title: Knockdown of estrogen receptor-α induces autophagy and inhibits antiestrogen-mediated unfolded protein response activation, promoting ROS-induced breast cancer cell death.
abstract: Approximately 70% of all newly diagnosed breast cancers express estrogen receptor (ER)-α. Although inhibiting ER action using targeted therapies such as fulvestrant (ICI) is often effective, later emergence of antiestrogen resistance limits clinical use. We used antiestrogen-sensitive and -resistant cells to determine the effect of antiestrogens/ERα on regulating autophagy and unfolded protein response (UPR) signaling. Knockdown of ERα significantly increased the sensitivity of LCC1 cells (sensitive) and also resensitized LCC9 cells (resistant) to antiestrogen drugs. Interestingly, ERα knockdown, but not ICI, reduced nuclear factor (erythroid-derived 2)-like (NRF)-2 (UPR-induced antioxidant protein) and increased cytosolic kelch-like ECH-associated protein (KEAP)-1 (NRF2 inhibitor), consistent with the observed increase in ROS production. Furthermore, autophagy induction by antiestrogens was prosurvival but did not prevent ERα knockdown-mediated death. We built a novel mathematical model to elucidate the interactions among UPR, autophagy, ER signaling, and ROS regulation of breast cancer cell survival. The experimentally validated mathematical model explains the counterintuitive result that knocking down the main target of ICI (ERα) increased the effectiveness of ICI. Specifically, the model indicated that ERα is no longer present in excess and that the effect on proliferation from further reductions in its level by ICI cannot be compensated for by increased autophagy. The stimulation of signaling that can confer resistance suggests that combining autophagy or UPR inhibitors with antiestrogens would reduce the development of resistance in some breast cancers.
authors.affiliation: Department of Oncology and Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, District of Columbia, USA;
authors.forename: Katherine L
authors.initials: KL
authors.lastname: Cook
authors.affiliation: Department of Oncology and Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, District of Columbia, USA;
authors.forename: Pamela A G
authors.initials: PA
authors.lastname: Clarke
authors.affiliation: Department of Biological Sciences and.
authors.forename: Jignesh
authors.initials: J
authors.lastname: Parmar
authors.affiliation: Department of Oncology and Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, District of Columbia, USA;
authors.forename: Rong
authors.initials: R
authors.lastname: Hu
authors.affiliation: Department of Oncology and Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, District of Columbia, USA;
authors.forename: Jessica L
authors.initials: JL
authors.lastname: Schwartz-Roberts
authors.affiliation: Section of Immunopathology and Laboratory of Immunology, National Eye Institute, U.S. National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Mones
authors.initials: M
authors.lastname: Abu-Asab
authors.affiliation: Department of Oncology and Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, District of Columbia, USA;
authors.forename: Anni
authors.initials: A
authors.lastname: Wärri
authors.affiliation: Bradley Department of Electrical and Computer Engineering, Virginia Polytechnic Institute and State University, Blacksburg, Virginia, USA; and.
authors.forename: William T
authors.initials: WT
authors.lastname: Baumann
authors.affiliation: Department of Oncology and Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, District of Columbia, USA; clarker@georgetown.edu.
authors.forename: Robert
authors.initials: R
authors.lastname: Clarke
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects*; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D049109:Cell Proliferation; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004958:Estradiol / Q000031:analogs & derivatives / Q000494:pharmacology; D020847:Estrogen Receptor Modulators / Q000494:pharmacology*; D047628:Estrogen Receptor alpha / Q000037:antagonists & inhibitors*; D005260:Female; D005434:Flow Cytometry; D000077267:Fulvestrant; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D018613:Microscopy, Confocal; D008962:Models, Theoretical; D018384:Oxidative Stress / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D056811:Unfolded Protein Response / Q000187:drug effects*; D023041:Xenograft Model Antitumor Assays
chemical_list: C506487:ESR1 protein, human; D020847:Estrogen Receptor Modulators; D047628:Estrogen Receptor alpha; D017382:Reactive Oxygen Species; D000077267:Fulvestrant; D004958:Estradiol
keywords: ICI 182780; apoptosis; fulvestrant; reactive oxygen species