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

Abstract

In contrast to the well-established role of estrogen receptor alpha (ERα) in breast cancer, the significance of estrogen receptor beta (ERβ) remains controversial, especially in triple-negative breast cancer (TNBC). We sought to investigate the clinical importance of wild-type ERβ (ERβ1) 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 ERβ1, pAKT, PTEN, pERK, β-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 ERβ1 was detected in 30.4% of tumor samples. Patients with ERβ1 tended to be postmenopausal, and less likely to develop lymphatic metastasis. Multivariate analysis demonstrated that ERβ1 predicted a better OS, DFS, and DMFS independently. Regarding other biomarkers, only pAKT was identified as an independent negative predictor for survival. Additionally, ERβ1 expression was inversely associated with pAKT and the loss of PTEN. Notably, further survival analysis according to status of ERβ1/pAKT indicated that ERβ1(+)/pAKT(-) predicted the most favorable prognosis for TNBC. On the contrary, ERβ1(-)/pAKT(+) was associated with the worst outcomes. In summary, our findings indicate that ERβ1 independently predicts a better prognosis for TNBC and potentially interacts with the PTEN/PI3K/pAKT pathway. The role of ERβ1-specific agonists combined with the inhibitors of pAKT merits further investigation.

High Estrogen Receptor β Expression Is Prognostic among Adjuvant Chemotherapy–Treated Patients—Results from a Population-Based Breast Cancer Cohort

“…Our results regarding chemotherapy were in accordance with the recent study by Wang and colleagues, in which high ERb1 tumor expression was an independent prognostic marker for chemotherapy-treated patients with TNBC tumors without endocrine treatment or trastuzumab (16). The finding was also supported by a neoadjuvant study, in which high pretreatment ERb expression was associated with lower proliferation rates and better pathologic response in the posttreatment samples (38).…”

“…In the current study, we tried to address the above-mentioned issues by choosing a cutoff for which we could observe both associations with established clinicopathological characteristics and prognostic impact, as has been done previously (14,16,48). The recent meta-analysis reported ERb1 þ of 67% across studies, in spite of varying cut-off point definitions (11), and we reported ERb1 75 þ of 73%.…”

“…The cutoffs used to define positivity have been described in many ways, including not defined, as "distinct nuclear staining" (32), or more commonly defined as >10% of positively stained nuclei (14,34,35). Also, scoring systems based on combinations of fraction and intensity have been commonly applied (16,33,(46)(47)(48). Higher cutoffs, such as >20% (12,46,49,50) or higher (33,34,36), have also been applied.…”

“…However, the patients with ERa þ breast tumors with low, but not with high, ERb1 expression had a survival benefit from the switch from tamoxifen to exemestane (15). Furthermore, Wang and colleagues showed that high tumor ERb1 expression was an independent prognostic marker for DFS and OS in a large retrospective series of triple-negative breast cancer (TNBC) patients and proposed specific ERb agonists as a potential addition to chemotherapy for these patients (16). The ERb agonist S-equol is currently being evaluated in a presurgical setting for TNBC patients in a phase 0 clinical trial (ClinicalTrials.…”

Estrogen Receptor β in Melanoma: From Molecular Insights to Potential Clinical Utility

“…In agreement with our data, ERβ ligands have been previously shown to exert their antitumor effects through inactivation of RAS as well as of the PI3K/Akt pathway in some cancer cells (94, 141, 142). Moreover, Wang and coworkers (143) have recently reported an inverse correlation between the expression of ERβ and the activity of the PI3K/Akt pathway in aggressive, triple-negative, breast cancer. Chen et al (141) demonstrated that, in breast cancer cells, the isoflavone calycosin activates ERβ, and this is followed by a decreased activity of the PI3K/Akt pathway; on the other hand, calycosin did not affect the activity of the MAPK/ERK cascade.…”