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- W1481428288 abstract "Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CAOver two-thirds of all breast cancer patients are estrogen receptor alpha positive (ER+). However, almost 50% of all ER+ breast tumors do not respond or respond and later fail on endocrine therapy. Resistance to endocrine therapy remains a significant clinical problem and advanced ER+ breast cancer is largely an incurable disease. The mechanisms of resistance to endocrine therapy remain unclear. We have reported that the unfolded protein response (UPR), a stress-induced cellular adaptive mechanism, acts as a switch controlling the balance between cell death and cell survival in response to these therapies. UPR is activated by three molecular sensors: IRE1alpha, ATF6, PERK. Several components of the UPR, including IRE1alpha, are up-regulated in endocrine resistant cells. We now report a novel small molecule inhibitor of IRE1alpha: N-(4-Phenoxy-phenyl)-2-(5-pyridin-3-yl-2H-[1,2,4]triazol-3-ylsulfanyl)-acetamide (NPPTA). We show that NPPTA interacts with IRE1alpha in vitro and can decrease IRE1alpha protein levels. NPPTA treatment alone inhibits cell proliferation in antiestrogen resistant ER+ breast cancer cells more effectively than in sensitive cells, and in a dose- and time-dependent manner. Normal breast epithelial cells are unaffected by NPPTA. In addition, NPPTA and TAM synergistically inhibit cell proliferation in TAM resistant breast cancer cells. NPPTA's activities are associated with induced G1 cell cycle arrest, increased apoptosis/necrosis, and inhibition of anti-apoptotic signaling. Targeting IRE1alpha may be a new and effective strategy to reverse endocrine resistance in breast cancer.Citation Format: Ayesha N. Shajahan-Haq, Jacqueline Smith, Siva Dakshanamurthy, Difei Wang, Ahreej E. Eltayeb, Milton L. Brown, Robert Clarke. A novel small molecule inhibitor of IRE1alpha reverses endocrine resistance in breast cancer cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1634. doi:10.1158/1538-7445.AM2014-1634" @default.
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- W1481428288 date "2014-09-30" @default.
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- W1481428288 title "Abstract 1634: A novel small molecule inhibitor of IRE1alpha reverses endocrine resistance in breast cancer cells" @default.
- W1481428288 doi "https://doi.org/10.1158/1538-7445.am2014-1634" @default.
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