82P ER&agr; Expression Regulates Sensitivity to Paclitaxel In Neoadjuvant Chemotherapy for Breast Cancer

Abstract

ABSTRACT Neoadjuvant chemotherapy (NAC) has become the standard treatment for advanced breast cancer. Several prognostic markers, including estrogen receptor-a (ERa), are also used to predict the response to NAC. However, the molecular significance of ERa expression in the efficacy of chemotherapy is not yet fully understood. To examine this issue, we first evaluated ERa transcriptional activity in breast cancer cells derived from pre-NAC specimens using estrogen response element green fluorescent protein (EREGFP) as a reporter gene, and found that, in the cases for which ERa activities determined by GFP expression were not detected or low, pCR (pathological complete response) could be achieved even though ERa protein was expressed by immunohistochemistry. Next, we examined the effects of alterations in ERa expression levels on sensitivity to paclitaxel, a key drug in NAC, by stable expression of ERa in ER-negative SKBR3 cells and by siRNA-mediated down-regulation of ERa in ER-positive MCF-7 cells, and showed that ERa expression and sensitivity to paclitaxel showed an inverse correlation. We also established paclitaxel-resistant MCF-7 cell clones and found that they have higher estrogen induced ER activity than parent cells. Paclitaxel is a microtubule-stabilizing agent, while HDAC6 (histone deacetylase 6), which we previously identified as an estrogen-regulated gene, enhances cell motility by destabilizing microtubules via deacetylation of a-tubulin. Finally, we demonstrate herein that ERa knockdown in MCF-7 cells prevents deacetylation of a-tubulin, thereby increasing sensitivity to paclitaxel. Taken together, these results suggest that ERa expression directly regulates sensitivity to paclitaxel in NAC for breast cancer via estrogen-induced deacetylation of tubulin mediated by HDAC6. Disclosure All authors have declared no conflicts of interest.