FOXA1 and AR in invasive breast cancer: new findings on their co-expression and impact on prognosis in ER-positive patients

Nelson Rangel,Paola Cassoni,Renzo Boldorini,Nicoletta Fortunati,Letizia Rinella,Isabella Castellano,Francesca Marano,Pietro Ferrando,Anna Sapino,Laura Annaratone,Claudio Isella,Maria Graziella Catalano,Jasna Metovic,Davide Balmativola,Simona Osella-Abate

doi:10.1186/s12885-018-4624-y

Abstract

BackgroundThe role of forkhead-box A1 (FOXA1) and Androgen receptor (AR) in breast cancer (BC) has been extensively studied. However, the prognostic role of their co-expression in Estrogen receptor positive (ER+) BC has not been investigated so far. The aim of the present study was thus to assess the co-expression (protein and mRNA) of FOXA1 and AR in BC patients, in order to evaluate their prognostic impact according to ER status.MethodsImmunohistochemical expression of AR and FOXA1 was evaluated on 479 consecutive BC, with complete clinical-pathological and follow up data. Fresh-frozen tissues from 65 cases were available. The expression of AR and FOXA1 with ER was validated using mRNA analyses. Survival and Cox proportional hazard analyses were used to evaluate the relationship between FOXA1, AR and prognosis.ResultsExpression of ER, AR and FOXA1 was observed in 78, 60 and 85% of cases respectively. Most AR+ cases (97%) were also FOXA1+. The level of FOXA1 mRNA positively correlated with level of both AR mRNA (r = 0.8975; P < 0.001) and ER mRNA (r = 0.7326; P < 0.001). In ER+ BC, FOXA1 was associated with a good prognosis independently of AR expression in the three subgroups analyzed (FOXA1+/AR+; FOXA1+/AR-; FOXA1−/AR-). Multivariate analyses confirmed that FOXA1 may provide more information than AR in Disease-Free Interval (DFI) of ER+ BC patients.ConclusionOur results suggest that in BC the expression of FOXA1 is directly related to the expression of AR. Despite that, FOXA1 is found as superior predicting marker of recurrences compared to AR in ER+ BC patients.

Highlights

The role of forkhead-box A1 (FOXA1) and Androgen receptor (AR) in breast cancer (BC) has been extensively studied
We found that (i) the expression of FOXA1 and AR was closely related: the majority of cases expressing AR showed FOXA1 positivity, negative expression of FOXA1 correlates with very low level of AR; (ii) the expression of FOXA1 is strictly related to good outcome, and in the subgroup of patients with ER+ BC may provide more information on Disease-Free Interval (DFI) than AR
Our results suggest that in BC the expression of FOXA1 is directly proportional to the expression of AR

Summary

Introduction

The role of forkhead-box A1 (FOXA1) and Androgen receptor (AR) in breast cancer (BC) has been extensively studied. The prognostic role of their co-expression in Estrogen receptor positive (ER+) BC has not been investigated so far. In breast cancer (BC), Estrogen (ER) and Androgen Receptors (AR) regulate cell proliferation and differentiation. They are frequently co-expressed, AR may be expressed in ER-negative (ER-) BC, where it modulates gene transcription by using regulatory molecules and pathways normally activated by ER [1]. FOXA1, a member of the forkhead family protein [7], is an important regulator of ER DNA binding and transcription of its target genes [8] In both ER+ and ER- BC cells, FOXA1 promotes AR DNA binding [1, 9, 10]. The role of FOXA1/AR co-expression in ER+ BC has not been investigated, it has been suggested that the relative ratio

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