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.

该建议将进行临床前研究以解决乳腺癌（BC）的风险和治疗问题 跨性别者（女性到男女过渡）。该建议还将阐明miRNA的相互作用 和睾丸激素在乳腺发育，致癌作用和对卑诗省治疗的反应中。最多 跨性别的个体追求睾丸激素治疗（TT）来治疗其性别烦躁不安。乳房是 性马敏感器官。现在接收TT的跨性别人士现在是一个关注的主题 - 非常 对于如此高的睾丸激素如何影响乳房，随后有发展的风险，知之甚少 公元前。前瞻性人类研究将需要数十年。与小鼠衰老相比，衰老的加速度为70倍 人类和乳房发育的激素调节在小鼠和人类中相似。 AIM 1将使用两个 小鼠模型以阐明TT影响雌激素受体阳性（ER+）的风险的程度 和负（ER-）BC。我们将比较雌性小鼠（完整）中的发明和肿瘤特异性生存率和 接受TT的卵形雌性小鼠与未接受TT的各自的小鼠（AIM 1.1）。 在频谱的另一端，对于被诊断为BC的跨性腺菌患者，既没有临床 指南或风险效益研究是否可以在接受卑诗省治疗时继续进行TT。有差距 了解睾丸激素是否影响卑诗省治疗的效率。 TT的中断是 不希望的，因为它会影响这些患者的情绪健康和身体形象，并使他们的癌症复杂化 - 诱发的情绪困扰。 AIM 2将解决是否继续睾丸激素的临床治疗问题 影响卑诗省的治疗结果。 AIM 2将使用相同的两个鼠标模型来调查是否继续 睾丸激素影响alpelisib（FDA批准的ER+具有PIK3CA突变的肿瘤）或Olaparib （FDA批准了具有BRCA1突变的ER肿瘤的治疗）治疗结果（AIM 2.1）。我们将 杠杆旨在1.1和2.1，以进行有关TT对雄激素受体和的影响的分子研究 ER介导的转录程序 - MRNA和miRNA表达 - 调节乳腺 发育和致癌作用（AIM 1.2）以及对BC治疗的反应（AIM 2.2）。变性人是 LGBTQ社区中增长最快的小组。我们需要开始了解他们的癌症风险和 TT的长期健康结果。我们的建议将是第一个从根本上获得新见解的人 了解BC风险并制定公司治疗指南，以改善医学上的BC结果 服务不足的跨性质种群。对性激素在卑诗省风险中的作用的了解增加了 和治疗以及在确定雄激素表达中的miRNA景观中，不仅是 对于改善跨性质健康和减少其医疗保健分配至关重要。这些知识将有 对了解BC风险的直接影响并为Sisgender男性和 女人也是。