ERβ1 inversely correlates with PTEN/PI3K/AKT pathway and predicts a favorable prognosis in triple-negative breast cancer

In contrast to the well-established role of estrogen receptor alpha (ER alpha) in breast cancer, the significance of estrogen receptor beta (ER beta) remains controversial, especially in triple-negative breast cancer (TNBC). We sought to investigate the clinical importance of wild-type ER beta (ER beta 1) in TNBC based on a large population, and to explore the potential molecular pathways involved in. A total of 571 patients with invasive TNBC undergoing curative surgery were included in this study. Immunohistochemical staining for ER beta 1, pAKT, PTEN, pERK, beta-catenin, EGFR, p53, and E-cadherin was performed on tissue microarrays. Prognostic determinants for overall survival (OS) and disease-free survival (DFS), as well as the risk factors for distant metastasis-free survival (DMFS) and locoregional recurrence-free survival, were evaluated in univariate and multivariate analyses. Overexpression of ER beta 1 was detected in 30.4 % of tumor samples. Patients with ER beta 1 tended to be postmenopausal, and less likely to develop lymphatic metastasis. Multivariate analysis demonstrated that ER beta 1 predicted a better OS, DFS, and DMFS independently. Regarding other biomarkers, only pAKT was identified as an independent negative predictor for survival. Additionally, ER beta 1 expression was inversely associated with pAKT and the loss of PTEN. Notably, further survival analysis according to status of ER beta 1/pAKT indicated that ER beta 1(+)/pAKT(-) predicted the most favorable prognosis for TNBC. On the contrary, ER beta 1(-)/pAKT(+) was associated with the worst outcomes. In summary, our findings indicate that ER beta 1 independently predicts a better prognosis for TNBC and potentially interacts with the PTEN/PI3K/pAKT pathway. The role of ER beta 1-specific agonists combined with the inhibitors of pAKT merits further investigation.