In this talk, she focused on the impact of TRF on cancer risk in mice. To do so, she first starts with an overview of circadian rhythms, then provided an overview of her work with TRF in mice, and then introduced new data using their novel postmeonopausal obese mouse model of breast cancer.
Circadian rhythms are entrained by light, food, and activity/sleep. Behaviors that modify any of these can affect circadian rhythms are result in: cancers, obesity, CVD, IBD, psychiatric illnesses, cognitive impairment, etc. These clocks regulate biologic processes in 24-hr cycles. Important pathways include:
She provided historical data that demonstrated that disruption of the circadian rhythms is associated with increased cancer risk:
- Tumor suppression is controlled by the Circadian rhythm
- Regulates expression of oncogenes and tumor suppressors
- Gastric cancer and prostate cancer
- Disruption of the clock promotes tumor growth
- Increased oncogenic potential
- Increased cell growth and proliferation
- Decreased apoptosis
- Increased lung/liver tumorigenesis
- Increased breast cancer risk
Circadian misalignment of food intake (humans meant to take in food during daylight hours, mice during night-time) has detrimental cancer-related metabolic consequences:
- Food intake at night associated with increased obesity and reduced wt loss
- Hormones that are active at night interfere with insulin action
- Insulin resistance increases
- Acutely, and over time, nutrient metabolites in circulation during “off” times will blunt or change gene expression of metabolic or proliferation pathways regulating fuel storage and cell growth – direct impact on cancer growth and prevention
- Eating in regulation with circadian rhythms is associated with reduced risk of chronic diseases
She briefly introduced her postmenopausal obese mouse model in breast cancer development. In this model, oophorectomy in mice simulates a postmenopausal state. It is known that obesity increased breast cancer risk 2-fold in postmenopausal women. Following oophorectomy, Py230 cell line is injected into the mammary glands of these mice. They tested whether or not lean mice vs. obese mice had any difference in tumor growth – and they stratified the obese mice by diet-induced or genetically-induced obesity. Across the board, diet-induced and genetically-induced obese mice had much greater tumor volume and growth than lean mice.
TRF in mouse models is another area she has done much work in. In mice, normal feeding is nocturnal. So, in one group, they provided the mice around-the-clock, which they continued to eat. In the other, they provided the same 24-hour volume of food during a short 8-hour window overnight – TRF. In two separate studies, TRF protected against obesity and associated metabolic disturbances.
When they assessed impact on breast cancer, they found that even though TRF partially reduced body and fat weight without altering caloric intake, and partially improved glucose regulation, it also significantly reduced/blunted breast cancer tumor growth – almost to the level of lean mice.
This is very interesting work and still has a lot of potential. They are naturally looking to assess this in human studies.
Speaker: Dorothy D. Sears, PhD
Written by: Thenappan Chandrasekar, MD, Clinical Instructor, Thomas Jefferson University, @tchandra_uromd, at the 19th Annual Meeting of the Society of Urologic Oncology (SUO), November 28-30, 2018 – Phoenix, Arizona