Chemoprevention Efficacy of Sulforaphane Against Obesity-Induced Endometrial Carcinogenesis

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The obesity epidemic has contributed to increased incidence and mortality of endometrial cancer (EC) in the United States, particularly among younger women. Although EC is associated with a good prognosis in comparison to other cancers, surgery remains the cornerstone therapy for EC patients due to loss of hormone receptors contributing hormonal resistance in more than 30% cases. However, surgery is not a good option for obesity-related co-morbid conditions, and women of childbearing age, which prevents individual’s candidacy for surgical operation. Therefore, newer prevention strategies are needed to reduce EC incidence, morbidity, mortality, and to save fertility. In the search for new preventive drugs for EC, we demonstrated significant anticancerous activity of sulforaphane (SFN), a naturally occurring dietary isothiocyanate, in-vivo and in-vitro, in addition to its Histone deacetylase (HDAC) inhibition activity in EC. Due to the lack of significant toxicity in normal cells, SFN has garnered significant attention as a cancer preventive agent for humans: currently, several ongoing phase-I and phase-II clinical trials are evaluating its chemo-preventive role in different types of cancers. Furthermore, recent studies have established SFN’s critical role in the management of obesity and obesityrelated disorders. SFN has been shown to regulate adipogenesis and lipogenesis, as well as apoptosis and lipolysis in adipocytes. Since regulation of the key risk factor, obesity, as well as regression or treatment of EC precursor lesions such as endometrial hyperplasia (AEH/EH) to normal endometrium are rational approaches to prevent EC development, we hypothesized that SFN is a promising chemo-preventive agent for EC due to its ability to regulate obesity and exert anti-proliferative activity on the endometrium. We also expect that the HDAC inhibition activity of SFN will contribute to enhanced sensitivity of progesterone therapy via upregulation of the progesterone receptors. Therefore, in this study, we propose to develop an obesity-associated animal model of AEH/EH to explore the underlying mechanism and association of obesity with the development of AEH/EH. We also plan to evaluate the chemo-preventive efficacy of SFN alone or in combination with progesterone besides exploring the anti-obesity mechanism of SFN in our obesity associated EH/AEH animal model. This project fits within the parent grant goal to raise the standard of care and improve clinical outcomes for all women with gynecologic cancers with an emphasis on addressing cancer problems relevant to Oklahoma. Oklahoma has highest rates of obesity and worst records of the US States for nutrition and women’s health care. The mechanistic insight into how obesity drives EC, gained from this study will be used to develop novel molecularly targeted intervention strategies. Establishing SFN as a therapeutic alternative for AEH may provide a less invasive and less costly preventive strategy for EC. Furthermore, the use of SFN as a dietary supplement for the elimination of AEH/EH or prevention of its progression to cancer would provide a unique opportunity to avoid the loss of fertility and complications of surgery and chemotherapy.