中国科学院机构知识库网格
Chinese Academy of Sciences Institutional Repositories Grid
首页 机构 成果 学者
  
  1. CAS IR Grid
  2. 上海药物研究所
  3. 中国科学院上海药物研究所
  4. 药理学第一研究室
Combined Src and Aromatase Inhibition Impairs Human Breast Cancer Growth In vivo and Bypass Pathways Are Activated in AZD0530-Resistant Tumors

文献类型：期刊论文

作者Chen, Yi3,5; Guggisberg, Natalia5; Jorda, Merce5,6; Gonzalez-Angulo, Ana2,4; Hennessy, Bryan2,4; Mills, Gordon B.2,4; Tan, Chen-Keat5; Slingerland, Joyce M.1,5
刊名CLINICAL CANCER RESEARCH
出版日期2009-05-15
卷号15期号:10页码:3396-3405
ISSN号1078-0432
DOI10.1158/1078-0432.CCR-08-3127
文献子类Article
英文摘要Purpose: Antiestrogens are used to treat estrogen receptor (ER)-alpha-positive breast cancers and cause a p27-dependent G(1) arrest. Estrogen-bound ER recruits Src to mediate proteolysis of p27 and drive cell proliferation. Here, we tested the antitumor efficacy of combined Src and aromatase inhibition for ER-positive breast cancer. Experimental Design: Antiproliferative effects of the aromatase inhibitor, anastrozole, and Src inhibitor, AZD0530, alone or in combination were tested in vitro and in vivo on aromatase-transfected MCF-7Arom5 xenografts. Xenografts were analyzed by immunohistochemistry and proteomic analysis to identify potential biomarkers of drug response and resistance. Results: AZD0530 and anastrozole together increased p27 and caused greater G(1) cell cycle arrest than either drug alone. AZD0530 monotherapy initially retarded xenograft growth in vivo, but drug resistance rapidly emerged. Combined anastrozole/AZD0530 reduced drug resistance and showed greater antitumor efficacy in vivo with greater Src and epidermal growth factor receptor inhibition and a greater increase in p27 and reduction of Ki-67 than either drug alone, supporting further evaluation of these putative predictors of response to combined Src/aromatase inhibition in vivo. Anastrozole alone stimulated Src activity both in vitro and in vivo. AZD0530-resistant tumors showed activation of bypass pathways including MEK and phosphatidylinositol 3-kinase (Pl3K)/Akt/mammalian target of rapamycin, raising the possibility that MEK, mammalian target of rapamycin (mTOR), or PI3K inhibitors may augment Src inhibitor efficacy. Conclusions: These data support clinical investigation of anastrozole-AZD0530 therapy for postmenopausal ER-positive breast cancer. Loss of p27 and increased Ki-67 may predict response and further clinical studies should evaluate for activation of bypass pathways including MEK and PI3K pathways during Src inhibitor therapy.
WOS关键词CELL-CYCLE ARREST ; NUDE-MOUSE MODEL ; ESTROGEN-RECEPTOR ; C-SRC ; RETINOBLASTOMA PROTEIN ; DEPENDENT KINASE ; MCF-7 CELLS ; P27(KIP1) ; THERAPY ; PHOSPHORYLATION
资助项目Breast Cancer Research Foundation[00000000] ; Flight Attendants Medical Research Institute[00000000] ; Avon Foundation[00000000]
WOS研究方向Oncology
语种英语
WOS记录号WOS:000266282600018
出版者AMER ASSOC CANCER RESEARCH
源URL[http://119.78.100.183/handle/2S10ELR8/279240]  
专题药理学第一研究室
通讯作者Slingerland, Joyce M.
作者单位1.Univ Miami, Miller Sch Med, Dept Biochem & Mol Biol, Miami, FL 33136 USA;
2.Univ Texas MD Anderson Canc Ctr, Dept Syst Biol, Houston, TX 77030 USA;
3.Chinese Acad Sci, Shanghai Inst Mat Med, Div Antitumor Pharmacol, Shanghai 200031, Peoples R China
4.Univ Texas MD Anderson Canc Ctr, Dept Gynecol Med Oncol, Houston, TX 77030 USA;
5.Univ Miami, Miller Sch Med, Sylvester Comprehens Canc Ctr, Braman Family Breast Canc Inst, Miami, FL 33136 USA;
6.Univ Miami, Miller Sch Med, Dept Pathol, Miami, FL 33136 USA;
推荐引用方式
GB/T 7714		 Chen, Yi,Guggisberg, Natalia,Jorda, Merce,et al. Combined Src and Aromatase Inhibition Impairs Human Breast Cancer Growth In vivo and Bypass Pathways Are Activated in AZD0530-Resistant Tumors[J]. CLINICAL CANCER RESEARCH,2009,15(10):3396-3405.
APA Chen, Yi.,Guggisberg, Natalia.,Jorda, Merce.,Gonzalez-Angulo, Ana.,Hennessy, Bryan.,...&Slingerland, Joyce M..(2009).Combined Src and Aromatase Inhibition Impairs Human Breast Cancer Growth In vivo and Bypass Pathways Are Activated in AZD0530-Resistant Tumors.CLINICAL CANCER RESEARCH,15(10),3396-3405.
MLA Chen, Yi,et al."Combined Src and Aromatase Inhibition Impairs Human Breast Cancer Growth In vivo and Bypass Pathways Are Activated in AZD0530-Resistant Tumors".CLINICAL CANCER RESEARCH 15.10(2009):3396-3405.

入库方式： OAI收割

来源：上海药物研究所

浏览0
下载0
收藏0
其他版本

除非特别说明，本系统中所有内容都受版权保护，并保留所有权利。