Masculinizing Testosterone Therapy Reduces the Incidence of PIK3CA-Mutant/ER⁺ Breast Cancer but Not BRCA1-Associated Triple-Negative Breast Cancer

作者：Lin Wang, Barbara Sardella, Abhishek Thavamani, Erica S. Massicott, Vanessa C. Bret-Mounet, Gabrielle M. Baker, Yaileen D. Guzmán‐Arocho, Adam M. Tobias, Richard A. Bartlett, E Aronson, Steven Vandal, Zhaoji Liu, Jonah Lee, Mitko Veta, Suzanne C. Wetstein, Soe Yu Aung, Michelle L Lui, Kenrick Cato, Christine H. Rohde, Kevin L Gardner, Hanina Hibshoosh, Walter Bockting, Lauren C. Houghton, Brittany M. Charlton, Shana Berwick, Alicia Smart, Megan E. Tesch, Arielle J. Medford, Cornelia W Peterson, Jason Domogauer, Jia Li, John G. Clohessy, Nadine Tung, Gerburg M. Wulf, Yujing J. Heng · 发表于：medRxiv · 年份：2025 · DOI：10.1101/2025.09.15.25335324 · 被引用次数：1 · 研究领域：BRCA gene mutations in cancer、PARP inhibition in cancer therapy、Male Breast Health Studies

Abstract Background We investigated the impact of gender-affirming testosterone therapy (TT) on breast cancer (BC) risk and tumor progression. Materials and methods We leveraged a large human breast tissue dataset (n=417) to assess TT and terminal duct lobular unit (TDLU) involution, complemented with tissue markers (ER, PR, AR, and Ki67; n =24) and transcriptome profiling ( n =8). Preclinical models assessed the effect of TT on BC incidence ( MMTV-Cre Pik3ca f/wt n =149 and K14-Cre Brca f/f Tp53 f/f n =153), murine mammary gland architecture ( n =60), and tumor transcriptome ( n =10). Lastly, we discuss trans masculine invasive BC cases and summarize tumor characteristics in this population ( n =24). Results TT promotes TDLU involution by reducing epithelial proliferation via altered estrogen signaling and increases ER+, PR+, and Ki67+ extralobular stromal cells. In mice, TT similarly reduced mammary gland ductal branching and terminal end buds. TT decreased Pik3ca -related ER+ BC incidence by 81% compared to female controls (adj RR 0.19, 95% CI 0.08-0.45), but did not affect Brca1 -related triple negative BC incidence. TT did not influence tumor progression in either model but shaped the Pik3ca -related ER+ tumor microenvironment toward a pro-tumor phenotype. Most trans masculine BC cases were ER+ (83.3%), small and node-negative, but were also moderately to poorly differentiated (70.8%). Conclusion TT reduces ER+ BC risk but does not eliminate risk, and has a negligible im...