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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]

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