Androgen Receptor Signalling Promotes a Luminal Phenotype in Mammary Epithelial Cells
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Androgens influence mammary gland development but the specific role of the androgen receptor (AR) in mammary function is largely unknown. We identified cell subsets that express AR in vivo and determined the effect of AR activation and transgenic AR inhibition on sub-populations of the normal mouse mammary epithelium by flow cytometry and immunohistochemistry. Immunolocalisation of AR with markers of lineage identity was also performed in human breast tissues. AR activation in vivo significantly decreased the proportion of basal cells, and caused an accumulation of cells that expressed a basal cell marker but exhibited morphological features of luminal identity. Conversely, in AR null mice the proportion of basal mammary epithelial cells was significantly increased. Inhibition of AR increased basal but not luminal progenitor cell activity in vitro. A small population of AR-positive cells in a basal-to-luminal phenotype transition was also evident in human breast lobules. Collectively, these data support a role for AR in promoting a luminal phenotype in mammary epithelial cells.
KeywordsAndrogens Mammary epithelium Androgen receptor
Fluorescence-activated cell sorting
Hormone-sensing mammary epithelial cell
Mammary epithelial cell
The authors wish to acknowledge the support of the University of Adelaide Laboratory Animal Services, University of Adelaide Microscopy for imaging support, Dr. Randall Grose from the South Australian Heath and Medical Research Institute for providing cell sorting services, Ms. Marie Pickering and Ms. Zoya Khityak for assistance with histological experiments, and Ms. Tamara Crittenden from Flinders Medical Centre for recruitment and consent of patients for primary breast tissue collection.
This work was supported by funding from the National Breast Cancer Foundation (ID PS-15-041 to GAT and WDT), the National Health and Medical Research Council of Australia (ID APP1130077 and ID 1084416 to WDT and TEH), and Cancer Australia (ID 1043497). IMD is supported by a National Breast Cancer Foundation Fellowship ID PF-17-006. The laboratory of WDT & TEH is supported by research funds from GTx Inc., the manufacturers and suppliers of GTx-024 used in this study.
Compliance with Ethical Standards
Conflict of Interests
The authors declare no competing or financial interests.
Independent Author Contributions
GAT: Devised concepts & hypotheses, performed experiments, interpreted data, devised conclusions, prepared manuscript. GLL: Performed experiments and analyzed data. MS: Performed single-cell RNA experiments and analyzed data. IMD: Assisted in performing mammary digestion and cell labelling. MMR: Assisted in performing mammary digestion and cell labelling. KAW & DJH: Design and development of AR null mice and supply of their mammary tissue. WDT: Reviewed data, manuscript preparation and editing. TEH: Experimental conceptual design, data revision, study supervision, manuscript editing.