Estrogen receptor-α directly regulates sensitivity to paclitaxel in neoadjuvant chemotherapy for breast cancer

Emi Tokuda, Yuko Seino, Atsushi Arakawa, Mitsue Saito, Fujio Kasumi, Shin Ichi Hayashi, Yuri Yamaguchi

Research output: Contribution to journalArticlepeer-review

22 Citations (Scopus)

Abstract

Neoadjuvant chemotherapy (NAC) has become the standard treatment for advanced breast cancer. Several prognostic markers, including estrogen receptor-α (ERα), are used to predict the response to NAC. However, the molecular significance of ERα expression in the efficacy of chemotherapy is not yet fully understood. To examine this issue, we first evaluated ERα transcriptional activity in breast cancer cells derived from pre-NAC specimens using estrogen response element-green fluorescent protein (ERE-GFP) as a reporter gene, and found that, in the cases for which ERα activities determined by GFP expression were not detected or low, pCR (pathological complete response) could be achieved even though ERα protein was expressed. Next, we examined the effects of alterations in ERα expression levels on sensitivity to paclitaxel, a key drug in NAC, by stable expression of ERα in ER-negative SKBR3 cells and by siRNA-mediated down-regulation of ERα in ER-positive MCF-7 cells, and showed that ERα 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 α-tubulin. Finally, we demonstrate herein that ERα knockdown in MCF-7 cells prevents deacetylation of α-tubulin, thereby increasing sensitivity to paclitaxel. Taken together, these results suggest that ERα expression directly regulates sensitivity to paclitaxel in NAC for breast cancer via the effect on microtubule stability.

Original languageEnglish
Pages (from-to)427-436
Number of pages10
JournalBreast Cancer Research and Treatment
Volume133
Issue number2
DOIs
Publication statusPublished - 2012 Jun

Keywords

  • Breast cancer
  • ERα
  • HDAC6
  • Neoadjuvant chemotherapy
  • Paclitaxel

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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