Uterine fibroids (UFs; leiomyomas) are the most important benign neoplastic threat to women's health worldwide, but disproportionately affect women of color, particularly African American (AA) women, who have a threefold higher incidence rate and relative risk of UFs than Caucasian (CC) women. While the underlying cause 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 determine relative risk are genetically or biochemically linked. In this regard, we and others have 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. 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 test these hypotheses, we will (1) Elucidate the molecular basis of genomic instability in MED12-mutant UFs. We will determine if DSB accumulation in MED12-mutant UF SCs derives from defects in DNA damage-induced checkpoint signaling and repair and/or R-loop-induced replication stress. (2) Investigate the relationship between vitamin D3 and MED12 in UF genome maintenance. We will ask whether and how vitamin D3 signaling strength modulates the DDR defects in MED12-mutant UF SCs, relate this activity to patient race and serum vitamin D levels, and elucidate the mechanism by which the vitamin D3/receptor axis and MED12 coordinately control the DDR network at the genomic and epigenomic levels; (3) Examine the therapeutic potential of vitamin D3 in a preclinical mouse model of human UFs. Using a renal capsule mouse model of human UFs, we will evaluate vitamin D3 and its potent non-hypercalcemic analogs for therapeutic efficacy, safety, and mechanism of action, including impact on tumor DNA damage load and DDR gene networks.

Public Health Relevance

Uterine fibroids (UFs; leiomyomas) are the most important benign neoplastic threat to women's health worldwide, but disproportionately affect women of color, particularly African American (AA) women, who have a threefold higher incidence rate and relative risk of UFs than Caucasian (CC) women. The underlying cause for this risk disparity is not fully understood, and it is unclear whether and how the processes that drive UF formation and determine relative risk are genetically or biochemically linked. This proposal is impactful as its suggests a mechanistic basis to couple UF etiology and relative risk association through a functional interplay between vitamin D3 and the DNA damage response network in MED12-mutant UFs, the predominant tumor subtype, and further offers proof of concept for therapeutic intervention in this genetic setting. The studies proposed herein thus 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.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD094378-04
Application #
10106643
Study Section
Special Emphasis Panel (ZHD1)
Program Officer
Tingen, Candace M
Project Start
2018-02-15
Project End
2023-01-31
Budget Start
2021-02-01
Budget End
2022-01-31
Support Year
4
Fiscal Year
2021
Total Cost
Indirect Cost
Name
University of Texas Health Science Center
Department
Genetics
Type
Schools of Medicine
DUNS #
800772162
City
San Antonio
State
TX
Country
United States
Zip Code
78229
Prusinski Fernung, Lauren E; Yang, Qiwei; Sakamuro, Daitoku et al. (2018) Endocrine disruptor exposure during development increases incidence of uterine fibroids by altering DNA repair in myometrial stem cells. Biol Reprod 99:735-748
Cheng, Donghang; Vemulapalli, Vidyasiri; Lu, Yue et al. (2018) CARM1 methylates MED12 to regulate its RNA-binding ability. Life Sci Alliance 1:e201800117
Ali, Mohamed; Shahin, Sara Mahmoud; Sabri, Nagwa Ali et al. (2018) Hypovitaminosis D exacerbates the DNA damage load in human uterine fibroids, which is ameliorated by vitamin D3 treatment. Acta Pharmacol Sin :
Simon, James A; Catherino, William; Segars, James H et al. (2018) Ulipristal Acetate for Treatment of Symptomatic Uterine Leiomyomas: A Randomized Controlled Trial. Obstet Gynecol 131:431-439
Ali, Mohamed; Jackson-Bey, Tia; Al-Hendy, Ayman (2018) Simvastatin and uterine fibroids: opportunity for a novel therapeutic option. Fertil Steril 110:1272-1273
Ali, Mohamed; Shahin, Sara Mahmoud; Sabri, Nagwa Ali et al. (2018) 1,25 Dihydroxyvitamin D3 Enhances the Antifibroid Effects of Ulipristal Acetate in Human Uterine Fibroids. Reprod Sci :1933719118812720
Carr, Bruce R; Stewart, Elizabeth A; Archer, David F et al. (2018) Elagolix Alone or With Add-Back Therapy in Women With Heavy Menstrual Bleeding and Uterine Leiomyomas: A Randomized Controlled Trial. Obstet Gynecol :
Elhusseini, Heba; Elkafas, Hoda; Abdelaziz, Mohamed et al. (2018) Diet-induced vitamin D deficiency triggers inflammation and DNA damage profile in murine myometrium. Int J Womens Health 10:503-514
Yang, Qiwei; Ali, Mohamed; El Andaloussi, Abdeljabar et al. (2018) The emerging spectrum of early life exposure-related inflammation and epigenetic therapy. Cancer Stud Mol Med 4:13-23
Yang, Qiwei; Al-Hendy, Ayman (2018) The Emerging Role of p27 in Development of Diseases. Cancer Stud Mol Med 4:e1-e3

Showing the most recent 10 out of 13 publications