The molecular consequences of androgen activity in the human breast (RNA-seq data)

The mammary gland is a hormone responsive organ and has been extensively studied under the influences of estrogen and progesterone. However, the molecular implications of androgen exposure in the normal breast remain elusive and unexplored, partially due to a lack of relevant tissue to study the functional consequences of androgen action. Transgender men are born female but identify as male, and many choose to undergo gender-affirming androgen therapy, which elicits wide-ranging masculinizing effects that help align their physical characteristics and gender identity. Here we perform single cell resolution profiling of androgen treated breast tissue from transgender men at the transcriptome, chromatin, and spatial level to elucidate the regulatory action of androgen. We show male-biased androgen receptor gene targets are specifically upregulated in androgen receptor expressing cell types, and that other sex-relevant changes are also initiated in cells lacking androgen receptor expression, through paracrine signaling cascades. We observe a functionally and structurally altered epithelium, shifts in immune populations and directed reduction of capillary vasculature. Finally, we discover evidence of the metabolic impact of androgen and demonstrate how the treatment induces fat loss by specifically targeting adipocyte function. This work provides a comprehensive and mechanistic characterization of the mammary tissue responses to androgen activity at single-cell resolution. Overall design: single nuclei RNA and ATAC sequencing was used to interrogate molecular responses in breast tissue cells of transgender men and cis-gender females.