Estrogen receptor α attenuates therapeutic efficacy of paclitaxel on breast xenograft tumors.

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.