The Effect of Time-Restricted Eating on the Efficiency of Chemo- and Hormonal-Therapy in Breast Cancer - 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 incidence increases approximately 10-fold for women age 60 and above, compared to women 50 or younger. This increase in breast cancer risk parallels an increase in obesity. Indeed, obesity increases the risk of triple negative breast cancer in pre-menopausal women and estrogen receptor positive breast cancer in post-menopausal women. A rarer form of inflammatory breast cancer is dramatically increased (up to 5-fold) in both groups. More importantly, obesity shortens decrease-free survival in both pre- and post-menopausal women. Patient mortality in breast cancer is primarily caused by distant metastases and obesity at the time of diagnosis is associated with increased risk of distant metastasis and mortality. Studies in rodents have confirmed these relationships, 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. One possibility is that the obesity causes insulin resistance in the liver that causes insulin levels to rise to control glucose levels, but other tissues, including tumors, may not be insulin resistant so are exposed to increased insulin signaling. Indeed, we have found that reducing insulin resistance by treating with omega-3 fatty acids reduces breast cancer growth in mice. We have also found that a time-restricted, high-fat diet improves insulin resistance despite continuing obesity, and not coincidentally inhibits tumor growth. But many important questions remain to be answered. Firstly, how does insulin drive tumor growth? Is it a direct effect on the tumor cell, or on the microenvironment? Secondly, does correction of the circadian rhythms in the tumor cell by TRF contribute to the reduced tumor growth? Thirdly, how do nutrients and insulin regulate the circadian clock in the tumors? Lastly, we know that obesity alters an individual's response to chemotherapy and anti-estrogen therapy, but is the response of the tumor altered by nutritional interventions such as TRF? In summary, aging and obesity are strong risk factors for breast cancer in 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 weight loss through diet and exercise is not sustainable for most obese individuals. We have shown that a novel dietary intervention using time-restricted feeding of a western-style, high-fat diet prevents the effect of obesity to drive breast cancer in mice; the proposed studies will investigate whether this nutritional intervention can enhance the response to normal chemo- and hormonal therapy for breast cancer.
