title: Estrogen receptor α attenuates therapeutic efficacy of paclitaxel on breast xenograft tumors.
abstract: Through transfection of ERα into ERα- breast cancer BCap37 cells, we previously established a pair of isogenic ERα-/ERα+ tumor cell lines BC-V/BC-ER, and demonstrated that ERα induces chemoresistance in vitro. The present study is designed to investigate whether this ERα-mediated chemoresistance also occurs in xenograft models. Meanwhile, we would test whether fulvestrant, a clinically-used antiestrogen agent, can reverse ERα-mediated chemoresistance in vivo. Xenograft models were established through transplantation of BC-ER and BC-V cells into nude mice. Mice were then treated with vehicle, paclitaxel, with or without administration of estrogen (E2). The potential influence of E2/ERα on the therapeutic efficacy of paclitaxel was then evaluated. Furthermore, we investigated whether fulvestrant can sensitize ERα+ tumors to paclitaxel in vivo. Compared with the group treated with PTX alone, co-treatment of E2 significantly reduced the therapeutic efficacy of paclitaxel in BC-ER tumors (51.23 vs. 36.71%, p < 0.01). Biochemical studies demonstrated that E2 significantly interfered with paclitaxel's cytotoxicity in BC-ER tumors. Importantly, we found that fulvestrant significantly repressed ERα expression, potentiated paclitaxel-induced apoptosis and sensitized BC-ER tumors to PTX in the presence of E2 (39.12 vs. 53.64%, p < 0.01). In summary, this study demonstrated that E2/ERα attenuates therapeutic efficacy of paclitaxel in an isogenic ERα+ xenograft model. Furthermore, we demonstrated that fulvestrant significantly reversed the ERα-mediated chemoresistance in vivo. These findings may have potential implications on the clinical practice of antiestrogen and chemotherapeutic agents.
authors.affiliation: Program of Innovative Cancer Therapeutics, First Affiliated Hospital of Zhejiang University College of Medicine, Hangzhou, China.
authors.forename: Jinjia
authors.initials: J
authors.lastname: Chang
authors.forename: Meihua
authors.initials: M
authors.lastname: Sui
authors.forename: Weimin
authors.initials: W
authors.lastname: Fan
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D004958:Estradiol / Q000031:analogs & derivatives / Q000494:pharmacology; D004965:Estrogen Antagonists / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism*; D004967:Estrogens / Q000494:pharmacology; D005260:Female; D000077267:Fulvestrant; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D017239:Paclitaxel / Q000008:administration & dosage / Q000494:pharmacology*; D000091402:Prohibitins; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics; D023041:Xenograft Model Antitumor Assays; D051020:bcl-X Protein / Q000235:genetics
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D004965:Estrogen Antagonists; D047628:Estrogen Receptor alpha; D004967:Estrogens; C000717331:PHB2 protein, human; C000717333:Phb2 protein, mouse; D000091402:Prohibitins; D019253:Proto-Oncogene Proteins c-bcl-2; D051020:bcl-X Protein; D000077267:Fulvestrant; D004958:Estradiol; D017239:Paclitaxel