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Male breast cancer (MBC) is rare and poorly characterized. Like the female counterpart, most MBCs are hormonally driven, but relapse after hormonal treatment is also noted. The pan-hormonal action of steroid hormonal receptors, including estrogen receptor alpha (ERα), androgen receptor (AR), progesterone receptor (PR), and glucocorticoid receptor (GR) in this understudied tumor type remains wholly unexamined. This study reveals genomic cross-talk of steroid hormone receptor action and interplay in human tumors, here in the context of MBC, in relation to the female disease and patient outcome. Here we report the characterization of human breast tumors of both genders for cistromic make-up of hormonal regulation in human tumors, revealing genome-wide chromatin binding landscapes of ERα, AR, PR, GR, FOXA1, and GATA3 and enhancer-enriched histone mark H3K4me1. We integrate these data with transcriptomics to reveal gender-selective and genomic location-specific hormone receptor actions, which associate with survival in MBC patients.

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., (© 2017 Society for Endocrinology.)

Estrogen receptor alpha (ERα)-positive breast cancers are frequently treated with tamoxifen, but resistance is common. It remains elusive how tamoxifen resistance occurs and predictive biomarkers for treatment outcome are needed. Because most biomarker discovery studies are performed using pre-treatment surgical resections, the effects of tamoxifen therapy directly on the tumor cell in vivo remain unexamined. In this study, we assessed DNA copy number, gene expression profiles and ERα/chromatin binding landscapes on breast tumor specimens, both before and after neoadjuvant tamoxifen treatment. We observed neoadjuvant tamoxifen treatment synchronized ERα/chromatin interactions and downstream gene expression, indicating that hormonal therapy reduces inter-tumor molecular variability. ERα-synchronized sites are associated with dynamic FOXA1 action at these sites, which is under control of growth factor signaling. Genes associated with tamoxifen-synchronized sites are capable of differentiating patients for tamoxifen benefit. Due to the direct effects of therapeutics on ERα behavior and transcriptional output, our study highlights the added value of biomarker discovery studies after neoadjuvant drug exposure., Competing Interests: The authors declare no conflict of interest.