Abstract
The present study aimed to examine the associations between androgen receptor (AR) and forkhead box A1 (FOXA1) and to investigate clinicopathological features and survival according to both biomarker status in estrogen receptor (ER)-positive breast cancers using in vitro study, patient cohort data, and the cBioPortal for Cancer Genomics and Kaplan-Meier Plotter websites. Experiments using T47D and ZR75-1 demonstrated AR-overexpressing cell lines decreased in cell proliferation through downregulation of ER, but FOXA1 did not change. Knockdown of FOXA1 resulted in a significantly reduced cell viability. Patients with immunohistochemically AR(-)/FOXA1(-) tumor frequently showed node metastasis, high grade, and high Ki-67 proliferation, therefore, significantly worse survival in ER-positive disease. AR and FOXA1 mRNA levels were significantly higher in ER-positive than in ER-negative tumors and AR-low/FOXA1-low tumors showed high grade, frequent basal-like subtype and worse disease-free survival in ER-positive cancers of public gene dataset, similarly to patient cohort results. The Kaplan-Meier Plotter analysis independently validated patients with both low AR/FOXA1 tumor were significantly associated with worse relapse-free survival in ER-positive cancers. This study suggests that distinctive clinicopathological features according to AR and FOXA1 are determined and a lack of both biomarkers is an independent poor prognostic factor in ER-positive tumors.
Highlights
Recent attention has focused on the emerging roles of androgen receptor (AR) as a prognostic and predictive factor, and as a therapeutic target in breast cancer patients [1, 2]
The present study aimed to examine the associations between androgen receptor (AR) and forkhead box A1 (FOXA1) and to investigate clinicopathological features and survival according to both biomarker status in estrogen receptor (ER)-positive breast cancers using in vitro study, patient cohort data, and the cBioPortal for Cancer Genomics and Kaplan-Meier Plotter websites
There was no alteration in ESR1 mRNA and only mRNA downregulation was presented in FOXA1
Summary
Recent attention has focused on the emerging roles of androgen receptor (AR) as a prognostic and predictive factor, and as a therapeutic target in breast cancer patients [1, 2]. A systematic review and meta-analysis showed that positive AR expression was significantly associated with better survival of patients with early breast cancer irrespective of estrogen receptor (ER) status [3]. In vitro evidence partly supported clinical studies and AR showed antiproliferative activity in only ER-positive breast cancers but rather AR signaling promoted tumor growth in ER-negative and human epidermal growth factor receptor 2 (HER2)positive breast tumors [1, 4]. Recent meta-analyses of breast cancers demonstrated that high FOXA1 levels were positively correlated with ER-positive and progesterone receptor (PR)-positive tumors [11]. The data concluded that FOXA1 was closely associated with the ER signaling pathway and suggested that FOXA1 may explain heterogeneous features of hormone receptor-positive tumors
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