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Study Finds Androgen Therapy Triggers Gene Expression Changes in Breast Tissue

A single-cell analysis of breast tissue from transgender men undergoing gender-affirming androgen therapy reveals that the treatment activates male gene expression programs, while also suppressing gene expression associated with certain breast cancers. The effects of the female hormones estrogen and progesterone in the mammary gland have been extensively studied, but the molecular effects of androgen in the breast remain largely unexplored. In the study, which appears this week in Cell Genomics, a team led by scientists from Cedars-Sinai Medical Center perform single cell-resolution transcriptome, chromatin, and spatial profiling of breast tissues from transgender men following androgen therapy, comparing them to samples from cosmetic breast surgeries in cisgender women. They find that androgen therapy shrunk ductal structures, induced sex-biased transcriptional changes, and reshaped the stromal compartment of the breast, either directly in hormone receptor-expression cells or indirectly via paracrine signaling to other cell types. Notably, the investigators also discover that androgen therapy inhibits estrogen receptor (ER) signaling in ER-positive breast cancer cells by sequestering essential coactivators. Androgen receptor activation, they write, may be a valid preventive or therapeutic strategy for ER-positive breast cancer and clinical trials testing androgen receptor activation in this breast cancer subtype have been implemented.