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The impact of interactions between the two estrogen receptor (ER) subtypes, ERα and ERβ, on gene expression in breast cancer biology is not clear. The goal of this study was to examine transcriptomic alterations in cancer cells co-expressing both receptors and the association of gene expression signatures with disease outcome.    Methods  Transcriptional effects of ERβ overexpression were determined in a stably transfected cell line derived from ERα-positive T-47D cells. Microarray analysis was carried out to identify differential gene expression in the cell line, and expression of key genes was validated by quantitative polymerase chain reaction. Microarray and clinical data from patient samples were then assessed to determine the  in vivo  relevance of the expression profiles observed in the cell line.    Results  A subset of 14 DNA replication and cell cycle-related genes was found to be specifically downregulated by ERβ. Expression profiles of four genes,  CDC2 ,  CDC6 ,  CKS2 , and  DNA2L , were significantly inversely correlated with ERβ transcript levels in patient samples, consistent with  in vitro  observations. Kaplan-Meier analysis revealed better disease outcome for the patient group with an expression signature linked to higher ERβ expression as compared to the lower ERβ-expressing group for both disease-free survival ( p  = 0.00165) and disease-specific survival ( p  = 0.0268). These findings were further validated in an independent cohort.    Conclusion  Our findings revealed a transcriptionally regulated mechanism for the previously described growth inhibitory effects of ERβ in ERα-positive breast tumor cells and provide evidence for a functional and beneficial impact of ERβ in primary breast tumors.

breast cancer research

Inhibitory effects of estrogen receptor beta on specific hormone-responsive gene expression and association with disease outcome in primary breast cancer