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Crosstalk between integrin ?v?3 and ER? 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 ?v?3 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 ?v or ?3 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 ? (ER?). Confocal microscopy indicated that both T4 and estradiol (E2) caused nuclear translocation of integrin ?v and phosphorylation of ER?. The specific ER? antagonist (ICI 182,780; fulvestrant) blocked T4-induced ERK1/2 activation, ER? phosphorylation, PCNA expression and proliferation. The nuclear co-localization of integrin ?v and phosphorylated ER? was inhibited by ICI. ICI time-course studies indicated that mechanisms involved in T4- and E2-induced nuclear co-localization of phosphorylated ER? and integrin ?v are dissimilar. Chromatin immunoprecipitation results showed that T4-induced binding of integrin ?v monomer to ER? promoter and this was reduced by ICI. In summary, thyroid hormone stimulates proliferation of ovarian cancer cells via crosstalk between integrin ?v and ER?, mimicking functions of E2.

SUBMITTER: Hsieh MT

PROVIDER: S-EPMC5421843 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature

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Crosstalk between integrin αvβ3 and ERα contributes to thyroid hormone-induced proliferation of ovarian cancer cells.

Hsieh Meng-Ti MT Wang Le-Ming LM Changou Chun A CA Chin Yu-Tang YT Yang Yu-Chen S H YSH Lai Hsuan-Yu HY Lee Sheng-Yang SY Yang Yung-Ning YN Whang-Peng Jacqueline J Liu Leroy F LF Lin Hung-Yun HY Mousa Shaker A SA Davis Paul J PJ

Oncotarget 20170401 15

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 s ...[more]

PMID: 27458161

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Project description:Background: The constitutively active ESR1 Y537S mutation is associated with endocrine therapy resistance and progression of metastatic breast cancer through its effects on estrogen receptor (ERα) gene regulatory functions. However, the complex relationship between ERα and the progesterone receptor (PR), known as ERα/PR crosstalk, has yet to be characterized in the context of the ERα Y537S mutation. This study aimed to elucidate the effects of the ERα Y537S mutation on ERα/PR crosstalk and resultant transcriptional activity and to identify potential therapeutic sensitivities that may offer novel treatment options to patients with endocrine therapy-resistant breast cancer. Methods: Proximity-based interactions of ERα and PR were assessed via proximity ligation assay (PLA). Gene expression in MCF7 and T47D cells was assessed by RNA-seq analysis with comparison to publicly available patient tumor transcriptome data. Chromatin immunoprecipitation (ChIP)-qPCR and immunoblotting were used to assess ERα/PR-associated gene expression and protein expression, respectively. Data were analyzed by ordinary two-way ANOVA (α = 0.05) with Tukey’s multiple comparisons tests. Results: Physical interaction of ERα and PR was increased in the context of the ERα Y537S mutation, including in the nucleus where this interaction may translate to altered gene expression. As such, more than 30 genes were differentially expressed in both patient tumor and cell line data (MCF7 and/or T47D cells) in the context of the ERα Y537S mutation compared to ERα WT. Of these, IRS1 stood out as a gene of interest, and ERα and PR occupancy at chromatin binding sites along IRS1 were uniquely altered in the context of ERα Y537S. Furthermore, siRNA knockdown of IRS1 or treatment with the IRS1 inhibitor NT-157 indicated a significant anti-proliferative effect of IRS1 depletion or inhibition in ERα Y537S cell lines. Conclusions: Previous research has characterized gene regulatory changes associated with the ERα Y537S mutation from the viewpoint of ERα. Here, we identify consequential changes to both ERα and PR transcription factor activity, including at chromatin binding sites for the signaling adaptor protein IRS1. We identified a significant dependence of ERα Y537S-expressing cells on IRS1 for proliferation, implicating IRS1 as a potential therapeutic target for restoring treatment sensitivity to patients with breast cancers harboring ERα Y537S mutations.

Dataset Information

Crosstalk between integrin ?v?3 and ER? contributes to thyroid hormone-induced proliferation of ovarian cancer cells.

Publications

Crosstalk between integrin αvβ3 and ERα contributes to thyroid hormone-induced proliferation of ovarian cancer cells.

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