Obese women clearly are at increased risk for developing endometrial cancer. Numerous epidemiologic studies have demonstrated that obesity is strongly associated with an increased risk of endometrial cancer. While an average woman has a 3% lifetime risk of endometrial cancer, obese women have a 9-10% lifetime risk of endometrial cancer. In a review of diet and cancer by the American Institute for Cancer Research and World Cancer Research Fund (WCRF), authors stated that the evidence relating body mass index and cancer is strongest for endometrial cancer. While excessive production of extragonadal estrogens (estrone) in the adipose tissue of obese women is presumed to be the major contributor to the risk of endometrial cancer, increased serum estrogen levels alone are unlikely to fully account for this effect. Studies by our group and others suggest that insulin resistance associated with obesity contributes to the increased risk of endometrial cancer. In addition, data from our previous funding period suggest that other mechanisms are involved in activating pro-proliferative signaling pathways in the obese endometrium. For the current proposal, our central hypothesis is that metformin can decrease endometrial hyperproliferation and can act as a chemopreventive agent in insulin-resistant obese women. Our three specific aims are 1) to test the hypothesis that metformin can reverse the estrogen-dependent hyperproliferation in the endometrium in an animal model of obesity- induced insulin-resistance, 2) to study novel mechanisms related to the use of metformin for the prevention of endometrial cancer. More specifically, we will examine the hypothesis that adipokines expressed in adipose tissue regulate endometrial proliferation via adipokine receptors, and metformin treatment can prevent this proliferation, and 3) to assess the ability of metformin to modulate surrogate endometrial biomarkers in a cohort of obese, insulin resistant women. It is the goal of this Project to develop novel strategies for the chemoprevention of endometrial cancer in obese, insulin resistant women, a high risk cohort.

Public Health Relevance

The long term goal of this Project is to develop novel strategies for the chemoprevention of endometrial cancer in obese, insulin-resistant women, a high risk cohort. A clinical prevention trial will examine whether metformin, a widely used drug for insulin resistance and diabetes, can potentially prevent endometrial hyperplasia and cancer. Studies that seek to understand the fundamental changes in the endometrium of obese versus lean women will also be performed.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center (P50)
Project #
5P50CA098258-10
Application #
8724913
Study Section
Special Emphasis Panel (ZCA1-RPRB-M)
Project Start
Project End
Budget Start
2014-09-01
Budget End
2015-08-31
Support Year
10
Fiscal Year
2014
Total Cost
$921,220
Indirect Cost
$736,888
Name
University of Texas MD Anderson Cancer Center
Department
Type
DUNS #
800772139
City
Houston
State
TX
Country
United States
Zip Code
77030
Bottsford-Miller, Justin; Choi, Hyun-Jin; Dalton, Heather J et al. (2015) Differential platelet levels affect response to taxane-based therapy in ovarian cancer. Clin Cancer Res 21:602-10
Wen, Yunfei; Graybill, Whitney S; Previs, Rebecca A et al. (2015) Immunotherapy targeting folate receptor induces cell death associated with autophagy in ovarian cancer. Clin Cancer Res 21:448-59
Previs, Rebecca A; Coleman, Robert L; Harris, Adrian L et al. (2015) Molecular pathways: translational and therapeutic implications of the Notch signaling pathway in cancer. Clin Cancer Res 21:955-61
Yang, Lifeng; Moss, Tyler; Mangala, Lingegowda S et al. (2014) Metabolic shifts toward glutamine regulate tumor growth, invasion and bioenergetics in ovarian cancer. Mol Syst Biol 10:728
Cho, Min Soon; Vasquez, Hernan G; Rupaimoole, Rajesha et al. (2014) Autocrine effects of tumor-derived complement. Cell Rep 6:1085-95
Yang, Yang; Han, Leng; Yuan, Yuan et al. (2014) Gene co-expression network analysis reveals common system-level properties of prognostic genes across cancer types. Nat Commun 5:3231
Wu, Sherry Y; Lopez-Berestein, Gabriel; Calin, George A et al. (2014) RNAi therapies: drugging the undruggable. Sci Transl Med 6:240ps7
Cancer Genome Atlas Research Network (2014) Comprehensive molecular characterization of gastric adenocarcinoma. Nature 513:202-9
Peng, Guang; Chun-Jen Lin, Curtis; Mo, Wei et al. (2014) Genome-wide transcriptome profiling of homologous recombination DNA repair. Nat Commun 5:3361
Liu, Guoyan; Sun, Yan; Ji, Ping et al. (2014) MiR-506 suppresses proliferation and induces senescence by directly targeting the CDK4/6-FOXM1 axis in ovarian cancer. J Pathol 233:308-18

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