Principal Investigator

Nicholas J
Awardee Organization

University Of California, San Diego
United States

Fiscal Year
Activity Code
Early Stage Investigator Grants (ESI)
Not Applicable
Project End Date

Time-restricted feeding and breast cancer

There is abundant evidence that obesity confers increased risk for at least 13 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 over the of age 60, compared to age 50 or younger. This increase in breast cancer risk is associated with an increase in obesity. Indeed, obesity increases the risk of triple-negative breast cancer in premenopausal women and estrogen receptor positive breast cancer in postmenopausal women. A rarer form of inflammatory breast cancer is dramatically increased (up to 5-fold) in both groups. More importantly, obesity shortens disease-free survival in both pre- and postmenopausal women. Patient mortality in breast cancer is primarily caused by distant metastases. 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 and compensatory elevation in circulating insulin to control glucose levels. At the same time, other tissues, including tumors, may not be insulin resistant and so are exposed to increased insulin signaling. Indeed, we have shown that reducing insulin resistance by treating with omega-3 fatty acids reduces breast cancer growth in mice. We have also shown that time-restricted feeding (TRF) versus unrestricted feeding of a high-fat diet improves insulin resistance despite sustained obesity and equal caloric intake. Furthermore, we showed that TRF inhibited obesity-driven breast tumor growth and corrected tumor circadian rhythms, and that the TRF impact on tumor growth was mediated by reducing insulin levels. A number of important questions remain unanswered. 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 entrain the circadian clock in tumors? Due to the link between obesity, insulin resistance and breast cancer in pre- and postmenopausal women, and the translational potential of time-restricted feeding, we will investigate the effect of deleting the insulin receptor, mTORC1 signaling, or components of the circadian clock in tumor cells to test whether loss of these signals alters tumor growth in vivo and the response to TRF. We will also test whether TRF enhances chemotherapy to inhibit tumor growth. Accumulating evidence from TRF-related clinical studies support the translational relevance of our proposal. Translational, mechanistic findings from these studies will impact on breast cancer prevention and therapy.


