Estrogen Receptor α Attenuates Therapeutic Efficacy Of Paclitaxel On Bfeast Xenograft Tumors

[Purpose]:Through transfection of ERa into ERa-breast cancer BCap37cells, we previously established a pair of isogenic ERα-/ERa+tumor cell lines BC-V/BC-ER, and demonstrated that ERa induces chemoresistance in vitro. The present study is designed to investigate whether this ERa-mediated chemoresistance also occurs in xenograft models. Meanwhile, we would test whether fulvestrant, a clinically-used antiestrogen agent, can reverse ERa-mediated chemoresistance in vivo.[Experimental Design]:Xenograft models were established through transplantation of BC-ER and BC-V cells into nude mice. Mice were then treated with vehicle, paclitaxel (PTX), with or without administration of estrogen (E2). The potential influence of E2/ERa on the therapeutic efficacy of paclitaxel was then evaluated. Furthermore, we investigated whether fulvestrant can sensitize ERa+tumors to paclitaxel in vivo.[Results]:Compared with the group treated with PTX alone, co-treatment of E2significantly reduced the therapeutic efficacy of paclitaxel in BC-ER tumors (51.23%vs36.71%, p<0.01). Biochemical studies demonstrated that E2significantly interfered with paclitaxel’s cytotoxicity in BC-ER tumors. Importantly, we found that fulvestrant significantly repressed ERa expression, potentiated paclitaxel-induced apoptosis and sensitized BC-ER tumors to PTX in the presence of E2(39.12%vs53.64%,p<0.01).[Conclusions]:For the first time, this study demonstrated that E2/ERa attenuates therapeutic efficacy of paclitaxel in an isogenic ERα+xenograft model. More importantly, we demonstrated that fulvestrant significantly reversed the ERa-mediated chemoresistance in vivo. These findings may have potential implications on the clinical practice of antiestrogen and chemotherapeutic agents.