Enhanced expression of retinoic acid receptor alpha (RARA) induces epithelial-to-mesenchymal transition and disruption of mammary acinar structures

Ayano Doi; Kosuke Ishikawa; Nao Shibata; Emi Ito; Jiro Fujimoto; Mizuki Yamamoto; Hatsuki Shiga; Hiromi Mochizuki; Yoshifumi Kawamura; Naoki Goshima; Kentaro Semba; Shinya Watanabe

doi:10.1016/j.molonc.2014.09.005

Enhanced expression of retinoic acid receptor alpha (RARA) induces epithelial-to-mesenchymal transition and disruption of mammary acinar structures

Mol Oncol. 2015 Feb;9(2):355-64. doi: 10.1016/j.molonc.2014.09.005. Epub 2014 Sep 22.

Authors

Affiliations

¹ Department of Life Science and Medical Bioscience, School of Advanced Science and Engineering, Waseda University, 2-2 Wakamatsu-cho, Shinjuku-ku, Tokyo 162-8480, Japan. Electronic address: ad0i_i0da@yahoo.co.jp.
² Department of Life Science and Medical Bioscience, School of Advanced Science and Engineering, Waseda University, 2-2 Wakamatsu-cho, Shinjuku-ku, Tokyo 162-8480, Japan; Japan Biological Informatics Consortium (JBiC), 2-45 Aomi, Koto-ku, Tokyo 135-8073, Japan. Electronic address: IshikawaKosuke@gmail.com.
³ Department of Life Science and Medical Bioscience, School of Advanced Science and Engineering, Waseda University, 2-2 Wakamatsu-cho, Shinjuku-ku, Tokyo 162-8480, Japan.
⁴ Division of Gene Expression Analysis, Translational Research Center (Tokyo Branch), Fukushima Medical University, Shibuya-ku, Tokyo 151-0051, Japan.
⁵ Department of Life Science and Medical Bioscience, School of Advanced Science and Engineering, Waseda University, 2-2 Wakamatsu-cho, Shinjuku-ku, Tokyo 162-8480, Japan; Japan Biological Informatics Consortium (JBiC), 2-45 Aomi, Koto-ku, Tokyo 135-8073, Japan.
⁶ Japan Biological Informatics Consortium (JBiC), 2-45 Aomi, Koto-ku, Tokyo 135-8073, Japan.
⁷ Quantitative Proteomics Team, Molecular Profiling Research Center for Drug Discovery (molprof), National Institute of Advanced Industrial Science and Technology (AIST), 2-4-7 Aomi, Koto-ku, Tokyo 135-0064, Japan.
⁸ Department of Life Science and Medical Bioscience, School of Advanced Science and Engineering, Waseda University, 2-2 Wakamatsu-cho, Shinjuku-ku, Tokyo 162-8480, Japan; Division of Gene Function Analysis, Translational Research Center, Fukushima Medical University, 1 Hikarigaoka, Fukushima-city, Fukushima 960-1295, Japan. Electronic address: ksemba@waseda.jp.

Abstract

The early steps of mammary tumorigenesis include loss of epithelial cell polarity, escape from anoikis, and acquisition of proliferative capacity. The genes responsible for these processes are predicted to be early diagnostic markers or new therapeutic targets. Here we tested 51 genes coamplified with ERBB2 in the 17q12-21 amplicon for these tumorigenic activities using an MCF10A 3D culture-based screening system. We found that overexpression of retinoic acid receptor α (RARA) disrupted normal acinar structure and induced epithelial-to-mesenchymal transition (EMT). The mRNA levels of known EMT-inducing factors, including SLUG, FOXC2, ZEB1, and ZEB2, were significantly increased upon RARA overexpression. Knockdown of ZEB1 suppressed the RARA-mediated EMT phenotype. These results suggest that overexpression of RARA enhances malignant transformation during mammary tumorigenesis.

Keywords: 3D culture; Breast cancer; EMT; ERBB2; Gene amplification; RARA.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Breast Neoplasms / genetics
Breast Neoplasms / metabolism*
Breast Neoplasms / pathology
Cell Line, Tumor
Cell Transformation, Neoplastic / genetics
Cell Transformation, Neoplastic / metabolism*
Cell Transformation, Neoplastic / pathology
Epithelial-Mesenchymal Transition*
Female
Gene Expression Regulation, Neoplastic
Humans
Mammary Glands, Human / metabolism*
Mammary Glands, Human / pathology
Neoplasm Proteins / biosynthesis*
Neoplasm Proteins / genetics
Receptors, Retinoic Acid / biosynthesis*
Receptors, Retinoic Acid / genetics
Retinoic Acid Receptor alpha

Substances

Neoplasm Proteins
RARA protein, human
Receptors, Retinoic Acid
Retinoic Acid Receptor alpha