A comparative biomarker study of 514 matched cases of male and female breast cancer reveals gender-specific biological differences.

Male breast cancer remains understudied despite evidence of rising incidence. Using a co-ordinated multi-centre approach, we present the first large scale biomarker study to define and compare hormone receptor profiles and survival between male and female invasive breast cancer. We defined and compared hormone receptor profiles and survival between 251 male and 263 female breast cancers matched for grade, age, and lymph node status. Tissue microarrays were immunostained for ERα, ERß1, -2, -5, PR, PRA, PRB and AR, augmented by HER2, CK5/6, 14, 18 and 19 to assist typing. Hierarchical clustering determined differential nature of influences between genders. Luminal A was the most common phenotype in both sexes. Luminal B and HER2 were not seen in males. Basal phenotype was infrequent in both. No differences in overall survival at 5 or 10 years were observed between genders. Notably, AR-positive luminal A male breast cancer had improved overall survival over female breast cancer at 5 (P = 0.01, HR = 0.39, 95% CI = 0.26-0.87) but not 10 years (P = 0.29, HR = 0.75, 95% CI = 0.46-1.26) and both 5 (P = 0.04, HR = 0.37, 95% CI = 0.07-0.97) and 10 years (P = 0.04, HR = 0.43, 95% CI = 0.12-0.97) in the unselected group. Hierarchical clustering revealed common clusters between genders including total PR-PRA-PRB and ERß1/2 clusters. A striking feature was the occurrence of ERα on distinct clusters between genders. In female breast cancer, ERα clustered with PR and its isoforms; in male breast cancer, ERα clustered with ERß isoforms and AR. Our data supports the hypothesis that breast cancer is biologically different in males and females suggesting implications for clinical management. With the incidence of male breast cancer increasing this provides impetus for further study.

Differential regulation of oestrogen receptor ß isoforms by 5' untranslated regions in cancer.

Oestrogen receptors (ERs) are critical regulators of the behaviour of many cancers. Despite this, the roles and regulation of one of the two known ERs - ERß- are poorly understood. This is partly because analyses have been confused by discrepancies between ERß expression at mRNA and proteins levels, and because ERß is expressed as several functionally distinct isoforms. We investigated human ERß 5' untranslated regions (UTRs) and their influences on ERß expression and function. We demonstrate that two alternative ERß 5'UTRs have potent and differential influences on expression acting at the level of translation. We show that their influences are modulated by cellular context and in carcinogenesis, and demonstrate the contributions of both upstream open reading frames and RNA secondary structure. These regulatory mechanisms offer explanations for the non-concordance of ERß mRNA and protein. Importantly, we also demonstrate that 5'UTRs allow the first reported mechanisms for differential regulation of the expression of the ERß isoforms 1, 2 and 5, and thereby have critical influences on ERß function.