Hypovitaminosis D promotes MED12-associated genomic instability in uterine fibroids

资助家长资助金摘要 子宫肌瘤是全球女性健康面临的最重要的良性肿瘤威胁， 据估计，每年的医疗费用高达数千亿美元。UF导致- 疾病对所有族裔的妇女都有负面影响，但对非洲人的影响不成比例。 美国(AA)女性，UF的发病率和相对风险是 高加索(CC)女性。虽然这种风险差异的基础还不完全清楚，但最近 研究表明，维生素D缺乏症是主要原因。因此，AA女性有十倍于 与CC女性相比，维生素D缺乏的风险增加，正如我们第一次报告的那样，UF风险 与25-羟基维生素D血清水平呈负相关。尽管如此，目前还不清楚 以及导致UF形成和种族风险差异的过程是如何遗传的或 生物化学联系在一起。在此，我们提出了一种耦合UF病因和亲属的机制基础 通过维生素D3和DNA损伤改变之间的功能相互作用产生的风险关联 MED12突变尿路综合征的反应网络，并进一步为治疗提供概念证据 在这种遗传环境中的干预。最近，我们和其他人发现了体细胞突变 转录调节亚基MED12作为UF的主要驱动因素，占~70% 肿瘤。值得注意的是，MED12突变的UF具有显著的染色体丢失和 重排，表明基因组不稳定是肿瘤进展的驱动力。在此，我们 阐明突变的MED12驱动的基因组不稳定性的分子基础，并进一步鉴定 维生素D3受体信号可能是这一过程的抑制因子。我们证明了MED12突变体 超滤干细胞(SCs)积累高水平未修复的DNA双链断裂(DSB) 通过下调关键的DNA损伤反应(DDR)和修复基因，包括RAD50， RAD51和BRCA1。值得注意的是，我们发现维生素D3/受体轴是一种可变的调节器 MED12调控DDR基因表达。因此，我们发现维生素D3/受体减少 信号被抑制，而信号被提升 激活，在MED12突变的UF SCs中DDR基因下调。基于这些发现，我们 假设维生素D缺乏会加剧DNA损伤堆积和基因组 MED12突变UF中出现不稳定性，导致肿瘤进展和负担增强。 因此，我们建议，通过修复受损的DDR，维生素D3将提供 MED12突变肿瘤的治疗益处。为了证实和扩展这些假设，我们 提出以下目标，直接解决并机械地联系三个方面 该领域的主要问题：UF的分子发病机制，UF中的种族差异 风险，以及新的可耐受的、节省生育能力和成本效益的口腔疗法的开发 UFS。

Abstract of Funded Parent Grant UFs (leiomyomas) are the most important benign neoplastic threat to women’s health worldwide, with annual health care costs estimated in the hundreds of billions of dollars. UF caused- morbidities negatively impact women of all ethnicities, but disproportionately affect African American (AA) women, who have a threefold higher incidence rate and relative risk of UFs than Caucasian (CC) women. While the basis for this risk disparity is not fully understood, recent studies implicate hypovitaminosis D as a major contributor. Thus, AA women have a tenfold increased risk of vitamin D deficiency compared to CC women, and as we first reported, UF risk is inversely correlated with 25-hydroxy vitamin D serum levels. Nonetheless, it is not clear whether and how the processes that drive UF formation and racial risk disparity are genetically or biochemically linked. Herein, we suggest a mechanistic basis to couple UF etiology and relative risk association through a functional interplay between vitamin D3 and an altered DNA damage response network in MED12-mutant UFs, and further offer proof of concept for therapeutic intervention in this genetic setting. Recently, we and others identified somatic mutations in the transcriptional Mediator subunit MED12 as the dominant drivers of UFs, accounting for ~70% of tumors. Notably, MED12-mutant UFs are characterized by significant chromosomal loss and rearrangement, suggesting genomic instability as a driving force in tumor progression. Herein, we clarify the molecular basis for mutant MED12-driven genomic instability, and further identify vitamin D3 receptor signaling as a likely suppressor of this process. We show that MED12-mutant UF stem cells (SCs) accumulate high levels of unrepaired DNA double-strand breaks (DSBs) through downregulation of key DNA damage response (DDR) and repair genes, including RAD50, RAD51 and BRCA1. Notably, we find the vitamin D3/receptor axis to be a variable modulator of MED12-regulated DDR gene expression. Thus, we show that reduced vitamin D3/receptor signaling suppresses, while elevated signaling activates, DDR genes downregulated in MED12-mutant UF SCs. Based on these findings, we hypothesize that hypovitaminosis D exacerbates DNA damage accumulation and genomic instability arising in MED12-mutant UFs, leading to enhanced tumor progression and burden. Accordingly, we propose that vitamin D3, through reparation of an impaired DDR, will provide therapeutic benefit in MED12-mutant tumors. To confirm and extend these hypotheses, we propose the following aims, which directly address and mechanistically connect three overarching issues in the field: the molecular pathogenesis of UFs, the racial disparity in UF risk, and the development of novel tolerable fertility-saving and cost-effective oral therapies for UFs.