White S, Chu Q, et al 1 High elF 4 E, VEGF, and microvessel density in stage Ⅰ to Ⅲ breast cancer [J] 1 Ann Surg,2006,243 (5):684-690
[44]Nobukuni T, Joaquin M, Roccio M, et al. Amino acids mediate mTOR/raptor signaling through activation of class 3 phosphatidylinositol 3OH-kinase. Proc Natl Acad Sci,2005, 102 (40):14238-14243.
[45]Liu LZ, Zhou XD, Qian GS, et al. A KT1 amplif ication regulates cisplatin resistance in huma n lung ca ncer cells t hrough t he mammalia n ta rget of rapamycin/p70s6k1 pat hway [J]. Cancer Res,2007,67:6325-6332.
[46]Lu Ch, Wys Zomi Ers KI SL, Tsen G LM, et al. Preclinical testing of clinically applicable st rateies for overcoming t rastu2 zumab resista nce caused by PTEN deficiency [J]. Clin Ca ncer Res,2007,13:5883-5888.
[47]Connolly E, Braunstein S, Formenti S, et al. Hypoxia inhibits p rotein synthesis through a 4E-BP1 and elongation factor 2 kinase pathway controlled bymTOR and uncoup led in breast cancer cells. Mol CellBi2 ol,2006,26 (10):3955～3965.
[48]Martin JL, Baxter RC. Exp ression of insulin-like growth factor bind2 ing p rotein-2 byMCF-7 breast cancer cells is regulated through the phosphatidylinositol 3-kinase/AKT/ mammalian target of rapamycin pathway. Endocrinology,2007,148 (5):2532～2541.
[49]Shap iraM, Kakiashvili E, Rosenberg T, et al. The mTOR inhibitor ra2 pamycin down-regulates the exp ression of the ubiquitin ligase subunit Skp2 in breast cancer cells. Breast Cancer Res,2006,8 (4):46.
[50]Ito D, Fujimoto K, Mori T, et al. In vivo antitumor effect of t he mTOR inhibitor CCI2779 and gemcitabine in xenograft mod2 els of human pancreatic cancer [J]. Int J Cancer,2006, 118 (9):2337-2343.
[51]Stephan W, Robbie L, Michael N. TOR Signaling in Growth and Metabolism [J]. Cell, 2006,124:474-482.
[52]张涛,张保宁,张宏图等.乳腺癌前哨淋巴结微小转移的检测.中华肿瘤杂志,2007,29(2),116-118.
[53]章俊,张维元.eIF-4E、HER-2癌基因在鼻咽癌中表达的意义及其与PCNA和LMP-1的关系.诊断病理学杂志,2005,12(3)：211-213.
[54]于宝华,周晓燕.PI3K/Akt/mTOR的信号传导通路在恶性肿瘤中的研究进展.中华病理学杂志,2005,34(17)：674-676
[55]李孟圈,刘娟娟,李靖若等,mTOR在乳腺癌发生发展中的作用及其与C-erbB-2的关系.山东医药,2009,49(13)：59-61
[56]李金鸽,杨志宏.哺乳动物雷帕霉素靶蛋白信号通路与肿瘤的研究进展.医学综述,2007,13(23)：1766-1768
[57]Nancy E. Hynes, Anne Boulay. The mTOR Pathway in Breast Cancer. Journal of Mammary Gland Biology and Neoplasia.2006,1:53-61
[58]Wieslawa H. Dragowska, Maite Verreault, Donald T. T. Yapp,et al. Decreased levels of hypoxic cells in gefitinib treated ER+HER-2 overexpressing MCF-7 breast cancer tumors are associated with hyperactivation of the mTOR pathway:therapeutic implications for combination therapy with rapamycin. Breast Cancer Research and Treatment,2007, 12:319-331
[59]陈棵,张红锋.mTOR信号通路与癌症治疗.生命的化学,2005,25(2)：127-128
[1]ZhengJie, mTOR signaling pathway and cancer. Chinese Bulletin of life Sciences,2006, 18(3):261-265
[2]Asnaghil et al. Bruno P, Priulla M et al mTOR:a protein kinase swietching between life and death. Pharmacol Res 2004,50:545-549
[3]Sarbassow D D, Gmertin D A, Ali SM,et al. phosphorylation and regulation of Akt/PKB by the rictor mTOR complex Science,2005,307 (5712):1098-1101
[4]Huanys, Bjornsti MA, Houghton PJ-Papamy-cins:mechanisis of actor and cellular resistance[J].Cancer Biol Ther,2003,2(3):222-232
[5]Khaleghpour K, Pyronnet S, Gingras AC, et al. Translational homeostasis:eukaryotic translation initiation factor 4E control of 4E binding protein 1 and P70S6 Kinase activities. Mol cell Biol.1999,19(6):4302-4310
[6]Huang S, Hougheon PJ.Targeting mTOR signaling for cancer therapy opin pharmacol. 2003,3(4):371-377.
