Abstract B039: Effect of cross-sex testosterone therapy on Pik3ca-driven breast cancer incidence in mice
Authors: Wang Lin , Thavamani Abhishek , Massicott Erica S. , Bret-Mounet Vanessa C. , Abirached Joseph , Clohessy John G. , Baker Gabrielle M. , Wulf Gerburg M. , Heng Yujing Jan 
Published: December 2023

Abstract
Background: The majority of transmasculine individuals—assigned female at birth—pursue gender-affirming testosterone therapy (TT) to treat their gender dysphoria. It remains unknown the extent to which TT modulates the breast, including breast cancer (BC) risk, in transmasculine individuals. Given that hormone regulation of breast development is similar in mice and humans, mouse models are an excellent methodology to understand the effect of TT on BC development. We used a BC mouse model, MMTV-Cre Pik3caf/wt, to investigate the effect of testosterone on estrogen receptor positive (ER+) BC development. Method: Immunohistochemistry confirmed that our MMTV-Cre Pik3caf/wt tumors are ER+. We established 5 study arms: female controls (n=4), oophorectomized female controls (n=6), male mice (n=5), female mice receiving weekly 400 µg s.c. of testosterone cypionate (n=5), and oophorectomized female mice receiving weekly testosterone cypionate (n=5). Mammary tumor development was monitored weekly; palpable tumors were measured 3x a week. Mice were euthanized when their largest tumor reached 1cm, or if multiple tumors arise, when the combined tumor burden reaches 2 cm. Mice that have not reached endpoint by 48 weeks of age were euthanized and censored. The total number of tumors were observed during necropsy. Results: All 4 female controls developed a mean of 4 tumors each and were euthanized at around 35 weeks as the largest tumor reached 1 cm. The remaining mice were euthanized study endpoint of 48 weeks. Only 1 of 5 female mice receiving testosterone had a macroscopic tumor at 48 weeks. Hence, the total number of tumors developed among female mice receiving testosterone are similar or lower than female controls. Three out of 6 of oophorectomized females developed an average of 2 tumors while 2 of 5 female oophorectomized mice receiving testosterone developed 3 tumors each. Thus, when compared to intact females, oophorectomy appears to increase the lag time to Pik3ca tumor development. Lastly, 1 of 5 male mice developed 4 tumors. Conclusion: This pilot study demonstrated that testosterone does not increase ER+ BC incidence in Pik3ca-transgenic mice. Findings in oophorectomized mice suggest that aromatization of testosterone to estradiol may not contribute significantly to tumor development in these mice. Our findings provides insights into about BC risk associated with TT in transmasculine individuals. More studies are warranted to understand the health effects of gender-affirming hormone therapy, and reduce healthcare disparities in the transgender community.
Citation Format: Lin Wang, Abhishek Thavamani, Erica S. Massicott, Vanessa C. Bret-Mounet, Joseph Abirached, John G. Clohessy, Gabrielle M. Baker, Gerburg M. Wulf, Yujing Jan Heng. Effect of cross-sex testosterone therapy on Pik3ca-driven breast cancer incidence in mice [abstract]. In: Proceedings of the 16th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2023 Sep 29-Oct 2;Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2023;32(12 Suppl):Abstract nr B039.