Abstract 1258: The unfolded protein response may contribute to racial disparity in endocrine responsiveness in breast cancer

Abstract

Abstract About 70% of all breast cancers are estrogen receptor alpha positive (ER+) and depend on estrogen to grow and proliferate. Anti-hormone therapy such as antiestrogens (e.g., Tamoxifen; TAM) are often used to treat ER+ breast tumors but the cancer cells can develop resistance to these drugs (endocrine resistance). Unfortunately, ∼50% percent of all antiestrogen treated tumors eventually develop endocrine resistance, and therefore, there is an urgent need to find ways to treat this incurable disease. Nonetheless, little is known about the causes of endocrine resistance, and even less is known about the racial disparities that exist for antiestrogen responsiveness among ER+ breast cancer cases. Clinical investigations into ER+ breast cancer cases with similarly treated tumors showed that progression-free survival (PFS) and overall survival (OS) in African-American (AA) women were worse than in European-American (EA) women. The underlying causes of these racial differences within ER+ breast cancers is unknown. One cellular adaptive mechanism that allow endocrine resistant cells to survive antiestrogen treatment is a called the unfolded protein response (UPR) that is initiated within the endoplasmic reticulum caused by a stress stimulus. Cellular stress induced by antiestrogens can trigger the UPR leading to induce a pro-survival response by inhibiting cell death (by apoptosis) and promoting cell survival (by autophagy). Gene expression analysis for ER+ tumors of AA patients show up-regulation of UPR genes such as glucose-regulated protein 78, GRP78 (also known as HSP5A or BiP), activation transcription factor-6 (ATF6) and spliced X-box-protein-1 (XBP1s). Moreover, ER+ breast cancer cell lines derived from tumors of AA patients show increased levels of GRP78, ATF6 and XBP1 compared with cells derived from EA patients. The ER+ breast cancer cell lines derived from tumors of AA patients also show reduced sensitivity to Tamoxifen compared with cells derived from EA patients. Through our study, we will determine how up-regulation of the UPR contribute to the differences noted in anti-hormone therapy in treatment of ER+ breast cancer in AA versus EA women. Therefore, targeting critical pro-survival signaling molecules of the UPR can inhibit endocrine resistance and reduce growth of ER+ breast cancer cells more efficiently and avoid unsuccessful treatment in AA breast cancer patients. Citation Format: Ahreej E. Eltayeb, Diane M. Demas, Robert Clarke, Ayesha N. Shajahan-Haq. The unfolded protein response may contribute to racial disparity in endocrine responsiveness in breast cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1258. doi:10.1158/1538-7445.AM2015-1258