Skip to main content
NUTRITION 2024 Main banner
Icon Legend
This session is not in your schedule.
This session is in your schedule. Click again to remove it.
Back

Session: President's Oral Session: Abstracts of Distinction (Oral 33)

(OR33-02-24) Ketogenic Diet Enhances the Anti-Tumor Effect of Mifepristone in a Breast Cancer Mouse Model

Tuesday, July 2, 2024
10:12 AM – 10:24 AM CT
Location:  W375D
Objectives: Breast cancer is the most common diagnosed cancer in females. Germline BRCA1 mutation and/or prolonged or higher exposure to the hormone progesterone are known key drivers for poor prognosis. A breast cancer mouse model was used to elucidate a potential enhancement of the already known anti-tumor effect of mifepristone (MIF), a progesterone receptor modulator, in combination with a low-carbohydrate, high-fat ketogenic diet (KD). Moreover, we aimed to elucidate the effect of KD and MIF on the metabolome of breast cancer-bearing mice.

Methods: BALB/c mice were fed with control diet or KD. Mammary tumors were induced by subcutaneous implantation of slow-release medroxyprogesterone (MPA) pellets, followed by oral administration of 7,12-dimethylbenz[a]anthracene (DMBA). In addition, a slow-release MIF or placebo pellet was implanted. Blood glucose and ketones, tumor incidence and tumor growth were monitored. Targeted metabolomics was performed in plasma and tumor tissue. Moreover, we developed and validated a targeted HPLC-MS/MS approach to track the distribution of MIF and its active metabolite metapristone in several organs.

Results: KD and MIF delayed tumor occurrence compared to mice fed with control diet, respectively. KD+MIF further prolonged tumor-free and overall survival. MIF pellet implantation led to its systemic distribution, with highest MIF levels in breast tissue, indicating an accumulation of MIF and metapristone at the desired side of action. KD induced ketosis in mice while blood glucose levels remained unaffected. Metabolomics analysis revealed that KD had a stronger effect on metabolites and lipids compared to MIF.

Conclusions: Our data support the anti-tumor effect of KD+MIF, strengthening the idea to combine complementary nutritional approaches with anti-cancer drugs for cancer therapy. Further DNA methylation analysis will determine epigenetic signatures in both the tissue at risk (breast) and distant organs. These signatures will be integrated with metabolomics data to understand the interactions between cancer-related epigenetic regulators and metabolism and to mechanistically reveal the anti-tumor effect of KD+MIF.

Funding Sources: European Research Council
Land Tirol Support
The Eve Appeal Charity
Swedish Research Council
Children´s Cancer Foundation Salzburg
PMU-Research and Innovation Fund
Austrian Science Fund