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 amore thorough understanding of howestrogen 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, asmanifested 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.
|Number of pages||10|
|State||Published - Mar 2010|
Bibliographical noteFunding Information:
Abbreviations: ERα, estrogen receptor α; ERE, estrogen receptor response element; WT, wild-type; kd, kinase-deficient; CA, constitutively active; TAM, tamoxifen; shLuc, short hairpin RNA against luciferase; shABL, short hairpin RNA against c-ABL Address all correspondence to: Shao-Chun Wang, PhD, Department of Cancer and Cell Biology, 3125 Eden Ave, Cincinnati, OH 45267-0521. E-mail: firstname.lastname@example.org 1This work was supported in part by the startup fund of the University of Cincinnati Cancer Consortium, the Susan G. Komen Breast Cancer Research Award KG080540, the Department of Defense New Investigator Award PC073951, and the Marlene Harris-Ride Cincinnati Breast Cancer Pilot Grant Program (to S.-C.W.). This project was also supported in part by PHS grant P30 DK078392. 2This article refers to supplementary materials, which are designated by Figures W1 to W4 and are available online at www.neoplasia.com. 3These two authors contributed equally. Received 11 September 2009; Revised 2 January 2010; Accepted 5 January 2010 Copyright © 2010 Neoplasia Press, Inc. All rights reserved 1522-8002/10/$25.00 DOI 10.1593/neo.91576
ASJC Scopus subject areas
- Cancer Research