title: Estrogen regulates miRNA expression: implication of estrogen receptor and miR-124/AKT2 in tumor growth and angiogenesis.
abstract: It is currently known that estrogen plays an important role in breast cancer (BC) development, but the underlying molecular mechanism remains to be elucidated. Accumulating evidence has revealed important roles of microRNAs in various kinds of human cancers, including BC. In this study, we found that among the microRNAs regulated by estrogen, miR-124 was the most prominent downregulated miRNA. miR-124 was downregulated by estradiol (E2) treatment in estrogen receptor (ER) positive BC cells, miR-124 overexpression suppressed cell proliferation, migration and invasion in BC cells; while the suppression of miR-124 using Anti-miR-124 inhibitor had opposite cellular functions. Under the E2 treatment, miR-124 had stronger effect to inhibit cellular functions in MCF7 cells than that in MDA-MB-231 cells. In addition, we identified that ERα, but not ERβ, was required for E2-induced miR-124 downregulation. Furthermore, AKT2, a known oncogene, was a novel direct target of miR-124. AKT2 expression levels were inversely correlated with miR-124 expression levels in human breast cancer specimens. AKT2 was overexpressed in BC specimens, and its expression levels were much higher in ERα positive cancer tissues than those ERα negative cancer tissues. Consistent with miR-124 suppression, E2 treatment increased AKT2 expression levels in MCF7 cells via ERα. Finally, overexpression of miR-124 in MCF7 cells significantly suppressed tumor growth and angiogenesis by targeting AKT2. Our results provide a mechanistic insight into a functional role of new ERα/miR-124/AKT2 signaling pathway in BC development. miR-124 and AKT2 may be used as biomarkers for ERα positive BC and therapeutic effect in the future.
authors.affiliation: State Key Laboratory of Reproductive Medicine, Department of Pathology, Nanjing Medical University, Nanjing, China.
authors.forename: Cheng-Fei
authors.initials: CF
authors.lastname: Jiang
authors.affiliation: State Key Laboratory of Reproductive Medicine, Department of Pathology, Nanjing Medical University, Nanjing, China.
authors.forename: Dong-Mei
authors.initials: DM
authors.lastname: Li
authors.affiliation: State Key Laboratory of Reproductive Medicine, Department of Pathology, Nanjing Medical University, Nanjing, China.|Department of Neurosurgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
authors.forename: Zhu-Mei
authors.initials: ZM
authors.lastname: Shi
authors.affiliation: State Key Laboratory of Reproductive Medicine, Department of Pathology, Nanjing Medical University, Nanjing, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Wang
authors.affiliation: Huai'an First People's Hospital, Nanjing Medical University, Huai'an, China.
authors.forename: Min-Min
authors.initials: MM
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Reproductive Medicine, Department of Pathology, Nanjing Medical University, Nanjing, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Ge
authors.affiliation: State Key Laboratory of Reproductive Medicine, Department of Pathology, Nanjing Medical University, Nanjing, China.
authors.forename: Xue
authors.initials: X
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Reproductive Medicine, Department of Pathology, Nanjing Medical University, Nanjing, China.
authors.forename: Ying-Chen
authors.initials: YC
authors.lastname: Qian
authors.affiliation: State Key Laboratory of Reproductive Medicine, Department of Pathology, Nanjing Medical University, Nanjing, China.
authors.forename: Yi-Yang
authors.initials: YY
authors.lastname: Wen
authors.affiliation: Huai'an First People's Hospital, Nanjing Medical University, Huai'an, China.
authors.forename: Lin-Lin
authors.initials: LL
authors.lastname: Zhen
authors.affiliation: Faculty of Software, Fujian Normal University, Fuzhou, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Lin
authors.affiliation: Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA, USA.
authors.forename: Ling-Zhi
authors.initials: LZ
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Reproductive Medicine, Department of Pathology, Nanjing Medical University, Nanjing, China.|Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA, USA.
authors.forename: Bing-Hua
authors.initials: BH
authors.lastname: Jiang
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000473:pathology*; D002465:Cell Movement / Q000235:genetics; D004958:Estradiol / Q000378:metabolism* / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D064593:Heterografts; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009361:Neoplasm Invasiveness / Q000235:genetics; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*
chemical_list: D047628:Estrogen Receptor alpha; C509207:MIRN124 microRNA, human; D035683:MicroRNAs; D004958:Estradiol; C494921:AKT2 protein, human; D051057:Proto-Oncogene Proteins c-akt
keywords: AKT2; breast cancer; estrogen; estrogen receptors; miR-124