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Prevention of obesity-induced breast cancer and tamoxifen drug resistance.

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Introduction: Breast cancer is the most frequently diagnosed cancer in women; with approximately 232,000 new cases diagnosed each year. Obesity also is an epidemic in the USA, as over 60% of women are overweight or obese. Several studies have demonstrated a strong link between obesity and a greater risk of developing breast cancer. It is estimated that 3 out of 10 breast cancers may have been prevented if the women were not overweight, indicating the important role obesity in the etiology of breast cancer. The most prevalent type of breast cancer express the estrogen receptor and endocrine-targeted therapies are often used to combat these cancers. Results from the breast international group (BIG) I-98 study indicate that obese women treated with tamoxifen had a poorer overall survival when compared to healthy weight women, implicating a causal link between obesity and endocrine therapy resistance. My preliminary data shows obese mice are more likely to develop breast cancer and have a worse response rate to endocrine targeted therapies than lean mice. Molecular signaling pathways such as the endoplasmic reticulum stress pathway, the unfolded protein response (UPR), are identified as a contributor to breast tumor development and cancer therapy resistance.
Methods: We hypothesize that elevated UPR induction in mammary glands of obese mice modulates metabolism to promote tumor formation and impairs antiestrogen therapy responsiveness. We will investigate whether differing dietary fat composition in obesity inducing diets (e.g. saturated vs. monounsaturated vs polyunsaturated) impacts UPR signaling in the mammary glands of female BALB/c mice. Moreover, we will determine whether differing fatty acid compositions in high fat diets impacts breast tumor formation and response to antiestrogen therapies in wildtype and GRP78 heterozygous mice.
Importance: Modulating diet composition may result in reducing UPR signaling pathways and may prevent obesity-mediated primary breast cancer formation, thereby reducing overall breast cancer mortality.
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