Gender-affirming estrogen therapy and breast cancer treatment outcome

项目摘要 本研究的总体目标是建立一种乳腺癌（BC）的跨性别小鼠模型， 为接受雌激素治疗（ET）的跨女性个体制定BC治疗策略。跨女性 个人在出生时被指定为男性，他们中的大多数人追求ET以确认他们的女性身份。 将男性身体长时间暴露在极高的外源性雌激素中， 与顺性别妇女相当的水平引起了人们对ET不良影响的担忧。ET是必不可少的 他们的健康状况，但目前尚不清楚ET如何调节他们一生的乳腺癌（BC）风险，如果他们是 诊断为BC，ET如何影响他们的BC预后。其他研究小组已经建立了跨性别激素 治疗小鼠模型，以研究性别肯定激素治疗对骨和 心血管健康目前还没有动物模型来研究跨性别激素之间的联系 治疗与癌症这项提议将建立一个雌性化的跨性别小鼠模型，以确定 ET影响BC治疗结果的程度。我们将移植三种类型的乳腺肿瘤Pik 3camut， Brca 1 mut或Tp 53 mut-1基因转染ET雄性小鼠。我们将比较肿瘤生长率，乳腺组织学， 在用alpelisib进行BC治疗期间继续和停止ET的雄性小鼠之间的治疗结果 (for Pik 3camut肿瘤）、奥拉帕尼（用于Brca mut肿瘤）或艾日布林（用于Tp 53 mut肿瘤）。我们的长期目标是 为跨性别群体制定BC治疗战略。我们的临床前模型可用于 制定治疗其他BC亚型以及其他激素依赖性恶性肿瘤的策略， 前列腺癌我们的工作不仅对减少跨性别癌症差异有影响， 这些发现将有助于我们理解BC的性激素依赖性，从而改善治疗 为患有BC的顺性别男性和女性制定战略。

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.