Abstract P3-05-11: Glutamine metabolism promotes survival through the unfolded protein response in endocrine resistant breast cancer

About 70% of all breast cancers are estrogen receptor alpha positive (ER+). Anti-hormone therapy such as antiestrogens (e.g.,Tamoxifen; TAM) are often used to treat ER+ breast cancer but breast 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. Endocrine resistant cells survive antiestrogen treatment by initiating a pro-survival pathway mediated by an evolutionary conserved process call the unfolded protein response (UPR) within the endoplasmic reticulum. Cellular stress induced by therapeutics can be initiated by the UPR leading to a pro-survival response in the short-term and a pro-death response in the long-term, depending on the magnitude of the stress signal. Our studies show that antiestrogens can decrease glucose uptake in ER+ breast cancer cells, and in glucose-deprived conditions, presence of glutamine in the media can trigger the UPR through GRP78-IRE1a. Subsequently, a glutamine-dependent pathway can induce cell death via GRP78-IREa-JNK-CHOP and survival in others via GRP78-IRE1a-XBP1. Glutamine metabolites such as glutamate (essential substrate for many vital cellular processes) and proline (substrate for collagen production) are significantly elevated in endocrine resistant cells. Knockdown of glutaminase (GLS1) with siRNA or small molecule inhibitor, CB-839, significantly decreased cell proliferation in endocrine resistant cells compared with sensitive cells within 48 h. Moreover, cell lines derived from endocrine resistant cells that are grown in glucose-free media are significantly more sensitive to CB-839 compared with their respective controls, indicating an increased dependency on glutamine. Glutamine may offer an alternate source of energy and raw materials in periods of glucose deprivation, and in endocrine resistant cells, this adaptive pro-survival cellular metabolic mechanism is up-regulated. Thus, CB-839 may be a potent anti-cancer agent in treating antiestrogen resistant breast cancers. Citation Format: Ayeasha N Shajahan-Haq, Susan Demo, Robert Clarke. Glutamine metabolism promotes survival through the unfolded protein response in endocrine resistant breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P3-05-11.