(P13-007-23) Obesity and Breast Cancer Tumor Subtype Mediate the In Vitro Response to the Ketone β-Hydroxybutyrate

Objectives: There is growing interest in the use of ketogenic diets and ketone supplements for cancer prevention and treatment. β -hydroxybutyrate (BHB) is a ketone with potential anti-cancer properties. When circulating glucose levels lower, ketones become a key energy source. Metabolically flexible healthy cells use ketones for energy; it is unclear if cancer cells have the same response. Here, we examined the impact of BHB on the proliferation of hormone-dependent and independent breast cancer cell lines and primary tumor cells from a rat model of postmenopausal breast cancer. We hypothesized that BHB would decrease tumor cell proliferation.

Methods: Primary tumor cell lines were established from mammary tumors from lean (19% body fat) and obese (35% body fat) rats. Freshly dissected tumors were digested using the Miltenyi Biotec Tumor Dissociation Kit and single cells were plated and expanded to generate clonal cell lines. Hormone receptor status of cell lines was determined by qPCR. Cell growth was measured after 2 and 3 days (Hoechst assay) in response to BHB (3 mM, 10 mM, 25 mM) under low (5.6 mM), moderate (11.1 mM) and high (25 mM) glucose conditions. Effects of BHB on MCF7 and MDA-MB-231 breast cancer cells were also examined.

Results: Proliferation of hormone-dependent MCF7 cells increased as glucose concentration increased, and BHB treatment significantly reduced proliferation (p ≤ 0.05) at moderate and high glucose levels. Glucose and BHB did not affect the growth of hormone-independent MDA-MB-231 cells. Lean tumor cells did not respond to glucose; a nonsignificant trend to decrease proliferation with 25 mM BHB was observed. Conversely, proliferation increased in obese tumor cells in response to glucose, and preliminary results suggest that these cells are more sensitive to BHB.

Conclusions: Breast cancer subtype and host physiology modulate the inhibitory effects of BHB on breast cancer cell growth. Thus, adiposity and tumor subtype should be considered in future studies examining the efficacy of ketogenic diets or ketone supplements in breast cancer patients, as these may have a profound effect on findings in such studies.

Funding Sources: National Cancer Institute (EDG) and the Texas A&M Summer Research Experience Award (JMW)