Abstract 5397: MYC-driven glutamine metabolism promotes antiestrogen resistance in breast cancer.

Abstract

Abstract About 70% of newly diagnosed cases of invasive breast cancer in the U.S. will be estrogen receptor alpha positive (ER+). Endocrine therapy is the least toxic and most effective means to manage the hormone-dependent breast cancer, administered as an antiestrogen, e.g., Tamoxifen (TAM) or Faslodex (FAS; Fulvestrant; ICI 182,780) or an aromatase inhibitor (AI), e.g., Letrozole (LET). However, advanced ER+ breast cancer that has become resistant to endocrine therapy remains a significant clinical problem. Here we show that in breast cancer cells and rat tumors with acquired antiestrogen resistance, MYC, a oncogenic transcription factor, is overexpressed. Inhibition of MYC with small molecule inhibitor or siRNA resensitizes resistant cells to antiestorgens by inducing apoptosis. MYC inhibition in resistant cells also inhibited glutamine uptake and decreased levels of ASCT2/SLC1A5, a glutamine transporter. Resistant cells showed significant increase in cell proliferation in response to glutamine than sensitive cells. Moreover, resistant cells showed increased sensitivity to an inhibitor of glutaminase, GLS, an enzyme that hydrolysis of glutamine to glutamate. Thus, MYC promotes increased dependence on glutamine in antiestrogen resistant cells, and targeting glutamine metabolism could help circumvent antiestrogen resistance. Overreaching goal of this study is to and to identify effective therapies to treat endocrine resistant breast cancer. Citation Format: Ayesha N. Shajahan, Katherine L. Cook, Jessica L. Schwartz-Roberts, Ahreej E. Eltayeb, Diane M. Demas, Anni Warri, Leena Hilakivi-Clarke, Steven Metallo, Robert Clarke. MYC-driven glutamine metabolism promotes antiestrogen resistance in breast cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5397. doi:10.1158/1538-7445.AM2013-5397