title: Crosstalk between integrin αvβ3 and ERα contributes to thyroid hormone-induced proliferation of ovarian cancer cells.
abstract: Ovarian cancer is the leading cause of death in gynecological diseases. Thyroid hormone promotes proliferation of ovarian cancer cells via cell surface receptor integrin αvβ3 that activates extracellular regulated kinase (ERK1/2). However, the mechanisms are still not fully understood. Thyroxine (T4) at a physiologic total hormone concentration (10-7 M) significantly increased proliferating cell nuclear antigen (PCNA) abundance in these cell lines, as did 3, 5, 3'-triiodo-L-thyronine (T3) at a supraphysiologic concentration. Thyroid hormone (T4 and T3) treatment of human ovarian cancer cells resulted in enhanced activation of the Ras/MAPK(ERK1/2) signal transduction pathway. An MEK inhibitor (PD98059) blocked hormone-induced cell proliferation but not ER phosphorylation. Knock-down of either integrin αv or β3 by RNAi blocked thyroid hormone-induced phosphorylation of ERK1/2. We also found that thyroid hormone causes elevated phosphorylation and nuclear enrichment of estrogen receptor α (ERα). Confocal microscopy indicated that both T4 and estradiol (E2) caused nuclear translocation of integrin αv and phosphorylation of ERα. The specific ERα antagonist (ICI 182,780; fulvestrant) blocked T4-induced ERK1/2 activation, ERα phosphorylation, PCNA expression and proliferation. The nuclear co-localization of integrin αv and phosphorylated ERα was inhibited by ICI. ICI time-course studies indicated that mechanisms involved in T4- and E2-induced nuclear co-localization of phosphorylated ERα and integrin αv are dissimilar. Chromatin immunoprecipitation results showed that T4-induced binding of integrin αv monomer to ERα promoter and this was reduced by ICI. In summary, thyroid hormone stimulates proliferation of ovarian cancer cells via crosstalk between integrin αv and ERα, mimicking functions of E2.
authors.affiliation: Taipei Cancer Center, Taipei Medical University, Taipei, Taiwan.|The PhD Program for Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.
authors.forename: Meng-Ti
authors.initials: MT
authors.lastname: Hsieh
authors.affiliation: Department of Obstetrics and Gynecology, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan.
authors.forename: Le-Ming
authors.initials: LM
authors.lastname: Wang
authors.affiliation: The PhD Program for Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.|Integrated Laboratory, Center of Translational Medicine, Taipei Medical University, Taipei, Taiwan.|Core Facility, Taipei Medical University, Taipei, Taiwan.
authors.forename: Chun A
authors.initials: CA
authors.lastname: Changou
authors.affiliation: Taipei Cancer Center, Taipei Medical University, Taipei, Taiwan.|Department of Dentistry, Wan-Fang Medical Center, Taipei Medical University, Taipei, Taiwan.|School of Dentistry, Taipei Medical University, Taipei, Taiwan.|Center for Teeth Bank and Dental Stem Cell Technology, Taipei Medical University, Taipei, Taiwan.
authors.forename: Yu-Tang
authors.initials: YT
authors.lastname: Chin
authors.affiliation: Joint Biobank, Office of Human Research, Taipei Medical University, Taipei, Taiwan.
authors.forename: Yu-Chen S H
authors.initials: YSH
authors.lastname: Yang
authors.affiliation: Taipei Cancer Center, Taipei Medical University, Taipei, Taiwan.
authors.forename: Hsuan-Yu
authors.initials: HY
authors.lastname: Lai
authors.affiliation: Department of Dentistry, Wan-Fang Medical Center, Taipei Medical University, Taipei, Taiwan.|School of Dentistry, Taipei Medical University, Taipei, Taiwan.|Center for Teeth Bank and Dental Stem Cell Technology, Taipei Medical University, Taipei, Taiwan.
authors.forename: Sheng-Yang
authors.initials: SY
authors.lastname: Lee
authors.affiliation: Department of Pediatrics, E-DA Hospital, I-Shou University, Kaohsiung, Taiwan.
authors.forename: Yung-Ning
authors.initials: YN
authors.lastname: Yang
authors.affiliation: Taipei Cancer Center, Taipei Medical University, Taipei, Taiwan.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Whang-Peng
authors.affiliation: Taipei Cancer Center, Taipei Medical University, Taipei, Taiwan.
authors.forename: Leroy F
authors.initials: LF
authors.lastname: Liu
authors.affiliation: Taipei Cancer Center, Taipei Medical University, Taipei, Taiwan.|The PhD Program for Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.
authors.forename: Hung-Yun
authors.initials: HY
authors.lastname: Lin
authors.affiliation: Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences, Albany, New York, USA.
authors.forename: Shaker A
authors.initials: SA
authors.lastname: Mousa
authors.affiliation: Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences, Albany, New York, USA.|Department of Medicine, Albany Medical College, Albany, New York, USA.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Davis
mesh_terms: D045744:Cell Line, Tumor; D049109:Cell Proliferation; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D005260:Female; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000378:metabolism*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D010051:Ovarian Neoplasms / Q000378:metabolism* / Q000473:pathology; D011485:Protein Binding; D015398:Signal Transduction; D013963:Thyroid Hormones / Q000378:metabolism*
chemical_list: D047628:Estrogen Receptor alpha; D039302:Integrin alphaVbeta3; D013963:Thyroid Hormones; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3
keywords: ERα crosstalk; integrin αvβ3; ovarian cancer; thyroid hormone