[7]Yang YJ, Zhang YL, LiX,et al. Contribution of eIF4E inhibton to the express and activity of heparanase in human colon adenocarcinoma cell line:LS-174T. World J Gastroentrol. 2003,9(8):1707-1712
[8]West MG, Stoneley M, willis AE. Translation induction of the c-myc oncogene via activation of the FRAP/TOR signaling pathway. Oncogene.1998,17(6):769-780
[9]Cao N,Zhang Z,Jiang BH,et al.G1 cell cycle progression and the expression of G1 cyclins are regulated by PI3K/AKT/mTOR/P70s6k1 signaling in human ovarin cancer cells.Am J Physiol cell Physiol,2004,287:c281-c291
[10]Jacinto E TOR signaling in buys brain and brawn, Nat Rew Mol cell Biol.2003,4(2): 117-126
[11]Pene F, Claessens YE, Muller O, et al. Role of the phosphatidylinositol 3-kinase/Akt and mTOR/P70S6-kinase pathways in the proliferation and apoptosis in multiple myeloma. Oncogene,2002,21:6578-6589
[12]Hill MM, Hemmings BA.Inhibition of protein kinase B/Akt. implications for cancer therapy. Pharmacol Ther,2002,93:243-251
[13]Zhoax, TanM, Stone Hawthome V, et al. Activation of the Akt/mammalian target of Rapamycin/4E-BP 1 Pathway by ErbB2 overexpression predicts tumor progression in breast cancers. clin cancer Res,2004 10:6779-6788
[14]Schalm SS, Fingar DC, Sabatinin DM, et al. TOS motif-mediated raptor binding regulates 4E.BP1 multisite Phosphorylation and function.Curr Biol,2003,13:793-806
[15]Xu G,Zhang W,Bertram P,et al.Pharmacogenomic profiling of the P13k/PTEN-Akt-mTOR pathway in common human tumors. Int J Oncol,2004,24:893-900
[16]Potter CJ pedraza LG, Xu T. Akt regulates growth by directly phosphory biting TSC2 [J]. Nat Cell Biol 2002,(4)9:658-665
[17]Corradetti M.N, K. Inoki, N. bardeesy, et al. Regulation of the TSC pathway by LKB.1: evidence of a olecular link between tubers sclerosis complex and Peutzjepbers syndrome. Gens Dev.2004.18(13):1533-1538
[18]Wullschleger S, Loewith R, Hall MN. TOR singaling in growth and metabolism Cell,2006, 124(3):471-484
[19]Beck,T,M.N.Hall.The TOR signaling pathway controls nuclear calization of nutrient regulated transcription factors.Nature,1999,402 (6762):689-692
[20]Gao X, Zhang Y, Arrazola P, et al. Tsc tumour proteins antagonaize amino-acid-TOR signaling. Nat Cell Biol,2002,4(9):699-704
[21]Smith EM Finn SG, Tee AR, et al. The tuberous sclerosis proteins TSC2 is not required for the regulation of the mammalian target of rapamycin by amino acids and certain stresess [J], J Boil Chem.2005,280(19):18717-18727
[22]Byfield MP, Murray JT. Bocker JM. Hvps34 is a mutrient-regulated lipid kinase required for activation of p70S6 kinase [J] J Boil Chem.,2005,280(38):33076-33082
[23]Yokogami, K, S Wakisaka, J, Avruch, and S.A. Reeves.serine phosphorylation and maxmal activation of STAT3 during CNTF signaling is mediated by the rapamycin target Mtor. curr Biol,2000,10(1):47-50
[24]Mayer. C, J. zhao,X. Yuan, et al. mTOR-dependont actibation of the transcription factor TIF-1A Links rRNA synthesis to nutrient availability, Dev,2004,18(4):423-434
[25]HannaK. M, Y. Brandenburger, A. Jenkina, et al, mTOM-deperdent, of ribosomal genetranscripition requires s6k1 is mediated by phosphhorylation of the carboylterminal activation domain of the mucleolar thanscription fachor UBF. Mol cell Boil,2003,23(23): 8862-8877
