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

基本信息

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
项目类别：
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

项目摘要

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) 风险和治疗问题该提案还将阐明 miRNA 的相互作用。和睾酮在乳腺发育、癌变以及对 BC 治疗的反应中发挥着重要作用。跨男性个体寻求睾酮疗法（TT）来治疗他们的性别焦虑症。接受 TT 的跨男性个体现在成为一个令人担忧的话题——非常令人担忧。对于如此高水平的睾丸激素如何影响乳房以及随后的发育风险知之甚少 BC ，前瞻性人类研究将需要几十年的时间。人类，乳房发育的激素调节在小鼠和人类中是相似的，目标 1 将使用两种。小鼠模型阐明 TT 对雌激素受体阳性 (ER+) 风险的影响程度我们将比较雌性小鼠（完整）和阴性（ER-）BC 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，既没有临床关于他们在接受 BC 治疗的同时是否可以继续 TT 的指南和风险效益研究存在差距。关于睾酮是否影响 BC 治疗效果的知识 TT 的终止是这是不受欢迎的，因为它会影响这些患者的情绪健康和身体形象，并加剧他们的癌症- 目标2将解决是否持续使用睾酮的临床治疗问题。目标 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 批准治疗携带 PIK3CA 突变的 ER+ 肿瘤）或奥拉帕尼（FDA 批准治疗含有 BRCA1 突变的 ER 肿瘤）治疗结果（目标 2.1）。利用目标 1.1 和 2.1 进行有关 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——调节乳腺发展和致癌（目标 1.2），以及跨性别者对 BC 治疗的反应（目标 2.2）。 LGBTQ 群体中增长最快的群体，我们需要开始了解他们的癌症风险以及他们的癌症风险。 TT 的长期健康成果将是第一个带来全新见解的提案。 BC 风险并制定临床治疗指南，以从医学角度改善 BC 结局服务不足的跨男性人群对性激素在 BC 风险中的作用有了更多的了解。和治疗，以及调节 BC 中雄激素表达的 miRNA 景观，不仅是这些知识对于改善跨男性健康并减少他们的医疗保健差异非常重要。对了解 BC 风险和为顺性别男性开辟新的治疗途径有直接影响女性也是如此。