Postmenopausal breast cancer, androgens, and aromatase inhibitors

Recent data can help to better define the long debated relationship between androgens and breast cancer (BC) after menopause. We reviewed the available literature data on: the origin of androgens after menopause, the association between circulating androgens and BC incidence and recurrence, the relationship between circulating and intratumoral hormones, the prognostic significance of the presence of androgen receptors (ARs) in the different BC subtypes, the androgen effect on BC cell lines, and the relationship between androgens and aromatase inhibitors. Epidemiological, clinical, and preclinical data on the role of androgens and of ARs on estrogen receptor (ER)-negative BC are somewhat controversial. However, most preclinical studies suggest that activated ARs, when present, have a proliferative effect, particularly in HER2 expressing cell lines, due to the cross-talk between AR and HER2 pathways. As regards ER-positive BC, epidemiological studies associate androgen levels with increased incidence and risk of recurrences, whilst clinical studies associate the AR positivity with a better prognosis. Preclinical studies suggest that the action of androgens is bidirectional: mainly proliferative, because circulating androgens are the precursors of estrogens, but also anti-proliferative, because AR activation restrains ER activity. The relative increase of androgenic action that follows the blocking of androgen aromatization into estrogens by aromatase inhibitors (AIs), could contribute to their therapeutic efficacy in AR-positive cases. Available data, although defining a complex picture, suggest that circulating androgen levels are clinically relevant, particularly when AIs are used.