title: Anticancer effect of metformin on estrogen receptor-positive and tamoxifen-resistant breast cancer cell lines.
abstract: Acquisition of tamoxifen resistance (TR) during anti-estrogenic therapy using tamoxifen is a major obstacle in the treatment of estrogen receptor (ER)-positive breast cancer. As a biguanide derivative, metformin is commonly used to treat type II diabetes. It has recently emerged as a potential anticancer agent. The objective of the present study was to investigate the anticancer activity of metformin in relation to ERα expression and its signaling pathway in ERα-positive MCF-7 and MDA-MB-361 breast cancer cells as well as TR MCF-7 breast cancer cells. Metformin inhibited both protein and mRNA levels of ERα in the presence or absence of estrogen (E2) in the MCF-7, TR MCF-7 and MDA-MB-361 cells. Metformin repressed E2-inducible estrogen response element (ERE) luciferase activity, protein levels and mRNA levels of E2/ERα-regulated genes [including c-Myc, cyclin D1, progesterone receptor (PR) and pS2] to a greater degree than tamoxifen, resulting in inhibition of cell proliferation of MCF-7, TR MCF-7 and MDA-MB-361 cells. Collectively, our results suggest that one of the anticancer mechanisms of metformin could be attributable to the repression of expression and transcriptional activity of ERα. Metformin may be a good therapeutic agent for treating ERα-positive breast cancer by inhibiting the expression and function of ERα. In addition, metformin may be useful to treat tamoxifen-resistant breast cancer.
authors.affiliation: Department of Pathology, Korea University Guro Hospital, Guro-gu, Seoul 08308, Republic of Korea.
authors.forename: Jinkyoung
authors.initials: J
authors.lastname: Kim
authors.affiliation: Department of Pathology, College of Medicine, Korea University, Seongbuk-gu, Seoul 02841, Republic of Korea.
authors.forename: Jiyun
authors.initials: J
authors.lastname: Lee
authors.affiliation: Department of Pathology, College of Medicine, Korea University, Seongbuk-gu, Seoul 02841, Republic of Korea.
authors.forename: Soon Young
authors.initials: SY
authors.lastname: Jang
authors.affiliation: Department of Pathology, Korea University Guro Hospital, Guro-gu, Seoul 08308, Republic of Korea.
authors.forename: Chungyeul
authors.initials: C
authors.lastname: Kim
authors.affiliation: Department of Pathology, Korea University Guro Hospital, Guro-gu, Seoul 08308, Republic of Korea.
authors.forename: Yoojin
authors.initials: Y
authors.lastname: Choi
authors.affiliation: Department of Pathology, Korea University Guro Hospital, Guro-gu, Seoul 08308, Republic of Korea.
authors.forename: Aeree
authors.initials: A
authors.lastname: Kim
mesh_terms: D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D004958:Estradiol / Q000502:physiology; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D020128:Inhibitory Concentration 50; D061986:MCF-7 Cells; D008687:Metformin / Q000494:pharmacology*; D013629:Tamoxifen / Q000494:pharmacology*; D015533:Transcriptional Activation
chemical_list: D018931:Antineoplastic Agents, Hormonal; C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D013629:Tamoxifen; D004958:Estradiol; D008687:Metformin