Contrasting activities of estrogen receptor beta isoforms in triple negative breast cancer

Purpose Triple negative breast cancer (TNBC), an aggressive subtype of breast cancer, lacks the three major receptors for predicting outcome or targeting therapy. Hence, our aim was to evaluate the potential of estrogen receptor beta (ER beta) as a possible endocrine therapy target in TNBC. Methods The expression and prognostic effect of ER beta isoforms were analyzed using TCGA breast tumor data, and the expression of ER beta isoform mRNA and protein in TNBC cell lines was assayed. Endogenous ER beta 2 and ER beta 5 were knocked down with siRNA, and ER beta 2, ER beta 5, and ER beta 1 were upregulated using a doxycycline-inducible lentiviral system. Cell proliferation, migration and invasion, and specific gene expressions were evaluated. Results ER beta 2 and ER beta 5 were the predominant endogenous forms of ER beta in TNBC tumors and cell lines. High ER beta 2 predicted worse clinical outcome. Knockdown of endogenous ER beta 2/ER beta 5 in cell lines suppressed proliferation, migration and invasion, and downregulated proto-oncogene survivin expression. ER beta 2/ER beta 5 upregulation did the reverse, increasing survivin and these cell activities. ER beta 1 was barely detectable in TNBC cell lines, but its upregulation reduced survivin, increased tumor suppressor expression (E-cadherin and cystatins), and suppressed proliferation, migration and invasion in both ligand-independent and dependent manners, suggesting the possible translational benefit of ER beta ligands. Conclusions ER beta 2/ER beta 5 and ER beta 1 exhibit sharply contrasting activities in TNBC cells. Our findings imply that delineating the absolute amounts and relative ratios of the different ER beta isoforms might have prognostic and therapeutic relevance, and could enable better selection of optimal approaches for treatment of this often aggressive form of breast cancer.

Automated summary

The study revealed that ER beta 2/ER beta 5 and ER beta 1 exhibit contrasting activities in TNBC cells, suggesting that the absolute amounts and relative ratios of different ER beta isoforms may impact prognosis and treatment selection.