Project Summary Our overall objectives in this proposal are to establish a cross-sex mouse model for breast cancer (BC) and develop BC treatment strategies for transfeminine individuals receiving estrogen therapy (ET). Transfeminine individuals are assigned male at birth and a majority of them pursue ET to affirm their feminine identity. Exposing the male body to extremely high exogenous estrogen over extended periods in order to achieve levels comparable to cisgender women raises concerns about the adverse effects of ET. ET is essential for their wellbeing but it remains unclear how ET modulates their lifetime breast cancer (BC) risk and, if they are diagnosed with BC, how ET affects their BC prognosis. Other groups have established cross-sex hormone treatment mouse models to investigate the impact of gender affirming hormone therapy on bone and cardiovascular health. There is no animal model to investigate the link between cross-sex hormone treatment and cancer. This proposal will develop a cross-sex mouse model of feminization to determine the extent which ET affects BC treatment outcomes. We will transplant three types of breast tumors—Pik3camut, Brca1mut, or Tp53mut—into male mice receiving ET. We will compare tumor growth rates, breast histology, and treatment outcomes between male mice that continue and discontinue ET during BC treatment with alpelisib (for Pik3camut tumors), olaparib (for Brca mut tumors), or eribulin (for Tp53mut tumors). Our long-term goal is to establish BC treatment strategies for the transgender community. Our preclinical model can be utlilized to develop strategies to treat other BC subtypes as well as other hormone- dependent malignancies such as prostate cancer. Our work will not only have implications in reducing transgender cancer disparities; our findings will contribute to our understanding of sex hormone dependencies in BC thus improving treatment strategies for cisgender men and women with BC as well.

Project Narrative As the transgender population increases and more individuals receive gender affirming hormone treatment, there will be a substantial number of individuals at risk for cancer as they age within the next 20 to 50 years. The medical community needs to be ready with knowledge and clinical guidelines to manage their cancer treatment. Towards that goal, we propose to utilize a preclinical cross-sex model of feminization to study the effect of estrogen treatment on breast cancer treatment outcome.