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Estrogen receptor ?2 induces proliferation and invasiveness of triple negative breast cancer cells: association with regulation of PHD3 and HIF-1?.

ABSTRACT: The two estrogen receptor (ER) subtypes, ER? and ER?, belong to the nuclear receptor superfamily. The human ER? variant ER?2 is proposed to be expressed at higher levels than ER?1 in many breast tumors and it has been suggested that ER?2, in contrast to ER?1, is associated with aggressive phenotypes of various cancers. However, the role of endogenous ER?2 in breast cancer cells remains elusive. In this study, we identified that triple negative breast cancer (TNBC) cell lines express endogenous ER?2, but not ER? or ER?1. This allows novel studies of endogenous ER?2 functions independent of ER? and ER?1. We show that overexpression of ER?2 in TNBC cells increased whereas knockdown of endogenous ER?2 decreased cell proliferation and cell invasion. To elucidate the molecular mechanism responsible for these cellular phenotypes, we assayed ER?2 dependent global gene expression profiles. We show that ER?2 decreases prolyl hydroxylase 3 (PHD3) gene expression and further show that this is associated with increased hypoxia inducible factor 1? (HIF-1?) protein levels, thus providing a possible mechanism for the invasive phenotype. These results are further supported by analysing the expression of ER?2 and PHD3 in breast tumor samples where a negative correlation between ER?2 and PHD3 expression was observed. Together, we demonstrate that ER?2 has an important role in enhancing cell proliferation and invasion, beyond modulation of ER? and ER?1 signalling which might contribute to the invasive characteristics of TNBC. The invasive phenotype could potentially be mediated through transcriptional repression of PHD3 and increased HIF-1? protein levels.

SUBMITTER: Bialesova L

PROVIDER: S-EPMC5652730 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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Estrogen receptor β2 induces proliferation and invasiveness of triple negative breast cancer cells: association with regulation of PHD3 and HIF-1α.

Bialesova Lucia L Xu Li L Gustafsson Jan-Åke JÅ Haldosen Lars-Arne LA Zhao Chunyan C Dahlman-Wright Karin K

Oncotarget 20170904 44

The two estrogen receptor (ER) subtypes, ERα and ERβ, belong to the nuclear receptor superfamily. The human ERβ variant ERβ2 is proposed to be expressed at higher levels than ERβ1 in many breast tumors and it has been suggested that ERβ2, in contrast to ERβ1, is associated with aggressive phenotypes of various cancers. However, the role of endogenous ERβ2 in breast cancer cells remains elusive. In this study, we identified that triple negative breast cancer (TNBC) cell lines express endogenous E ...[more]

PMID: 29100336

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Project description:Triple-negative breast cancer (TNBC) is an aggressive clinical subtype of breast cancer that is characterized by the lack of estrogen receptor (ER) and progesterone receptor (PR) expression as well as human epidermal growth factor receptor 2 (HER2) overexpression. The TNBC subtype constitutes approximately 10%-20% of all breast cancers, but has no effective molecular targeted therapies. Previous meta-analysis of gene expression profiles of 587 TNBC cases from 21 studies demonstrated high expression of Wnt signaling pathway-associated genes in basal-like 2 and mesenchymal subtypes of TNBC. In this study, we investigated the potential of Wnt pathway inhibitors in effective treatment of TNBC.Activation of Wnt pathway was assessed in four TNBC cell lines (BT-549, MDA-MB-231, HCC-1143 and HCC-1937), and the ER+ cell line MCF-7 using confocal microscopy and Western blot analysis of pathway components. Effectiveness of five different Wnt pathway inhibitors (iCRT-3, iCRT-5, iCRT-14, IWP-4 and XAV-939) on cell proliferation and apoptosis were tested in vitro. The inhibitory effects of iCRT-3 on canonical Wnt signaling in TNBC was evaluated by quantitative real-time RT-PCR analysis of Axin2 and dual-luciferase reporter assays. The effects of shRNA knockdown of SOX4 in combination with iCRT-3 and/or genistein treatments on cell proliferation, migration and invasion on BT-549 cells were also evaluated.Immunofluorescence staining of ?-catenin in TNBC cell lines showed both nuclear and cytoplasmic localization, indicating activation of Wnt pathway in TNBC cells. iCRT-3 was the most effective compound for inhibiting proliferation and antagonizing Wnt signaling in TNBC cells. In addition, treatment with iCRT-3 resulted in increased apoptosis in vitro. Knockdown of the Wnt pathway transcription factor, SOX4 in triple negative BT-549 cells resulted in decreased cell proliferation and migration, and combination treatment of iCRT-3 with SOX4 knockdown had a synergistic effect on inhibition of cell proliferation and induction of apoptosis.These data suggest that targeting SOX4 and/or the Wnt pathway could have therapeutic benefit for TNBC patients.

Dataset Information

Estrogen receptor ?2 induces proliferation and invasiveness of triple negative breast cancer cells: association with regulation of PHD3 and HIF-1?.

Publications

Estrogen receptor β2 induces proliferation and invasiveness of triple negative breast cancer cells: association with regulation of PHD3 and HIF-1α.

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