title: Estrogen receptor-α directly regulates sensitivity to paclitaxel in neoadjuvant chemotherapy for breast cancer.
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.
authors: Department of Breast and Endocrine Surgery, Graduate School of Medicine, Juntendo University, Tokyo, Japan.
authors: Emi
authors: E
authors: Tokuda
authors: Yuko
authors: Y
authors: Seino
authors: Atsushi
authors: A
authors: Arakawa
authors: Mitsue
authors: M
authors: Saito
authors: Fujio
authors: F
authors: Kasumi
authors: Shin-ichi
authors: S
authors: Hayashi
authors: Yuri
authors: Y
authors: Yamaguchi
mesh_terms: D000107:Acetylation; D000972:Antineoplastic Agents, Phytogenic / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D047628:Estrogen Receptor alpha / Q000235:genetics* / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D020360:Neoadjuvant Therapy; D017239:Paclitaxel / Q000627:therapeutic use*; D014158:Transcription, Genetic; D016896:Treatment Outcome; D014404:Tubulin / Q000378:metabolism
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D047628:Estrogen Receptor alpha; D014404:Tubulin; C433811:HDAC6 protein, human; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases; D017239:Paclitaxel