Role of microRNA221 in regulating normal mammary epithelial hierarchy and breast cancer stem-like cells
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Jia Ke1,*, Zhiju Zhao2,*, Su-Hyung Hong3, Shoumin Bai4, Zhen He1, Fayaz Malik5, Jiahui Xu2, Lei Zhou2, Weilong Chen2, Rachel Martin-Trevino5, Xiaojian Wu1, Ping Lan1, Yongju Yi6, Christophe Ginestier7, Ingrid Ibarra8, Li Shang5, Sean McDermott5, Tahra Luther5, Shawn G. Clouthier5, Max S. Wicha5, Suling Liu2
1Department of Colorectal Surgery, Sixth Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
2Innovation Center for Cell Biology and The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences and Medical Center, University of Science & Technology of China, Hefei, Anhui, China
3Department of Oral Microbiology, School of Dentistry Kyungpook National University, Jung-gu, Daegu, South Korea
4Department of Oncology, Sun Yat-Sen Memorial Hospital, Sun-Yat-Sen University, Guangzhou, China
5Comprehensive Cancer Center, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA
6Network Information Center, Sixth Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
7Centre de Recherche en Cancérologie de Marseille, Laboratoire d'Oncologie Moléculaire, UMR891 Inserm/Institut Paoli-Calmettes, Université de la Méditerranée, Marseille, France
8Cold Spring Harbor Laboratory, Program in Genetics and Bioinformatics, Cold Spring Harbor, NY, USA
*These authors have contributed equally to this work
Suling Liu, e-mail: [email protected]
Max S. Wicha, e-mail: [email protected]
Jia Ke, e-mail: [email protected]
Keywords: miR-221, breast stem-like cells, differentiation, hierarchy
Received: September 10, 2014 Accepted: December 09, 2014 Published: February 17, 2015
Increasing evidence suggests that lineage specific subpopulations and stem-like cells exist in normal and malignant breast tissues. Epigenetic mechanisms maintaining this hierarchical homeostasis remain to be investigated. In this study, we found the level of microRNA221 (miR-221) was higher in stem-like and myoepithelial cells than in luminal cells isolated from normal and malignant breast tissue. In normal breast cells, over-expression of miR-221 generated more myoepithelial cells whereas knock-down of miR-221 increased luminal cells. Over-expression of miR-221 stimulated stem-like cells in luminal type of cancer and the miR-221 level was correlated with clinical outcome in breast cancer patients. Epithelial-mesenchymal transition (EMT) was induced by overexpression of miR-221 in normal and breast cancer cells. The EMT related gene ATXN1 was found to be a miR-221 target gene regulating breast cell hierarchy. In conclusion, we propose that miR-221 contributes to lineage homeostasis of normal and malignant breast epithelium.
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