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Insights into the proliferation and invasiveness of breast cancer from genome-wide profiling of estrogen receptor beta 2

ABSTRACT: The human ERβ variant, ERβ2, is expressed at higher levels than ERβ1 in many breast cancer cell lines and breast tumours and increasing evidence supports the hypothesis that ERβ2, in contrast to ERβ1, is associated with aggressive phenotypes of various cancers. We identified a breast cancer cell line that expresses endogenous ERβ2, but not ERα or ERβ1, allowing studies of ERβ2 in the absence of other ER isoforms. Importantly, we show that knockdown of endogenous ERβ2 inhibited cell proliferation and cell invasion. To gain insights into the molecular mechanism responsible for these cellular phenotypes, we assayed ERβ2 dependent global gene expression profiles. A total of 263 genes were identified as potentially ERβ2-upregulated genes and 662 as ERβ2-downregulated genes. ERβ2-regulated genes were involved in cell morphology, DNA replication and repair, cell death and survival. Our findings demonstrate that ERβ2 alone has a key role in enhancing cell proliferation and invasion, beyond modulation of ERα and ERβ1 signalling.

ORGANISM(S): Homo sapiens

PROVIDER: GSE57379 | GEO | 2015/05/01

SECONDARY ACCESSION(S): PRJNA246367

REPOSITORIES: GEO

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Project description:The closely related transcription factors (TFs), estrogen receptors ERα and ERβ, regulate divergent gene expression programs and proliferative outcomes in breast cancer. Utilizing MCF-7 breast cancer cells with ERα, ERβ, or both receptors as a model system to define the basis of differing response specification by related TFs, we show that these TFs and their key coregulators, SRC3 and RIP140, generate overlapping as well as unique chromatin-binding and transcription-regulating modules. Cistrome and transcriptome analyses and use of clustering algorithms delineated 11 clusters representing different chromatin-bound receptor and coregulator assemblies that could be functionally associated through enrichment analysis with distinct patterns of gene regulation and preferential coregulator usage, RIP140 with ERβ and SRC3 with ERα. The receptors modified each other’s transcriptional effect, and ERβ countered the proliferative drive of ERα through several novel mechanisms associated with specific binding site clusters. Our findings delineate distinct TF-coregulator assemblies that function as control nodes specifying precise patterns of gene regulation, proliferation, and metabolism, as exemplified by two of the most important nuclear hormone receptors in human breast cancer. MCF-7 cells expressing endogenous ERalpha were infected with adenovirus carrying either estrogen receptor beta (AdERb) or no insert (Ad) at multiplicity of infection (moi) of 50. ERβ only cells were generated from these cells by knockdown of ERα in parental cells using the following siERα sequences from Dharmacon: forward, 5’-UCAUCGCAUUCCUUGCAAAdTdT-3’, and reverse, 5’-UUUGCAAGGAAUGCGAUGAdTdT-3’. siRNA experiments were performed as previously described, and resulted in knocknown of ERα mRNA and protein by greater than 95% (GSE4006, PMID 16809442). Briefly, cells were transfected with 20 nM siCtrl [GSE4006] or siERα for 48 h after infection. Then cells were treated with 0.1% EtOH (Veh) or 10 nM E2 (Sigma-Aldrich) for 24h. All experiments were conducted with two replicates. key words; Adenovirus infection,siRNA knock-down, ligand treatment

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Insights into the proliferation and invasiveness of breast cancer from genome-wide profiling of estrogen receptor beta 2

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