Obesity-Induced Autophagy as an Early Life Factor Mediating Breast Cancer
Studies have indicated that obesity elevates the risk of developing breast cancer by 30-50% in women. Moreover, an estimated 3 out of 10 breast cancers may have been prevented if the women were not overweight, indicating the important role obesity in breast cancer etiology. The BIG I-98 study indicated that obese women treated with antiestrogens had poorer overall survival when compared to health weight women, implicating a causative link between obesity and endocrine therapy resistance. Obesity is one of the few modifiable risk factors for breast cancer. Importantly, studies are beginning to emerge that indicates that timing of weight gain is important when determining the effect of obesity on breast cancer risk. Maternal obesity increases the likelihood of giving birth to an infant with high birth weight, and high birth weight is a risk factor for later breast cancer and increases breast cancer mortality. Over half of the pregnant women in the USA are overweight or obese, thereby elevating the risk of breast cancer development in their daughters. However, population-based studies have also noted that childhood obesity reduced breast cancer risk, later on in life. Although, it is inherently difficult to investigate the effects of childhood obesity due to the fact that high body weight as a child is predictive of adult obesity often confounding the results.
We have shown that upregulation of autophagy (a cellular pathway of “self-eating”) promotes therapy resistance and breast cancer cell survival. The purpose of this study is to investigate the role of autophagy signaling in mediating obesity-induced breast cancer formation and antiestrogen resistance. We hypothesize that elevated autophagy in mammary glands of obese mice promotes tumorigenesis and reduces antiestrogen responsiveness. Furthermore, we suggest that maternal obesity upregulates autophagy in the mammary glands of their daughters, increasing their breast cancer risk and promoting endocrine therapy resistance. The following aims address the hypothesis: Aim 1: Determine the effect of various lifespan exposures (maternal/in utero, pre-pubertal, pre-pubertal + adult, adulthood, or lifetime) to obesity-inducing diet has the greatest impact on breast tumorigenesis, endocrine therapy resistance, and autophagy signaling components in the mammary gland. Aim 2: Investigate whether autophagy inhibition prevents obesity-mediated breast tumorigenesis. Targeting autophagy may prevent primary tumor formation and prevent the resistant phenotype breast tumor reoccurrence, enabling better patient care. Successful completion of these aims may lead to the formation of a clinical trial using FDA approved chloroquine-based drugs (autophagy inhibitors), as a chemo-preventive drug to treat obese women or women that had an obese mother with a high risk of breast cancer.