Time-restricted feeding alters the efficiency of mammary tumor growth

ABSTRACT

Disruption of circadian rhythms has detrimental host consequences. Indeed, both clinical and foundational science demonstrate a clear relationship between disruption of circadian rhythms and cancer initiation and progression. Because timing of food intake can act as a zeitgeber (i.e., entrainment signal) for the circadian clock, and most individuals in the developed world have access to food at all times of the day in a “24/7” society, we sought to determine the effects of timing of food intake on mammary tumor growth. We hypothesized that restricting access to food to during the inactive phase would accelerate tumor growth. Adult female Balb/C mice received a unilateral orthotopic injection of murine mammary carcinoma 4T1 cells into the ninth inguinal mammary gland. Beginning on the day of tumor injection and continuing until the end of the experiment, mice were food restricted to their active phase (ZT12 (lights off)- ZT0 (lights on), inactive phase (ZT0 – ZT12), or had ad libitum access to food. Mice that were food restricted to their inactive phase displayed a significant increase in body mass on days 7 and 14 of tumor growth relative to active phase or ad libitum fed mice. Additionally, mice fed during their inactive phase demonstrated a 20% reduction in food consumption relative to mice fed during their active phase and a 17% reduction in food consumption relative to ab libitum fed mice. Tumor volume was not significantly different between groups. However, food restricting mice to their inactive phase increased mammary tumor growth efficiency (i.e., mg of tumor mass per gram of food intake) relative to mice fed during the active phase and approached significance (p = .06) relative to ad libitum fed mice. To determine a potential explanation for the increased tumor growth efficiency, we examined rhythms of activity and body temperature. Mice fed during the inactive phase displayed significantly disrupted daily activity and body temperature rhythms relative to both other feeding regimens. Together, these data demonstrate that improperly timed food intake can have detrimental consequences on mammary tumor growth likely via disrupted circadian rhythms.

KEYWORDS:

• Circadian rhythms
• breast cancer
• timed feeding
• tumor growth
• circadian disruption

Acknowledgements

The authors acknowledge the WVU animal resources personnel and Terri Poling for their excellent care provided to the animals used in these studies. The authors were supported by grants from NCI (5R01CA194924 to ACD), NINDS (5R01NS092388 to RJN/ACD), and NIGMS under award number 5U54GM104942-03. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Data availability statement

The data that support the findings of this study are available (in raw form) from the corresponding author upon reasonable request.

Author contributions

WHWII designed, completed, analyzed all experiments and wrote the manuscript; ALK, OHMF, JRB, JAL, JCW conducted experiments and provided editorial comments on the paper; ACD and RJN designed experiments and wrote and edited the manuscript.

Additional information

Funding

This work was supported by the National Institute of Neurological Disorders and Stroke [R01NS092388]; National Cancer Institute [R01CA194924]; National Institute of General Medical Sciences [5U54GM104942-03].