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

性别肯定睾酮疗法对乳腺癌风险和治疗结果的影响

• 批准号: 10912193
• 负责人: Yu Jing Jan Heng
• 金额: $ 29.99万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-18 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10912193
• 关键词: Acceleration; Address; Affect; Age; Aging; Androgen Receptor; Androgens; BRCA1 Mutation; BRCA1 gene; Basic Science; Benefits and Risks; Body Image; Breast; Breast Cancer Risk Factor; Breast Cancer Treatment; Breast Oncology; Cancer Control; Caring; Chest; Clinical; Clinical Treatment; Communities; Development; Diagnosis; Disease; Endocrinology; Estradiol; Estrogen Therapy; Estrogen receptor positive; FDA approved; Female; Fulvestrant; Future; Genetic Transcription; Goals; Gonadal Steroid Hormones; Guidelines; Health; Hormones; Human; Implant; Incidence; Individual; Investigation; Knowledge; Lesbian Gay Bisexual Transgender Queer; Letrozole; Malignant Neoplasms; Malignant neoplasm of ovary; Malignant neoplasm of prostate; Mammary Neoplasms; Mastectomy; Mediating; Messenger RNA; MicroRNAs; Modeling; Molecular; Mouse Mammary Tumor Virus; Mus; Mutation; Operative Surgical Procedures; Organ; Outcome; PIK3CA gene; Patients; Persons; Pharmaceutical Preparations; Population; Postmenopause; Premenopause; Recommendation; Research; Risk; Risk Assessment; Role; Study models; Testosterone; Treatment outcome; Treatment-Related Cancer; United States National Institutes of Health; Well in self; Woman; Work; alpelisib; arm; breast cancer diagnosis; breast tumorigenesis; cancer care; cancer health disparity; cancer risk; cancer therapy; carcinogenesis; cis-female; cis-male; cisgender; emotional distress; epidemiology study; estrogen-related receptor; gender affirmation; gender affirming hormone therapy; gender dysphoria; health care disparity; hormone regulation; improved; insight; male; malignant breast neoplasm; mammary gland development; medically underserved; mortality; mouse model; novel; novel strategies; preclinical study; programs; prophylactic mastectomy; prospective; response; therapeutic miRNA; transfeminine; transgender; transmasculine; treatment guidelines; tumor

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.

该提案将进行临床前研究，以解决乳腺癌（BC）的风险和治疗问题， 跨男性（transmammalian）（女性到男性的过渡）。这项提议也将阐明miRNAs之间的相互作用， 和睾酮在乳腺发育、致癌作用和对BC治疗的反应中的作用。最 跨男性个体寻求睾酮治疗（TT）来治疗他们的性别焦虑。乳房是一个 性敏感器官接受TT的男性患者现在是一个令人担忧的问题-非常 关于如此高水平的睾丸激素如何影响乳房以及随后发生乳腺癌的风险，人们知之甚少。 公元前未来的人类研究将需要几十年的时间。老鼠的衰老速度是 乳腺发育的激素调节在小鼠和人类中相似。目标1将使用两个 小鼠模型，以阐明TT影响雌激素受体阳性（ER+）风险的程度 和阴性（ER-）BC。我们将比较雌性小鼠（完整）和 接受TT的卵巢切除雌性小鼠与其相应的未接受TT的对应小鼠（目标1.1）。 另一方面，对于诊断为BC的跨男性患者，既没有临床表现， 指南也没有关于他们是否可以在接受BC治疗的同时继续TT的风险获益研究。有差距 了解睾酮是否影响BC治疗的疗效。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，并使他们的癌症恶化- 引发了精神痛苦目标2将解决临床治疗的问题，是否继续睾酮 影响BC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进行 睾酮影响alpelisib（FDA批准用于携带PIK 3CA突变的ER+肿瘤的治疗）或奥拉帕尼 (FDA已批准的ER-携带BRCA 1突变的肿瘤治疗）的治疗结局（目标2.1）。我们将 利用目标1.1和2.1开展TT对雄激素受体影响的分子研究， ER介导的转录程序-mRNA和miRNA表达-对乳腺的调控 发展和致癌作用（目标1.2），以及对BC治疗的反应（目标2.2）。变性人 LGBTQ社群中成长最快的群体我们需要开始了解他们患癌症的风险， TT的长期健康结果。我们的建议将是第一个导致从根本上新的见解， 了解BC风险并制定临床治疗指南，以改善医学上的BC结果 缺乏服务的跨性别人群对性激素在BC风险中的作用的认识增加 和治疗，以及调节BC雄激素表达的miRNA景观，不仅 重要的是改善跨男性健康和减少他们的医疗保健差距。这些知识将 对了解BC风险的直接影响，并为顺性别男性开辟新的治疗途径， 女人也一样。