title: Autophagy facilitates the progression of ERalpha-positive breast cancer cells to antiestrogen resistance.
abstract: A major impediment to the successful treatment of estrogen receptor alpha (ERalpha)-positive breast cancer is the development of antiestrogen resistance. Tamoxifen, the most commonly used antiestrogen, exerts its pharmacological action by binding to ERalpha and blocking the growth-promoting action of estrogen-bound ERalpha in breast cancer cells. Tamoxifen treatment primarily induces cytostasis (growth arrest) and the surviving breast cancer cells commonly acquire tamoxifen resistance. Numerous clinically-relevant mechanisms of acquired antiestrogen resistance have been identified by in vitro studies. Our recent studies (Mol Cancer Ther 2008; 7:2977-87) now demonstrate that autophagy (also referred to as macroautophagy) is critical to the development of antiestrogen resistance. Under conditions of compromised autophagy, including treatments with pharmacological inhibitors and RNAi targeting of the beclin 1 gene, the cytotoxicity (death-inducing effects) of the antiestrogen 4-hydroxytamoxifen (4-OHT) was significantly increased. 4-OHT is an active metabolite of tamoxifen commonly used for in vitro studies. A step-wise drug selection protocol, using 4-OHT as the selecting drug, established antiestrogen-resistant breast cancer cell lines. Analysis of a representative resistant cell line showed an increased ability of the cells to sustain high levels of antiestrogen-induced autophagy without progression to death. Importantly, blockade of autophagosome function in the 4-OHT-treated, antiestrogen-resistant cells induced a robust death response. These data provide strong evidence that autophagy is a key mechanism of cell survival during antiestrogen challenge and progression to antiestrogen resistance. We discuss the potential benefit of blocking autophagosome function to significantly reduce the emergence of antiestrogen-resistant breast cancer cells.
authors.affiliation: Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta, GA 30912, USA. pschoenl@mail.mcg.edu
authors.forename: Patricia V
authors.initials: PV
authors.lastname: Schoenlein
authors.forename: Sudharsan
authors.initials: S
authors.lastname: Periyasamy-Thandavan
authors.forename: Julia S
authors.initials: JS
authors.lastname: Samaddar
authors.forename: William H
authors.initials: WH
authors.lastname: Jackson
authors.forename: John T
authors.initials: JT
authors.lastname: Barrett
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D051017:Apoptosis Regulatory Proteins / Q000096:biosynthesis; D001343:Autophagy / Q000187:drug effects*; D000071186:Beclin-1; D001943:Breast Neoplasms / Q000188:drug therapy*; D016923:Cell Death; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D018450:Disease Progression; D019008:Drug Resistance, Neoplasm; D004965:Estrogen Antagonists / Q000494:pharmacology*; D006801:Humans; D008565:Membrane Proteins / Q000096:biosynthesis; D008954:Models, Biological; D010587:Phagocytosis; D034622:RNA Interference; D013629:Tamoxifen / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; C491997:BECN1 protein, human; D000071186:Beclin-1; D004965:Estrogen Antagonists; D008565:Membrane Proteins; D013629:Tamoxifen