[26]Avruch. J, G. Belham, a, weng, K. Hara, and K.Yonezawa. The P70S6K kisnase integrates nutrient and growth signals to control translational capacity. ProgMol subcell Biol,2001, 26(1):115-154
[27]Wong Y C, Wang YZ. Growth factors and epithelial-stromal interactions in prostate cancer development. Int Rew cytol,2000,199:65-116
[28]Murillo H, Huang H, Schmidt LJ, et al. Role of PI3K Signaling in survival and Progression of LNCap prostate cancer cells to the androgen refractory state. Endocrinology,2001,142: 4795-4805
[29]Parsons R. Human cancer, PTEN and PI3 kinase pathway. Semin Cell Dev Biol,2004,15: 171-176
[30]Gupta Ak, Gerniglia GJ, Mick K, et al. R adiation sensitization of human cancer cells in vivo by inhibiting the activity of PI3K using Ly294002. Int J Radiat Oncol Biol Phy3, 2003,56:846-853
[31]Neshat MS, Mellinghoff IK, Tranc C, et al. Enhanced sensitivity of PIEN-deficient tumors to inhibition of FRAP/mTOR. Proc Natl Acad Sci U S A,2001,98:10314-10319
[32]Simith PG, Wang F, Wickinson KN, et al, The phosphodiesterase PDE4B limits CAMP-associated PI3K/Akt-dependent apoptosis in diffuse large B cell Lymphoma-blood,2005, 105:308-316
[33]Wang L, Fortney JE, Gibson LF-Stromal cell protection of B-lineage acute lymphoblastic cells during chemotherapy requires active Akt.Leuk Res,2004,28:733-742
[34]Grewe M, Gansauge F, Schmid RM, et al. Regulation of cell growth and cyclin D, expression by the constitutively active FRAP-P70S6K pathway in human pancreatic cancer cells. Cancer Res,1999,59:3581-3587
[35]Proud CG. The multifaceted role of mTOR in cellular stress responses. DNA Repair (Amst),2004,3:927-934
[36]Wendel HG, De Stanchina E, Fridman J S,et al. Survival signalling by Akt and eIF4E in oncongenesis and cancer therapy. Nature,2004,428:332-337
[37]KnuefermannC, Luy, Liu B, et al. HER2/PI-3K/Akt activation leads to a multidrug resistance in human breast adenocarcinoma cells. Oncogene,2003,22:3205-3212
[38]Brognad J.Clark AS,Niy,et al. Akt/protein kinase B is constitu tively active in non-small cell lung cancer cells and promotes cellular survival and resistance to chemotherapy and radiation. Cancer Res,2001,61:3986-3997
[39]Langher E, Taghavi P, Chiles K, et al. HER2 (neu) signaling increases the rate of hypoxia-inducible factor 1 alpha (HIF-1 alpha) Synthesis:novel mechanism for HIF-1-madiated vascular edothelial growth factor expression. Mol Cell Biol,2001,21:3995-4004
[40]Gao N, Nester RA, Sarkar MA.4-Hydroxy estradiol but not 2-hydroxy estradiol induces expression of hypoxia-induible factor 1 alpha and vascular endithelial growth factor A through phosphatidylinositol 3-kinase/Akt/FBAP pathway in OVCAR-3 and A 2780-CP70 human ovarian carcinoma cells. Toxicol Appl Pharmaol,2004,196:124-135
[41]Tuck AB, Hotac, Wilsons M, et al. Osteopontin-indued migration of human mammary epithelial cells involves activation of EGF receptor and multiple signal transduction pathways. Oncogene,2003,22:1198-1205
[42]Gotoh M, Sakamoto M, kanetaka K, et al. Overexpression of osteopontin in hepatocellular carinoma. Pathol Int,2002,52:19-24.
