Gender-affirming estrogen therapy and breast cancer treatment outcome

项目摘要 我们在这项提案中的总体目标是建立一种跨性别乳腺癌(BC)小鼠模型，并 为接受雌激素治疗(ET)的变性女性个体制定BC治疗策略。跨女性的 个体在出生时就被指定为男性，他们中的大多数人追求ET以确认他们的女性身份。 使男性身体长期暴露在极高的外源性雌激素下，以实现 与顺性妇女相当的水平引起了人们对ET不利影响的担忧。外星人对 他们的健康状况，但仍不清楚ET是如何调节他们的终生乳腺癌(BC)风险的，如果他们是 诊断为BC，ET是如何影响BC预后的。其他群体已经建立了跨性别荷尔蒙 用小鼠模型研究性别肯定激素治疗对小鼠骨骼和骨骼的影响 心血管健康。目前还没有动物模型来研究异性荷尔蒙之间的联系 治疗和癌症。这项提议将开发一个女性化的跨性别老鼠模型，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-Pik3camut， Brca1mut，或Tp53mut-转入接受ET的雄性小鼠。我们将比较肿瘤生长速度、乳腺组织学和 在阿尔贝利西布BC治疗期间继续和停止ET的雄鼠之间的治疗结果 (对于Pik3camut肿瘤)、奥拉帕利(对于BRCA mut肿瘤)或eribuin(对于Tp53mut肿瘤)。我们的长期目标是 为变性人社区制定BC治疗策略。我们的临床前模型可以用来 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，如 前列腺癌。我们的工作不仅对减少变性人癌症的差异有影响；我们的 这些发现将有助于我们理解BC的性激素依赖，从而改进治疗 对于患有BC的顺性男性和女性的策略也是如此。

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.