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
MeSH 主题词
Breast Neoplasms/genetics,metabolism,pathology
Cell Line, Tumor
Cell Transformation, Neoplastic/genetics,metabolism,pathology
Epithelial-Mesenchymal Transition
Female
Gene Expression Regulation, Neoplastic
Humans
Mammary Glands, Human/metabolism,pathology
Neoplasm Proteins/biosynthesis,genetics
Receptors, Retinoic Acid/biosynthesis,genetics
Retinoic Acid Receptor alpha
化学物质
Neoplasm Proteins
RARA protein, human
Receptors, Retinoic Acid
Retinoic Acid Receptor alpha
作者与单位
共 12 位作者，点击展开单位 / ORCID
Doi Ayano
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:
[email protected].
Ishikawa Kosuke
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:
[email protected].
Shibata Nao
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.
Ito Emi
Division of Gene Expression Analysis, Translational Research Center (Tokyo Branch), Fukushima Medical University, Shibuya-ku, Tokyo 151-0051, Japan.
Fujimoto Jiro
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.
Yamamoto Mizuki
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.
Shiga Hatsuki
Japan Biological Informatics Consortium (JBiC), 2-45 Aomi, Koto-ku, Tokyo 135-8073, Japan.
Mochizuki Hiromi
Japan Biological Informatics Consortium (JBiC), 2-45 Aomi, Koto-ku, Tokyo 135-8073, Japan.
Kawamura Yoshifumi
Japan Biological Informatics Consortium (JBiC), 2-45 Aomi, Koto-ku, Tokyo 135-8073, Japan.
Goshima Naoki
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.
Semba Kentaro
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:
[email protected].
Watanabe Shinya
Division of Gene Expression Analysis, Translational Research Center (Tokyo Branch), Fukushima Medical University, Shibuya-ku, Tokyo 151-0051, Japan.
