Uterine Fibroids (UFs, AKA: leiomyoma) are the most important benign neoplastic threat to women's health. They are the most common cause of hysterectomy causing untold personal consequences and hundreds of billions of health care dollars worldwide. Currently, there is no long term effective FDA-approved medical treatment available, and surgery is the mainstay. The etiology of UFs is not fully understood. In this regard, we and others have recently reported that somatic mutations in the gene encoding the transcriptional Mediator subunit MED12 are found to occur at a high frequency (~85%) in UFs. UFs likely originate when a Med12 mutation occurs in a myometrial stem cell converting it into a tumor-forming stem cell leading to a clonal fibroid lesion. UFs do not affect all races equally. Increased prevalence of UFs in African- American (AA) women has been consistently observed for >120 years. The molecular attributes behind UFs ethnic disparity are not fully realized; however, a growing body of literature implicates unfavorable early life environmental exposures as potentially important contributors. Environmental exposures during sensitive windows of development can reprogram normal physiological responses and alter disease susceptibility later in adult life. In the Eker UF rat model, we have recently reported in PNAS that early life exposure to environmental xeno-estrogens increased tumor-suppressor-gene penetrance in adult rats up to ~100%. Compelling preliminary data from our laboratory further identified that such exposure exerts two alterations in exposed rat myometrium: (1) permanently expands myometrial stem cell compartment and, (2) decreases DNA damage repair capacity. Quantitative PrimePCR array indicated that several DNA damage repair genes are significantly down regulated including RAD50, Sirt, and TP53 in myometrium from rats neonatally exposed to xenoestrogens. Importantly, in the human equivalent, we have encountered similar observations. MyoF (high risk myometrium from fibroid uteri) exhibited expanded myometrial stem cell compartment as well as a decrease in DNA damage repair capacity as compared to MyoN (normal myometrium from healthy fibroid-free uteri). This was significantly more noticeable in AA women. Importantly, key DNA repair genes of RAD50, Sirt1, MLH1, and MLH3 were markedly decreased in MyoF vs MyoN. Our central Hypothesis: Early life exposure, during the sensitive period of uterine development, to environmental toxicants, which is more prevalent in AA, permanently expands the number of myometrial stem cells as well as permanently reprograms and attenuates key DNA damage repair genes leading to reduced myometrial DNA damage repair capacity. Chronic reduction in DNA repair capacity eventually leads to the emergence of mutations such as Med12 in myometrial stem cells converting them into fibroid tumor-forming stem cells and subsequently leads to the development of UFs. We will address this hypothesis using the following three specific aims;
Specific Aim 1 : Determine whether a small but distinct myometrial stem cell population serves as pre-fibroid tumor progenitors in AA versus Caucasian (C) women.
Specific Aim 2 : Identify PcG/ TrxG (histone methylation regulators) regulated DNA repair target genes that contribute to developmental reprogramming in UF development.
Specific Aim 3 : Characterize whether Vitamin D3 is capable of increasing DNA repair capacity via reversing disrupted epigenetic programming in myometrial stem cells. Impact: These paradigm shifting concepts will enable us to identify genomic and epigenomic risk profiles associated with increased susceptibility to UFs in AA women. Such knowledge will inform an efficient precision medicine approach towards the development of novel preventative and therapeutics strategies for this common health disparity challenge.
| Hu, Guoku; Yelamanchili, Sowmya; Kashanchi, Fatah et al. (2017) Proceedings of the 2017 ISEV symposium on ""HIV, NeuroHIV, drug abuse, & EVs"". J Neurovirol 23:935-940 |
