ERβ1 inhibits metastasis of androgen receptor-positive triple-negative breast cancer by suppressing ZEB1

Background: Increasing evidence has indicated an important role for estrogen receptor beta 1 (ER beta 1) in breast cancer. However, the role of ER beta 1 in the metastasis of androgen receptor (AR)-positive triple-negative breast cancer (TNBC) and the underlying mechanisms are still unknown. Methods: Stable ER beta 1-expressing TNBC cell lines were generated for this study. We detected the abilities of cell migration and invasion by wound-healing and transwell assays and the expression of E-cadherin and N-cadherin by quantitative RT-PCR (qRT-PCR) and western blotting assays in TNBC cell lines. Chromatin immunoprecipitation (ChIP) analysis was performed to assess the effect of AR on ER beta 1 promoter. Tumor metastasis was evaluated in vivo using a lung metastasis mouse model. Lastly, immunohistochemical expression of ER beta 1 in TNBC tissues was analyzed and correlated with clinicopathological features. Results: ER beta 1 suppressed the invasion and migration abilities of AR-positive TNBC cells and induced the downregulation of ZEB1. ZEB1 overexpression abrogated the increase in E-cadherin expression and the decrease in N-cadherin expression modulated by ER beta 1. A lung metastasis mouse model showed that the incidence of metastasis was lower in ER beta 1-expressing TNBC cells. Further, AR activation increased the anti-metastatic effect of ER beta 1 in AR-positive TNBC cells, which accelerated ER beta 1 transcription by functioning as a transcription factor that bound to the promoter of ER beta 1. No significant change was observed in AR expression induced by ER beta 1. Immunohistochemistry (IHC) analysis of TNBC clinical samples showed that ER beta 1 and AR were positive in 31. 7% and 23.2% of samples, respectively. ER beta 1 expression was negatively correlated with ZEB1 expression and lymph node metastasis, and positively correlated with the expression of AR and E-cadherin. Conclusion: Our findings suggested a potential role of ER beta 1 in metastasis of AR-positive TNBC and provided novel insights into the mechanism of action of ER beta 1 and the possible relationship between ER beta 1 and AR.