Enhanced resistance to tamoxifen by the c-ABL proto-oncogene in breast cancer.
Targeting the estrogen receptor is an important strategy in breast cancer therapy. However, although inhibiting estrogen receptor function with specific estrogen receptor modulators can achieve a primary response in cancer patients, intrinsic or subsequently acquired resistance to the therapy remains a major obstacle in the clinic. Thus, it is critical to gain a more thorough understanding of how estrogen receptor functions are regulated in breast cancer.Here, we demonstrate that the non-receptor tyrosine kinase c-ABL is a functional partner of the estrogen receptor, as expression of c-ABL sustained transcriptional activity of the estrogen receptor. More importantly, inhibition of c-ABL resulted in sensitization to treatment by tamoxifen (TAM) in estrogen receptor-positive breast cancer cells, as manifested by inhibition of cell survival and suppression of anchorage-independent growth. We found that c-ABL interacts with estrogen receptor in breast cancer cells and that expression of c-ABL is a frequent event in primary breast cancer tumor tissues. In estrogen receptor-positive tumors, the expression of c-ABL significantly correlated with disease progression and metastasis. This study shows that c-ABL regulates the cellular response to TAM through functional interaction with the estrogen receptor, which suggests c-ABL as a therapeutic target and a prognostic tumor marker for breast cancer.
Department of Cancer and Cell Biology, University of Cincinnati College of Medicine, 3125 Eden Ave, Cincinnati, OH 45267-0521, USA.
Huajun
H
Zhao
Fu
F
Ou-Yang
I-Fen
IF
Chen
Ming-Feng
MF
Hou
Shyng-Shiou F
SS
Yuan
Hsueh-Ling
HL
Chang
Yi-Chen
YC
Lee
Rina
R
Plattner
Susan E
SE
Waltz
Shuk-Mei
SM
Ho
Jonathan
J
Sims
Shao-Chun
SC
Wang
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D018270:Carcinoma, Ductal, Breast / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D002285:Carcinoma, Intraductal, Noninfiltrating / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D018275:Carcinoma, Lobular / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D016313:Genes, abl / Q000502:physiology*; D006801:Humans; D008875:Middle Aged; D000090063:Proto-Oncogene Mas; D034741:RNA, Small Interfering / Q000494:pharmacology; D011980:Receptors, Progesterone / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013629:Tamoxifen / Q000627:therapeutic use*; D046888:Tissue Array Analysis
D018931:Antineoplastic Agents, Hormonal; C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D034741:RNA, Small Interfering; D011980:Receptors, Progesterone; D013629:Tamoxifen