FP07-2 Estrogen receptor-α (ER) integration of unfolded protein response signaling activates autophagy and production of reactive oxygen species to determine ER+ breast cancer cell fate

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: FP07-New Players in Hormonal Control of Breast & Prostate Cancer
Saturday, June 15, 2013: 11:00 AM-11:30 AM
Presentation Start Time: 11:15 AM
Room 206 (Moscone Center)

Poster Board SAT-317
Robert Clarke*1, Pamela Clarke2, Rong Hu2, Mones Abu-Asab3, Anni M Warri4 and Katherine L Cook2
1Georgetown Univ Med Ctr, Washington, DC, 2Georgetown University, 3NIE/NIH, Bethesda, MD, 4Univ of Turku, Turku, Finland
Approximately 70% of all newly diagnosed invasive breast cancers express the estrogen receptor-α (ER). Inhibiting ER action using targeted therapies such as tamoxifen (TAM) or Fulvestant (Faslodex; ICI) are often effective in treating this breast cancer subtype. Unfortunately, the curative potential of these interventions is limited in many patients due to the initial presence or later emergence of an antiestrogen resistant phenotype. Understanding how this resistance occurs could lead to improved approaches to eradicate some ER+ breast cancers. Increased activation of the unfolded protein response (UPR) in response to endoplasmic reticulum stress and the subsequent induction of autophagy reduce antiestrogen sensitivity in ER+ breast cancer. We used antiestrogen sensitive MCF7/LCC1 (LCC1) and resistant MCF7/LCC9 (LCC9) cell lines to determine the effect of antiestrogens and ERα on regulating autophagy and UPR signaling. Knockdown of ERα expression using RNAi significantly increases the sensitivity of LCC1 cells to antiestrogen-mediated cell death and also resensitizes LCC9 cells to these drugs, reflecting an ERα-mediated inhibition of UPR signaling and concurrent stimulation of autophagy. Furthermore, ERα knockdown stimulates ROS production and potentiates the cell death response to antiestrogens. Interestingly, ERα knockdown, but not ICI treatment, reduces nuclear NRF2 (a UPR-induced antioxidant signaling protein) and increases cytosolic KEAP1 (an inhibitor of NRF2), likely explaining the observed increases in ROS production. ATG7 silencing inhibits autophagy and increases cell death and apoptosis in LCC1 ERα knockdown cells. Thus, autophagy induction by antiestrogens is prosurvival. Together, these data suggest that UPR and autophagy are stimulated by antiestrogen therapy through two distinct mechanisms of ER action/regulation. Hence, antiestrogens promote the accumulation of ERα protein in the cytosol that is associated with increased UPR signaling, while the inhibition of ERα promotes prosurvival autophagy. The stimulation by antiestrogens of signaling that can confer resistance, presumably in response to the stress of the treatment, suggests that combining autophagy or UPR inhibitors with antiestrogens may reduce the development of acquired antiestrogen resistance in some breast cancers.

Nothing to Disclose: RC, PC, RH, MA, AMW, KLC

*Please take note of The Endocrine Society's News Embargo Policy at http://www.endo-society.org/endo2013/media.cfm

Sources of Research Support: NIH Grants U54 CA149147 and R01 CA131465 awarded to Clarke; USAMRMC U.S. Army Breast Cancer Postdoctoral Fellowships BC1000073 awarded to Hu and BC112023 awarded to Cook