A review of estrogen receptor/androgen receptor genomics in male breast cancer

Abstract

Male breast cancer is a rare disease, of which little is known. In contrast to female breast cancer, the very vast majority of all cases are positive for estrogen receptor alpha (ERα), implicating the function of this steroid hormone receptor in tumor development and progression. Consequently, adjuvant treatment of male breast cancer revolves around inhibition of ERα. In addition, the androgen receptor (AR) gradually receives more attention as a relevant novel target in breast cancer treatment. Importantly, the rationale of treatment decision making is strongly based on parallels with female breast cancer. Yet, prognostic indicators are not necessarily the same in breast cancer between both genders, complicating translatability of knowledge developed in female breast cancer toward male patients. Even though ERα and AR are expressed both in female and male disease, are the genomic functions of both steroid hormone receptors conserved between genders? Recent studies have reported on mutational and epigenetic similarities and differences between male and female breast cancer, further suggesting that some features are strongly conserved between the two diseases, whereas others are not. This review critically discusses the recent developments in the study of male breast cancer in relation to ERα and AR action and highlights the potential future studies to further elucidate the genomic regulation of this rare disease.

Characterizing steroid hormone receptor chromatin binding landscapes in male and female breast cancer

“…Even though many sites for GATA3, FOXA1, and PR were not shared with ERα, both AR and GR show virtually no unique binding sites with respect to ERα binding. AR has been shown to compensate for ERα in ERα-/AR+ female breast cancers 40 , 44 , however the biological interaction between ERα and AR is relatively unknown in both FBC and MBC 45 . The observed genomic overlap of steroid hormone receptor binding profiles is likely due to the close sequence homology of DNA binding domains between all steroid hormone receptors, which warrants potential competition between them in DNA binding.…”

Gene-specific methylation profiles in BRCA-mutation positive and BRCA-mutation negative male breast cancers

“…Specifically for MBC, AR expression has been reported as a positive prognostic marker for overall and disease-free survival [ 32 ]. Notably, AR has also received attention as a valid drug target in MBC patients [ 33 ]. Overall, our data add further evidence to a relevant role of AR in MBC and suggest that methylation status of AR promoter may eventually impact on the clinical management of MBC patients.…”

Clinical significance of PDEF factor expression and its relation to androgen receptor in ER− breast cancer

“…It has been reported that AR is expressed in 60–70% of ER − BC and in approximately 68% of the cases in this research . The AR signalling pathway has a significant role in the proliferation and survival of ER − BCs, and inhibition of AR has a therapeutic value in in‐vitro and in‐vivo models of ER − AR + BC cells . PDEF was first identified as an AR co‐regulator and an activator of prostate‐specific antigen (PSA) in the prostate .…”

“…26,27 The AR signalling pathway has a significant role in the proliferation and survival of ER À BCs, and inhibition of AR has a therapeutic value in in-vitro and in-vivo models of ER À AR + BC cells. 28 PDEF was first identified as an AR co-regulator and an activator of prostate-specific antigen (PSA) in the prostate. 9 Duane et al performed genomewide expression analysis of 99 primary BC samples and eight BC cell lines, and found that AR and PDEF were overexpressed in ER À BC.…”