  • Chung H, Chou W, Sears DD, Patterson RE, Webster NJ, Ellies LG. Time-restricted feeding improves insulin resistance and hepatic steatosis in a mouse model of postmenopausal obesity. Metabolism: clinical and experimental. 2016 Dec;65(12):1743-1754. Epub 2016 Sep 22. PMID: 27832862
  • Lee J, Zhang J, Chung YJ, Kim JH, Kook CM, González-Navajas JM, Herdman DS, Nürnberg B, Insel PA, Corr M, Mo JH, Tao A, Yasuda K, Rifkin IR, Broide DH, Sciammas R, Webster NJ, Raz E. Inhibition of IRF4 in dendritic cells by PRR-independent and -dependent signals inhibit Th2 and promote Th17 responses. eLife. 2020 Feb 4;9. PMID: 32014112
  • Cho CG, Pak K, Webster N, Kurabi A, Ryan AF. Both canonical and non-canonical NF-κB activation contribute to the proliferative response of the middle ear mucosa during bacterial infection. Innate immunity. 2016 Nov;22(8):626-634. Epub 2016 Sep 23. PMID: 27655045
  • Das M, Webster NJG. Obesity, cancer risk, and time-restricted eating. Cancer metastasis reviews. 2022 Sep;41(3):697-717. Epub 2022 Aug 19. PMID: 35984550
  • Tang K, Pasqua T, Biswas A, Mahata S, Tang J, Tang A, Bandyopadhyay GK, Sinha-Hikim AP, Chi NW, Webster NJ, Corti A, Mahata SK. Muscle injury, impaired muscle function and insulin resistance in Chromogranin A-knockout mice. The Journal of endocrinology. 2017 Feb;232(2):137-153. Epub 2016 Oct 31. PMID: 27799464
  • Rickert E, Fernandez MO, Choi I, Gorman M, Olefsky JM, Webster NJG. Neuronal SIRT1 Regulates Metabolic and Reproductive Function and the Response to Caloric Restriction. Journal of the Endocrine Society. 2018 Dec 24;3(2):427-445. doi: 10.1210/js.2018-00318. eCollection 2019 Feb 1. PMID: 30746504
  • Choi I, Rickert E, Fernandez M, Webster NJG. SIRT1 in Astrocytes Regulates Glucose Metabolism and Reproductive Function. Endocrinology. 2019 Jun 1;160(6):1547-1560. PMID: 31127273
  • Das M, Sauceda C, Webster NJG. Mitochondrial Dysfunction in Obesity and Reproduction. Endocrinology. 2021 Jan 1;162. (1). PMID: 32945868
  • Kumar D, Das M, Oberg A, Sahoo D, Wu P, Sauceda C, Jih L, Ellies LG, Langiewicz MT, Sen S, Webster NJG. Hepatocyte Deletion of IGF2 Prevents DNA Damage and Tumor Formation in Hepatocellular Carcinoma. Advanced science (Weinheim, Baden-Wurttemberg, Germany). 2022 Jul;9(21):e2105120. Epub 2022 May 26. PMID: 35615981
  • Das M, Ellies LG, Kumar D, Sauceda C, Oberg A, Gross E, Mandt T, Newton IG, Kaur M, Sears DD, Webster NJG. Time-restricted feeding normalizes hyperinsulinemia to inhibit breast cancer in obese postmenopausal mouse models. Nature communications. 2021 Jan 25;12(1):565. PMID: 33495474
  • Ellies LG. Collagen and fibronectin: threads linking obesity and breast cancer. Annals of translational medicine. 2016 Oct;4(Suppl 1):S50. PMID: 27868018
  • Kumar D, Das M, Sauceda C, Ellies LG, Kuo K, Parwal P, Kaur M, Jih L, Bandyopadhyay GK, Burton D, Loomba R, Osborn O, Webster NJ. Degradation of splicing factor SRSF3 contributes to progressive liver disease. The Journal of clinical investigation. 2019 Aug 8;129(10):4477-4491. PMID: 31393851
  • Fernandez MO, Sharma S, Kim S, Rickert E, Hsueh K, Hwang V, Olefsky JM, Webster NJ. Obese Neuronal PPARγ Knockout Mice Are Leptin Sensitive but Show Impaired Glucose Tolerance and Fertility. Endocrinology. 2017 Jan 1;158(1):121-133. PMID: 27841948
  • Huang PP, Brusman LE, Iyer AK, Webster NJ, Mellon PL. A Novel Gonadotropin-Releasing Hormone 1 (Gnrh1) Enhancer-Derived Noncoding RNA Regulates Gnrh1 Gene Expression in GnRH Neuronal Cell Models. PloS one. 2016 Jul 7;11(7):e0158597. doi: 10.1371/journal.pone.0158597. eCollection 2016. PMID: 27389022
  • Webster NJG, Kumar D, Wu P. Dysregulation of RNA splicing in early non-alcoholic fatty liver disease through hepatocellular carcinoma. Scientific reports. 2024 Jan 30;14(1):2500. PMID: 38291075
  • Mandt T, Bangar A, Sauceda C, Das M, Moderbacher C, Ghani M, Webster N, Newton I. Stimulating Antitumoral Immunity by Percutaneous Cryoablation and Combination Immunoadjuvant Therapy in a Murine Model of Hepatocellular Carcinoma. Journal of vascular and interventional radiology : JVIR. 2023 Sep;34(9):1516-1527.e6. Epub 2023 May 11. PMID: 37178816
  • Zeng L, Herdman DS, Lee SM, Tao A, Das M, Bertin S, Eckmann L, Mahata SK, Wu P, Hara M, Byun JW, Devulapalli S, Patel HH, Molina AJA, Osborn O, Corr M, Raz E, Webster NJG. Loss of cAMP Signaling in CD11c Immune Cells Protects Against Diet-Induced Obesity. Diabetes. 2023 Sep 1;72(9):1235-1250. PMID: 37257047