[43]Chen J, Fang Y.A novel pathway requlating the mammalian target of Rapamycin (mTOR) singaling. Biochem Pharmacol,2002,64:1071-1077
[44]Rowinsky Ek.Targeting the molecular target of rapamycin (mTOR) Curr Opin Oncol,2004, 16(6):564-575
[45]Gera J F Mellinghoff I K.Shi y. et al. Akt activity getermines mins seneitivity to mammalian target of Rapamycin (mTOR) inhibitors by regulating cyclin D1 and c-myc expessionJ Bion Chem.2004,279(4):2737-2746
[46]BrianK.LawRapamycin:Ananti-cancerimmunosuppressant[J]oncology-huematolo-gy,2005, 56(1):47-60
[47]Schoppmann SF, Fenzl A, Nagy K, et al. VEGF 2C expressing tumor2associated macrophages in lymph node positive breast cancer:impact on lymphangiogenesis and survival [J]1 Surgery,2006,139 (6):839-8461
[48]Li YS, Kaneko M, Amatya VJ, et al. Expression of vascular endot helial growt h factor2C and it s receptor in invasive micropapillary carcinoma of t he breast [J] 1 Pat hol Int,2006, 56(5):256-2611
[49]Byrnes K, White S, Chu Q, et al. High eIF 4 E, VEGF, and microvessel density in stage Ⅰ to Ⅲ breast cancer [J]1Ann Surg,2006,243 (5):684-690
[50]Sancak Y, Thoreen CC, Peterson TR, et al. PRAS40 is an insulin-regulated inhibitor of the mTORC1 protein kinase. Mol Cell,2007,25 (6):903-915.
[51]Nobukuni T, Joaquin M, Roccio M, et al. Amino acids mediate mTOR/raptor signaling through activation of class 3 phosphatidylinositol 3OH-kinase. Proc Natl Acad Sci,2005, 102 (40):14238-14243.
[52]苑红,牛燕媚,刘彦辉,等.mTOR/S6K1信号通路与有氧运动改善小鼠高脂饮食诱导胰岛素抵抗间的关系.中国康复医学杂志,2009,24(4)：297-302.
[53]牛燕媚,苑红,刘彦辉,等.有氧运动对胰岛素抵抗小鼠骨骼肌球形脂联素及腺苷酸活化蛋白激酶的响.中国运动医学杂志,2009,28(1)：36-40.
[54]Dreyer HC, Fujita S, Cadenas JG, et al. Resistance exercise increases AMPK activity and reduces 4E-BP1 phosphorylation and protein synthesis in human skeletal muscle. J Physiol,2006,576 (2):613-624.
[55]O'Neil TK, Duffy LR, Frey JW, et al. The role of phosphoinositide 3-kinase and phosphatidic acid in the regulation of mTOR following eccentric contractions. J Physiol, 2009,587 (Pt 14):3691-701.
[56]Carriere A, Cargnello M, Julien LA, et al. Oncogenic MAPK Signaling stimulates mTORC 1 activity by promoting RSK-mediated raptor phosphorylation. Current Biol 2008, 18 (17):1269-1277.
[57]Bose S, Chandran S, Mirocha JM, et al. The Akt pat h2 way in huma n breast ca ncer:a tissue2ar ray2based analysis [J]. Mod Pat hol,2006,19:238-245.
[58]Faivr RE S, Kroemer G, Raumond E. Cur rent develop2 ment of mTOR inhibitors as anticancer agents [J]. Nat Rev Drug Discov,2006,5:671-688.
[59]Mirsha HI P, Topra K S K, Faussa T AM, et al. Malignant hematop oietic cells induce a n increased exp ression of V EGFR21 a nd V EGFR23 on bone mar row endot helial cells via A KT a nd mTOR signalling pat hways [J]. Biochem Biop hys Res Com2 mun,2006,349 (3):1003-1010.
[60]Weppl ER SA, Krause M, Z Yroms KA A, et al. Resp onse of U87 glioma xenograf ts t reated wit hconcurrent rapamycin and fractionated radiot herapy:possible role f or t hrombosis [J]. Radiot her Oncol,2007,82 (1):96-104.
[61]Ama TO RJ, Misella TI A, Khan M, et al. A p hase Ⅱt rial of RAD001 in patients wit h metastatic renal cell ca rcinoma (MRCC) [J]. J Clin Oncol,2006,24:4530.
[62]Jo Hnston PB, Ansell SM, Col Gan J P, et al. Phase Ⅱ trial of the oral mTOR inhibitor everolimus (RAD001) for pa2 tients wit h relapsed or ref ractory lymp homa [J]. J Clin Oncol,2007,25:8055.
[63]Liu LZ, Zhou XD, Qian GS, et al. A KT1 amplif ication regulates cisplatin resistance in huma n lung ca ncer cells through the mammalia n ta rget of rapamycin/p70s6k1 pat hway [J]. Cancer Res,2007,67:6325-6332.
