Introduction: Androgens inhibit normal breast growth, while both androgen receptor (AR) agonists and antagonists are being trialled in women with different subtypes of breast cancer, including estrogen receptor (ERa)-positive and ERa-negative. However, AR signaling exhibits context-dependent activity among breast cancers1. We hypothesize that these disparities reflect differences in AR expression or action in the normal breast. Therefore, we undertook an in situ investigation of AR expression in relation to expression of established markers of mammary epithelial cell (MEC) proliferation and differentiation in normal human breast, and associated this with the presence of an adjacent benign or malignant ERa-positive lesion.
Methods: Confocal immunofluorescence was employed to associate expression of AR in normal MECs with markers of proliferation (Ki67) and differentiation (basal - P63, SCF; alveolar – KIT, ELF5; luminal hormone-sensing - ERa, progesterone receptor (PR)). A separate assessment was made of the relationship between the expression of AR, ERa, PR and markers of AR activity (PSA, apolipoprotein D) in normal breast tissue adjacent to benign or malignant ERa-positive lesions, to associate androgen responsiveness with progression of breast cancer.
Results: High AR expression in normal MECs associated with hormone-sensing cells expressing ERa and/or PR, and were largely negative for alveolar, luminal progenitor and basal markers. A small proportion of AR-expressing MECs co-expressed the alveolar marker KIT, illustrating the potential for AR signalling to play roles in regulating the development or function of multiple MEC lineages. The expression of AR-responsive genes was reduced in normal MECs adjacent to malignant versus benign breast lesions.
Conclusions: AR expression in normal human breast was associated with the hormone-sensing lineage and an inactive state of growth and differentiation. That expression of AR-responsive genes is decreased in tissue adjacent to malignant lesions supports the use of AR agonists as targeted therapy for ER-positive breast cancer.