title: Enhanced expression of retinoic acid receptor alpha (RARA) induces epithelial-to-mesenchymal transition and disruption of mammary acinar structures.
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.
authors.affiliation: 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.
authors.forename: Ayano
authors.initials: A
authors.lastname: Doi
authors.affiliation: 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.
authors.forename: Kosuke
authors.initials: K
authors.lastname: Ishikawa
authors.affiliation: 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.
authors.forename: Nao
authors.initials: N
authors.lastname: Shibata
authors.affiliation: Division of Gene Expression Analysis, Translational Research Center (Tokyo Branch), Fukushima Medical University, Shibuya-ku, Tokyo 151-0051, Japan.
authors.forename: Emi
authors.initials: E
authors.lastname: Ito
authors.affiliation: 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.
authors.forename: Jiro
authors.initials: J
authors.lastname: Fujimoto
authors.affiliation: 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.
authors.forename: Mizuki
authors.initials: M
authors.lastname: Yamamoto
authors.affiliation: Japan Biological Informatics Consortium (JBiC), 2-45 Aomi, Koto-ku, Tokyo 135-8073, Japan.
authors.forename: Hatsuki
authors.initials: H
authors.lastname: Shiga
authors.affiliation: Japan Biological Informatics Consortium (JBiC), 2-45 Aomi, Koto-ku, Tokyo 135-8073, Japan.
authors.forename: Hiromi
authors.initials: H
authors.lastname: Mochizuki
authors.affiliation: Japan Biological Informatics Consortium (JBiC), 2-45 Aomi, Koto-ku, Tokyo 135-8073, Japan.
authors.forename: Yoshifumi
authors.initials: Y
authors.lastname: Kawamura
authors.affiliation: 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.
authors.forename: Naoki
authors.initials: N
authors.lastname: Goshima
authors.affiliation: 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.
authors.forename: Kentaro
authors.initials: K
authors.lastname: Semba
authors.affiliation: Division of Gene Expression Analysis, Translational Research Center (Tokyo Branch), Fukushima Medical University, Shibuya-ku, Tokyo 151-0051, Japan.
authors.forename: Shinya
authors.initials: S
authors.lastname: Watanabe
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D042361:Mammary Glands, Human / Q000378:metabolism* / Q000473:pathology; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000235:genetics; D018168:Receptors, Retinoic Acid / Q000096:biosynthesis* / Q000235:genetics; D000072482:Retinoic Acid Receptor alpha
chemical_list: D009363:Neoplasm Proteins; C000607071:RARA protein, human; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha
keywords: 3D culture; Breast cancer; EMT; ERBB2; Gene amplification; RARA