There is abundant evidence that obesity confers increased risk for various forms of cancer. The incidence of breast, colon, and liver cancer are all increased in obese populations, and the epidemiologic evidence for the obesity-breast cancer connection is particularly strong. One in eight women will be diagnosed with breast cancer during their lifetime. Breast cancer is incidence increases 10-fold for women age 60 and above, compared to women 50 or younger. The increased breast cancer risk seems to be related to post- menopausal hormone levels, as the increased risk is only seen in women not on hormone replacement therapy. Furthermore the Metabolic Syndrome, which is characterized by obesity, insulin resistance, hypertension, dyslipidemia and elevated risk of diabetes, polycystic ovary syndrome, stroke and Alzheimer's disease, is associated with a higher incidence of more aggressive triple negative breast tumors. The increased risk is accelerated by the decline in ovarian estrogen levels after menopause, as pre-menopausal women are protected from the deleterious metabolic effects of obesity, including chronic tissue inflammation and insulin- resistance. Studies in rodents have confirmed this relationship, showing that dietary-induced obesity and high fat diets lead to increased incidence and growth of tumors in oncogene and carcinogen-induced breast cancers. Despite this body of correlative evidence, the mechanisms of obesity-induced breast cancer risk remain poorly understood. Dietary composition is an important factor as diets rich in saturated and omega 6 fatty acids are pro-inflammatory and increase breast cancer risk, but diets rich in omega 3 fatty acids are anti-inflammatory and decrease cancer risk. The clinical data in humans is less clear but meta-analyses of multiple human breast cancer risk studies have suggested that the ratio of pro-inflammatory to anti-inflammatory fatty acids is the critical factor. Although what you eat is important, when you eat i also important. We have found that reducing inflammation and insulin resistance reduces breast cancer growth in mice. We have also found that a time-restricted, high-fat diet improves insulin resistance despite continuing obesity. Due to the link between obesity, insulin resistance and breast cancer risk in post-menopausal women, and the potential that a similar time-restricted, dietary intervention could protect against breast cancer in humans, we will test the dietary intervention on breast cancer growth in mice and investigate the physiological changes that may drive tumor growth in obesity.
Obesity is a strong risk factor for breast cancer in post-menopausal women because as ovarian estrogen declines, women have less protection from the harmful effects of obesity, which causes inflammation and increases insulin levels. These harmful effects can be reversed by weight loss but this is often not sustainable. This proposal will test whether a novel dietary intervention using time-restricted feeding of a western-style, high-fat diet will protect against breast cancer.
| Fernandez, Marina O; Sharma, Shweta; Kim, Sun et al. (2017) Obese Neuronal PPAR? Knockout Mice Are Leptin Sensitive but Show Impaired Glucose Tolerance and Fertility. Endocrinology 158:121-133 |
| Tang, Kechun; Pasqua, Teresa; Biswas, Angshuman et al. (2017) Muscle injury, impaired muscle function and insulin resistance in Chromogranin A-knockout mice. J Endocrinol 232:137-153 |
| Cho, Chang Gun; Pak, Kwang; Webster, Nicholas et al. (2016) Both canonical and non-canonical NF-?B activation contribute to the proliferative response of the middle ear mucosa during bacterial infection. Innate Immun 22:626-634 |
| Chung, Heekyung; Chou, Winjet; Sears, Dorothy D et al. (2016) Time-restricted feeding improves insulin resistance and hepatic steatosis in a mouse model of postmenopausal obesity. Metabolism 65:1743-1754 |
