Introduction: Androgens have long been used in advanced breast cancer therapy, though the basis for androgen receptor (AR) action in normal mammary epithelial cells (MECs) is poorly understood. Mammary epithelium is composed of three principal lineages: one basal lineage and two luminal sub-lineages: milk-producing alveolar MECs, and oestrogen receptor (ER)- and progesterone receptor (PR)-positive hormone-sensing MECs (HS-MECs). The prevailing view is that androgens act in breast cancer to inhibit the function of ER and PR, particularly in HS-MECs.
Hypothesis/Aims: With the hypothesis that androgens act beyond ER- and PR-expressing HS-MECs, this study aimed to assess the effect of AR activation using a non-steroid agonist, GTx-024, and inactivation through transgenic knockout on the differentiation of MEC sub-populations. Mouse MEC sub-populations were assessed by flow cytometry and immunohistochemistry for markers of MEC lineage specification (P63 - basal, ER – HS-MEC, ELF5 – alveolar). Differentiation potential of basal and luminal progenitors was assessed using in vitro Matrigel colony assays. Finally, association of AR with markers of MEC lineage specification was assessed in normal pre-menopausal breast tissue.
Results/Conclusion: AR was expressed in basal and luminal MECs. AR activation in vivo increased the proportion of luminal MECs and decreased the proportion of basal MECs. Conversely, inhibition of AR in vivo decreased the proportion of luminal MECs and increased the proportion of basal MECs. Concordantly, in vitro inhibition of AR increased basal but not luminal progenitor activity. A small population of AR-positive cells in a basal-to-luminal transition were evident in human breast lobules. Collectively, this data support a role for AR to promote luminal differentiation in basal MECs. This data provides a novel potential basis for the benefit of androgen therapy in breast cancer through the promotion of a luminal phenotype.