Leiomyomas are highly pervasive benign tumors of the uterus that have an overall prevalence of 70% in women by the age of 50. They are the leading cause of hysterectomy in the United States, accounting for almost 50% of the 600,000 hysterectomies performed annually and $34 billion dollars in annual healthcare costs. Despite their prevelance and public health impact, the cellular and molecular mechanisms regulating the development and growth of leiomyoma are not well understood. Phenotypically, these tumors are distinct from the adjacent normal tissue largely due to the overproduction of extracellular matrix component. We and others have demonstrated that amongst the differentially expressed genes between LEIO and MYO, is EFEMP1, suggesting a role in the pathogenesis of these tumors. Among the 20 most differentially expressed genes, we identified Epidermal-growth factor-containing fibulin-like extracellular matrix 1 (EFEMP1). EFEMP1 encodes one of the fibulins (fibulin-3; FBLN3), a family of extracellular matrix glycoproteins that has been demonstrated to play roles in angiogenesis, extracellular matrix production, organogenesis, and cell morphology and growth. Differential expression of EFEMP1 has been implicated in tumor growth, angiogenesis, and extracellular matrix production in a number of malignancies. Specifically, the downregulation of EFEMP1 has been demonstrated to promote growth and altered intracellular signaling in prostate, lung, endometrial, and colorectal cancer. Neither the expression pattern nor the role of EFEMP1 and its protein product have been investigated in leiomyomas. Our lab has generated preliminary data that demonstrate that EFEMP1 is markedly downregulated in leiomyomas. Based on its role as a tumor suppressor in various cancers, we hypothesize that aberrant expression of EFEMP1 contributes to the pathophysiology of leiomyomas. We propose to test our hypothesis in two specific aims.
In Specific Aim 1 we will determine the contribution of EFEMP1 to the tumorigenesis in leiomyoma.
In Specific Aim 2 we will determine the mechanism by which EFEMP1 is differentially expressed in leiomyoma versus myometrium. We predict that the findings generated in this study will bring us one step closer to developing long-term nonhormonal therapeutic and preventative interventions for these highly morbid tumors, underscoring the translational potential of this study.
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