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

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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.

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Acknowledgments

We thank all staff members of the Department of Breast Oncology, including physicians, nurses, and sonography technicians, at Juntendo University Hospital for their valuable suggestions and generous cooperation. We also thank Dr. Shigehira Saji at Kyoto University for his valuable advice, and are especially grateful to Akiyo Yamashita and Dr. Tetsuji Suda at Saitama Cancer Center and Makiko Hirose at Tokyo Metropolitan Komagome Hospital for their excellent technical assistance. This study was supported in part by a Grant-in-Aid for Scientific Research from the Ministry of Education, Science, Sports, and Culture, Japan; a Grant-in Aid for Cancer Research from the Ministry of Health, Labor, and Welfare, Japan; the Program for Promotion of Fundamental Studies in Health Science of the National Institute of Biomedical Innovation (NIBIO); and a grant from the Smoking Research Foundation.

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Authors and Affiliations

  1. Department of Breast and Endocrine Surgery, Graduate School of Medicine, Juntendo University, Tokyo, Japan

    Emi Tokuda, Mitsue Saito & Fujio Kasumi

  2. Research Institute for Clinical Oncology, Saitama Cancer Center, 818 Komuro, Ina-machi, Saitama-ken, 362-0806, Japan

    Emi Tokuda, Yuko Seino & Yuri Yamaguchi

  3. Center for Regulatory Epigenome and Diseases, Department of Molecular and Functional Dynamics, Graduate School of Medicine, Tohoku University, Sendai, Japan

    Yuko Seino & Shin-ichi Hayashi

  4. Department of Human Pathology, Juntendo University Hospital, Tokyo, Japan

    Atsushi Arakawa

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  1. Emi Tokuda
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  2. Yuko Seino
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  3. Atsushi Arakawa
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  4. Mitsue Saito
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  5. Fujio Kasumi
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  6. Shin-ichi Hayashi
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  7. Yuri Yamaguchi
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Correspondence to Yuri Yamaguchi.

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Tokuda, E., Seino, Y., Arakawa, A. et al. Estrogen receptor-α directly regulates sensitivity to paclitaxel in neoadjuvant chemotherapy for breast cancer. Breast Cancer Res Treat 133, 427–436 (2012). https://doi.org/10.1007/s10549-011-1758-x

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  • DOI: https://doi.org/10.1007/s10549-011-1758-x

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