Gender-Affirming Testosterone Therapy on Breast Cancer Risk and Treatment Outcomes

这项提案将进行临床前研究，以解决乳腺癌(BC)的风险和治疗方面的问题 变性人(女性到男性的转变)。这项提议还将阐明miRNAs之间的相互作用 和睾丸激素在乳腺发育、癌变和BC治疗反应中的作用。多数 跨男性个体寻求睾酮疗法(TT)来治疗他们的性别焦虑症。乳房是一种 性激素敏感器官。接受TT的变性人现在是一个令人担忧的话题-非常 关于如此高水平的睾丸素如何影响乳房以及随后发生乳腺癌的风险，我们知之甚少。 公元前。未来的人体研究将需要数十年的时间。小鼠的衰老速度比 荷尔蒙对乳房发育的调节在老鼠和人类身上是相似的。目标1将使用两个 用小鼠模型阐明TT对雌激素受体阳性(ER+)风险的影响程度 和阴性(ER-)BC。我们将比较雌性小鼠(完整)和雌性小鼠的发病率和肿瘤特异性存活率。 接受TT的卵巢切除雌性小鼠与未接受TT的相应对应小鼠(目标1.1)。 在光谱的另一端，对于被诊断为BC的跨男性患者，既没有临床上的 指南也没有关于他们在接受BC治疗的同时是否可以继续进行TT的风险-效益研究。在……方面有差距 关于睾丸素是否影响BC治疗疗效的知识。TT的终止是 不受欢迎，因为它影响这些患者的情绪健康和身体形象，并加剧他们的癌症- 引发的情绪困扰。目标2将解决临床治疗问题，即是否持续睾丸素 会影响BC的治疗结果。Aim 2将使用相同的两个小鼠模型来研究是否继续 睾酮影响alpelisib(FDA批准用于携带PIK3CA突变的ER+肿瘤的治疗)或olaparib (FDA批准了对携带BRCA1突变的ER肿瘤的治疗)治疗结果(目标2.1)。我们会 LIBILE AILES 1.1和2.1进行TT对雄激素受体和 ER介导的转录程序--mRNA和miRNA表达--对乳腺的调节 发展和致癌(目标1.2)和对BC治疗的反应(目标2.2)。变性人是 LGBTQ社区中增长最快的群体。我们需要开始了解他们的癌症风险和 TT的长期健康结果。我们的提案将是第一个从根本上对 了解BC风险并制定临床治疗指南以改善BC在医学上的结局 服务不足的跨性男性人口。对性激素在患BC风险中的作用的认识日益加深 而治疗，以及在调节BC雄激素表达方面的miRNA景观，不仅是 这对改善跨性男性健康和减少他们的医疗保健差距很重要。这些知识将会有 对了解BC风险的直接影响，并开辟顺性男性和 女性也是如此。

This proposal will undertake preclinical studies to address breast cancer (BC) risk and treatment concerns of transmasculine people (female-to-male transition). This proposal will also elucidate the interplay of miRNAs and testosterone in mammary gland development, carcinogenesis, and response to BC treatment. Most transmasculine individuals pursue testosterone therapy (TT) to treat their gender dysphoria. The breast is a sex hormone-sensitive organ. Transmasculine individuals who receive TT are now a subject of concern – very little is known about how such high levels of testosterone affect the breast and subsequently risk of developing BC. Prospective human studies will take decades. Mouse aging is accelerated by a factor of 70 compared to humans, and the hormone regulation of breast development is similar in mice and humans. Aim 1 will use two mouse models to clarify the extent to which TT affects the risk of developing estrogen receptor positive (ER+) and negative (ER-) BC. We will compare the incidences and tumor specific survival in female mice (intact) and oophorectomized female mice receiving TT with their respective counterparts that do not receive TT (Aim 1.1). On the other end of the spectrum, for transmasculine patients diagnosed with BC, there are neither clinical guidelines nor risk-benefit studies on whether they can continue TT while being treated for BC. There is a gap in knowledge about whether testosterone affects the efficacy of BC treatment. The discontinuation of TT is undesirable as it affects these patients’ emotional wellbeing and body image, and compounds their cancer- induced emotional distress. Aim 2 will address the clinical treatment issue of whether continuing testosterone affects BC treatment outcomes. Aim 2 will use the same two mouse models to investigate whether continuing testosterone affects alpelisib (FDA approved therapy for ER+ tumors harboring a PIK3CA mutation) or olaparib (FDA approved therapy for ER- tumors harboring a BRCA1 mutation) treatment outcomes (Aim 2.1). We will leverage Aims 1.1 and 2.1 to conduct molecular investigations about the effect of TT on androgen receptor and ER mediated transcriptional programs—mRNA and miRNA expression—on regulating mammary gland development and carcinogenesis (Aim 1.2), and response to BC treatment (Aim 2.2). Transgender people are the fastest growing group in the LGBTQ community. We need to start understanding their cancer risk and the long-term health outcomes of TT. Our proposal will be the first to lead to fundamentally new insights to understand BC risk and develop clincial treatment guidelines to improve BC outcome in the medically underserved transmasculine population. The increased understanding of the role of sex hormones in BC risk and treatment, as well as the miRNA landscape in regulating androgen expression in BC, are not only important to improve transmasculine health and reduce their healthcare disparities. These knowledge will have direct implications for understanding BC risk and open up new avenues of treatment for cisgender men and women as well.