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.