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:
- 金额:$ 29.99万
- 依托单位:
- 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:
- 关键词:AccelerationAddressAffectAgeAgingAndrogen ReceptorAndrogensBRCA1 MutationBRCA1 geneBasic ScienceBenefits and RisksBody ImageBreastBreast Cancer Risk FactorBreast Cancer TreatmentBreast OncologyCancer ControlCaringChestClinicalClinical TreatmentCommunitiesDevelopmentDiagnosisDiseaseEndocrinologyEstradiolEstrogen TherapyEstrogen receptor positiveFDA approvedFemaleFulvestrantFutureGenetic TranscriptionGoalsGonadal Steroid HormonesGuidelinesHealthHormonesHumanImplantIncidenceIndividualInvestigationKnowledgeLesbian Gay Bisexual Transgender QueerLetrozoleMalignant NeoplasmsMalignant neoplasm of ovaryMalignant neoplasm of prostateMammary NeoplasmsMastectomyMediatingMessenger RNAMicroRNAsModelingMolecularMouse Mammary Tumor VirusMusMutationOperative Surgical ProceduresOrganOutcomePIK3CA genePatientsPersonsPharmaceutical PreparationsPopulationPostmenopausePremenopauseRecommendationResearchRiskRisk AssessmentRoleStudy modelsTestosteroneTreatment outcomeTreatment-Related CancerUnited States National Institutes of HealthWell in selfWomanWorkalpelisibarmbreast cancer diagnosisbreast tumorigenesiscancer carecancer health disparitycancer riskcancer therapycarcinogenesiscis-femalecis-malecisgenderemotional distressepidemiology studyestrogen-related receptorgender affirmationgender affirming hormone therapygender dysphoriahealth care disparityhormone regulationimprovedinsightmalemalignant breast neoplasmmammary gland developmentmedically underservedmortalitymouse modelnovelnovel strategiespreclinical studyprogramsprophylactic mastectomyprospectiveresponsetherapeutic miRNAtransfemininetransgendertransmasculinetreatment guidelinestumor
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)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。
项目成果
期刊论文数量(0)
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Yu Jing Jan Heng其他文献
Yu Jing Jan Heng的其他文献
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{{ truncateString('Yu Jing Jan Heng', 18)}}的其他基金
Admin Suppl Gender-affirming estrogen therapy and breast cancer treatment outcome
行政补充性别肯定雌激素治疗和乳腺癌治疗结果
- 批准号:
10783533 - 财政年份:2023
- 资助金额:
$ 29.99万 - 项目类别:
Gender-affirming estrogen therapy and breast cancer treatment outcome
性别肯定雌激素治疗和乳腺癌治疗结果
- 批准号:
10543116 - 财政年份:2021
- 资助金额:
$ 29.99万 - 项目类别:
Gender-affirming estrogen therapy and breast cancer treatment outcome
性别肯定雌激素治疗和乳腺癌治疗结果
- 批准号:
10350731 - 财政年份:2021
- 资助金额:
$ 29.99万 - 项目类别:
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