title: Anti-cancer effect of metformin by suppressing signaling pathway of HER2 and HER3 in tamoxifen-resistant breast cancer cells.
abstract: Development of new therapeutic strategies is becoming increasingly important to overcome tamoxifen resistance. Recently, much interest has been focused on anti-tumor effects of metformin commonly used to treat type II diabetes. Increased protein expression and signaling of epidermal growth factor receptor (EGFR) family is a possible mechanism involved in tamoxifen resistance. Since HER2/HER3 heterodimers are able to induce strong downstream signaling and activate various biological responses such as cellular proliferation and growth, we investigated the anti-cancer effect of metformin by inhibition of signaling pathway via downregulation of HER2 and HER3 using tamoxifen-resistant MCF-7 (TR MCF-7) cells. Compared to MCF-7 cells, TR MCF-7 cells showed increased expression of EGFR, HER2, and HER3, and metformin inhibited the expression of these proteins in a dose- and time-dependent manner. Metformin inhibited activation of HER2 (Tyr1248)/HER3 (Tyr1289)/Akt (Ser473) as well as cell proliferation and colony formation by estrogenic promotion in MCF-7 and TR MCF-7 cells. Known as a HER3 ligand, heregulin (HRG)-β1-induced phosphorylation of HER2, HER3 and Akt, and protein interaction of HER2/HER3 and colony formation were inhibited by metformin in both cells. Consistent with the results in the two cell lines, we identified that metformin inhibited HER2/HER3/Akt signaling axis activated by HRG-β1 using the HER2 and HER3-overexpressing breast cancer cell line SK-BR-3. Lastly, lapatinib-induced HER3 upregulation was significantly inhibited by treatment of metformin in HER3 siRNA-transfected TR MCF-7 cells. These data suggest that metformin might overcome tamoxifen resistance through the inhibition of expression and signaling of receptor tyrosine kinase HER2 and HER3.
authors.affiliation: Department of Pathology, Korea University Guro Hospital, #148 Gurodong-ro, Guro-gu, Seoul, 152-703, Korea.
authors.forename: Jinkyoung
authors.initials: J
authors.lastname: Kim
authors.affiliation: Department of Pathology, College of Medicine, Korea University, #73 Inchon-ro, Seongbuk-gu, Seoul, 136-705, Korea.
authors.forename: Jiyun
authors.initials: J
authors.lastname: Lee
authors.affiliation: Department of Pathology, Korea University Guro Hospital, #148 Gurodong-ro, Guro-gu, Seoul, 152-703, Korea.
authors.forename: Chungyeul
authors.initials: C
authors.lastname: Kim
authors.affiliation: Department of Pathology, Korea University Guro Hospital, #148 Gurodong-ro, Guro-gu, Seoul, 152-703, Korea.
authors.forename: Jinhyuk
authors.initials: J
authors.lastname: Choi
authors.affiliation: Department of Pathology, Korea University Guro Hospital, #148 Gurodong-ro, Guro-gu, Seoul, 152-703, Korea. ark@korea.ac.kr.
authors.forename: Aeree
authors.initials: A
authors.lastname: Kim
mesh_terms: D000230:Adenocarcinoma / Q000473:pathology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology; D001943:Breast Neoplasms / Q000473:pathology*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects* / Q000235:genetics; D004790:Enzyme Induction / Q000187:drug effects; D066246:ErbB Receptors / Q000096:biosynthesis; D004958:Estradiol / Q000494:pharmacology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D018773:Genes, erbB-1; D018734:Genes, erbB-2; D006801:Humans; D000077341:Lapatinib; D061986:MCF-7 Cells; D008687:Metformin / Q000494:pharmacology*; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D020890:Neuregulin-1 / Q000037:antagonists & inhibitors / Q000502:physiology; D011799:Quinazolines / Q000037:antagonists & inhibitors / Q000494:pharmacology; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D020893:Receptor, ErbB-3 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects*; D013629:Tamoxifen / Q000494:pharmacology*; D014410:Tumor Stem Cell Assay
chemical_list: D000970:Antineoplastic Agents; D018931:Antineoplastic Agents, Hormonal; D066246:ErbB Receptors; D004958:Estradiol; D000077341:Lapatinib; D008687:Metformin; D009363:Neoplasm Proteins; D020890:Neuregulin-1; D011799:Quinazolines; D034741:RNA, Small Interfering; D018719:Erb-b2 Receptor Tyrosine Kinases; D020893:Receptor, ErbB-3; D013629:Tamoxifen; C094131:NRG1 protein, human; C512478:EGFR protein, human; C508053:ERBB2 protein, human; C581292:ERBB3 protein, human
keywords: Breast cancer; HER3; HRG-β1; Metformin; Receptor tyrosine kinase HER2; Tamoxifen resistance