Androgen Receptor Function and Targeted Therapeutics Across Breast Cancer Subtypes

Emily A. Kolyvas; Carlos Caldas; Kathleen Kelly; Saif S. Ahmad


Breast Cancer Res. 2022;24(79) 

In This Article

Androgens in Breast Cancer Development

The role of androgens in BC development and progression has been contrasting. While it is well known that androgens can act to inhibit growth in BC, the androgen excess theory proposes that androgens are instrumental in the development of BC in both ER+ and ER− tumours (reviewed in Secreto et al.).[17] Studies have shown that androgens have anti-proliferative properties during puberty and oppose oestrogens, while oestrogen and progesterone promote breast development under physiologic conditions.[18,19] The equilibrium between oestrogen and androgen allows for the control of mammary epithelial growth. While androgens are growth inhibitory, they are also precursors to oestrogens, so they can also act to stimulate breast cell growth and consequently overstimulate cell proliferation through conversion to oestrogen.[17] Under conditions of excess androgens, the balance between androgen and oestrogen is maintained at a new higher level; however, eventually the stimulatory effects of oestrogens predominate. Through this mechanism, the imbalance of androgen and oestrogen has been shown to lead to the development of ER+ BC. Prospective studies have repeatedly shown a link between high circulating androgens and the development of ER+ BC.[20,21] Notably, this conversion from androgens to oestrogens is often inhibited through aromatase inhibitors (AIs) in ER+ BC, resulting in increased circulating androgens and decreased levels of oestrogen.[22] Circulating androgens are also associated with a roughly twofold increased BC risk in postmenopausal women. When adjusted for circulating oestrogen to account for the conversion of androgens to oestrogen the association is only partially diminished, confirming an effect of androgens on breast tissue independent of the effect of oestrogen.[20,21,23]

Androgens and AR expression have also been implicated in the development of ER– BC. AR positivity is shown to be associated with overexpression of HER2 in apocrine tumours, such as tumours of the mammary gland, suggesting an interaction of AR and HER2 signalling pathways in these cells.[24,25] When apocrine cells are stimulated by androgens, they produce epidermal growth factor (EGF), which results in cell growth and proliferation through stimulation of EGFR and HER2.[17] Notably, EGFR is often overexpressed in BC, and it is possible that androgen stimulation would lead to the growth of cells under these conditions. Activation of both these pathways provides an opportunity for the development of ER– BC through androgen stimulation. Additionally, ER– BCs that retain AR expression are shown to have gene expression profiles that closely resemble that of ER+ BC.