[64]Lu Ch, Wys Zomi Ers KI SL, Tsen G LM, et al. Preclinical testing of clinically applicable st rateies for overcoming t rastu2 zumab resista nce caused by PTEN def iciency [J]. Clin Cancer Res,2007,13:5883-5888.
[65]Connolly E, Braunstein S, Formenti S, et al. Hypoxia inhibits p rotein synthesis through a 4E-BP1 and elongation factor 2 kinase pathway controlled bymTOR and uncoup led in breast cancer cells. Mol CellBi2 ol,2006,26 (10):3955-3965.
[66]Martin JL, Baxter RC. Exp ression of insulin-like growth factor bind2 ing p rotein-2 byMCF-7 breast cancer cells is regulated through the phosphatidylinositol 3-kinase /AKT/mammalian target of rapamycin pathway. Endocrinology,2007,148 (5):2532～ 2541.
[67]Shap iraM, Kakiashvili E, Rosenberg T, et al. The mTOR inhibitor ra2 pamycin down-regulates the exp ression of the ubiquitin ligase subunit Skp2 in breast cancer cells. Breast Cancer Res,2006,8 (4):46.
[68]Ito D, Fujimoto K, Mori T, et al. In vivo antitumor effect of t he mTOR inhibitor CCI2779 and gemcitabine in xenograft mod2 els of human pancreatic cancer [J]. Int J Cancer,2006, 118 (9):2337-2343.
[69]Sabatini D M. mTOR and cancer:insights into a complex relationship [J]. Nat Rev Cancer, 2006,6(9):729-734.
[70]Stephan W, Robbie L, Michael N. TOR Signaling in Growth and Metabolism [J]. Cell, 2006,124:474-482.
[71]Ruvinsky I, Meyuhas O. Ribosomal protein S6 phosphorylation:from protein synthesis to cell size [J]. Trend Biochem Sci,2006,31(6):342-348.
[72]Cota D, Proulx K, Smith K A, et al.Hypothalamic mTOR signaling regulates food intake [J]. Science,2006,312(5775):861-864.
[73]张涛,张保宁,张宏图等.乳腺癌前哨淋巴结微小转移的检测.中华肿瘤杂志,2007,29(2),116-118.
[74]Abdul-Rasool S, Kidson SH, Panieri E, et al. An evaluation of molecular markers for improved detection of breast cancer metastases in sentinel nodes. J Clin Pathol,2006, 59(3):289-297.
[75]章俊,张维元.eIF-4E、HER-2癌基因在鼻咽癌中表达的意义及其与PCNA和LMP-1的关系.诊断病理学杂志,2005,12(3)：211-213.
[76]于宝华,周晓燕.PI3K/Akt/mTOR的信号传导通路在恶性肿瘤中的研究进展.中华病理学杂志,2005,34(17)：674-676
[77]李孟圈,刘娟娟,李靖若等,mTOR在乳腺癌发生发展中的作用及其与C-erbB-2的 关系.山东医药,2009,49(13)：59-61
[78]李金鸽,杨志宏.哺乳动物雷帕霉素靶蛋白信号通路与肿瘤的研究进展.医学综述,2007,13(23)：1766-1768
[79]陈棵,张红锋.]mTOR信号通路与癌症治疗.生命的化学,2005,25(2)：127-128
[80]Nancy E. Hynes, Anne Boulay. The mTOR Pathway in Breast Cancer. Journal of Mammary Gland Biology and Neoplasia.2006,1:53-61
[81]Diana Behrens, Anne E. Lykkesfeldt, Iduna Fichtner. The mTOR pathway inhibitor RAD001 (everolimus) is highly efficacious in tamoxifen-sensitive and-resistant breast cancer xenografts. Targeted Oncology,2007,7:135-144
[82]Wieslawa H. Dragowska,Maite Verreault,Donald T. T. Yapp,et al. Decreased levels of hypoxic cells in gefitinib treated ER+HER-2 overexpressing MCF-7 breast cancer tumors are associated with hyperactivation of the mTOR pathway:therapeutic implications for combination therapy with rapamycin. Breast Cancer Research and Treatment,2007, 12:319-331
© 2004-2018 中国地质图书馆版权所有 京ICP备05064691号 京公网安备11010802017129号 地址：北京市海淀区学院路29号 邮编：100083 电话：办公室：(+86 10)66554848；文献借阅、咨询服务、科技查新：66554700 |