title: MiRNA-155 mediates TAM resistance by modulating SOCS6-STAT3 signalling pathway in breast cancer.
abstract: Breast cancer is the second leading cause of cancer induced death in women. Tamoxifen is an endocrine therapy which is administered to 70% of all breast cancer patients with estrogen receptor alpha (ERα) expression. Despite the initial response, most patients eventually acquire resistance to the drug. MicroRNAs (miRNAs) are a class of small non-coding RNAs which have the ability to post-transcriptionally regulate gene expression. Although the role of a few miRNAs has been described in tamoxifen resistance, little is known about how concerted actions of miRNAs targeting biological networks contribute to its resistance. In this study, we identified that miR-155 is frequently up-regulated in breast cancer with tamoxifen resistance. Ectopic expression of miR-155 induces cell survival and resistance to TAM, whereas inhibition of miR-155 causes cells to apoptosis and enhances TAM sensitivity. Further, we identified SOCS6 as a new direct target of miR-155. Sustained overexpression of miR-155 resulted in repression of SOCS6 protein and mRNA levels, and knockdown of miR-155 increased SOCS6 expression. Introduction of SOCS6 cDNA lacking the 3'-UTR abrogated miR-155-induced cell survival and chemoresistance. Finally, it was verified that SOCS6 or inhibition of STAT3 could inhibit miR-155 STAT3 activation and cell proliferation. In conclusion, our study reveals a molecular link between miR-155 and SOCS6-STAT3 and presents an evidence that miR-155 is a critical therapeutic target in breast cancer.
authors.affiliation: Department of Chemotherapy, Shandong Provincial Hospital Affiliated to Shandong University Jinan 250021, China.
authors.forename: Rong
authors.initials: R
authors.lastname: Shen
authors.affiliation: Department of Radiotherapy, Shandong Provincial Hospital Affiliated to Shandong University Jinan 250021, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Chemotherapy, Shandong Provincial Hospital Affiliated to Shandong University Jinan 250021, China.
authors.forename: Cai-Xia
authors.initials: CX
authors.lastname: Wang
authors.affiliation: College of Life Science, Shandong Normal University Jinan 250014, China.
authors.forename: Miao
authors.initials: M
authors.lastname: Yin
authors.affiliation: Duke Cancer Institute, Duke University Medical Center Durham, North Carolina, NC 27710, USA.
authors.forename: Hong-Liang
authors.initials: HL
authors.lastname: Liu
authors.affiliation: Department of Chemotherapy, Shandong Provincial Hospital Affiliated to Shandong University Jinan 250021, China.
authors.forename: Jian-Peng
authors.initials: JP
authors.lastname: Chen
authors.affiliation: Department of Radiotherapy, Shandong Provincial Hospital Affiliated to Shandong University Jinan 250021, China.
authors.forename: Jun-Qing
authors.initials: JQ
authors.lastname: Han
authors.affiliation: Department of Chemotherapy, Shandong Provincial Hospital Affiliated to Shandong University Jinan 250021, China.
authors.forename: Wei-Bo
authors.initials: WB
authors.lastname: Wang
keywords: SOCS6; STAT3; breast cancer; miR-155; tamoxifen resistance