Abstract 3304: HCAR2 activation limits tumor growth by the activation of p53 signaling in breast cancer
Authors: SONIA BATAN, Nanditi Thangaraju, Jabuneesa Khanom, Kunal Kumar, Snigdha Ganjikunta, Subash Sundaram, Nikhil Patel, Santhakumar Manicassamy, Puttur D. Prasad, Muthusamy Thangaraju
Journal: Cancer Research (2025)

Abstract Breast cancer (BC) is the most common cause of cancer-related death in women. BC affects ∼2.3 million women worldwide, with ∼685, 000 deaths every year. Therefore, a clear understanding of the molecular mechanism(s) associated with BC formation and the development of more effective therapeutic strategies for the prevention and treatment of this disease are sorely needed. The p53 tumor suppressor protein, encoded by the TP53 gene, prevents multicellular organisms from developing cancer. However, p53 mutations occur in almost all tumors, emphasizing its role as a formidable barrier that must be breached to allow oncogenic transformation. p53 is the most frequently mutated gene in BC, especially in triple-negative breast cancer (TNBC). Although p53 mutation has been seen in 18-25% of primary BC, about 80% of TNBC is associated with p53 mutation or inactivation. p53 is a multi-functional protein that controls the cell cycle, cell proliferation, DNA repair, senescence, and apoptosis, thereby blocking the proliferation of damaged cells and preventing tumor formation. Therefore, the development of therapeutic strategies that will rejuvenate wild-type p53 (WTp53) function or target mutant p53 (p53α) should have a high clinical impact on the prevention and treatment of BC. We found that HCAR2 (Hydroxycarboxylic acid receptor 2) or NIACR1 (Niacin receptor 1) or HM74A or GPR109A, a G-protein coupled receptor for the vitamin B3 Niacin (NA), the bacterial fermentation product butyrate (BTR), and the ketone body β-hydroxybutyrate (BHB), activates WTp53 and also destabilizes p53α in BC cells. p53 is an NAD+-dependent molecule, and deficiency of NA, the precursor of NAD+ and HCAR2 agonist impairs p53 function. NA- and BTR-induced HCAR2 activation can enhance p53 function by decreasing cAMP, thereby attenuating the binding of MDM2 to p53 and the resulting proteasomal degradation and inhibiting SIRT1, a p53 deacetylase. Similarly, BHB, an HCAR2 agonist and the primary ketone body in mammals, potentiates p53 function by increasing p53 acetylation. Further, HCAR2 activation induces cytotoxicity in p53α BC cells via inhibition of HSP90-HDAC chaperone, which stabilizes the transcription of p53α in the mammary epithelium. Therefore, HCAR2 activation should have a high clinical translational potential for the prevention and treatment of BC by rejuvenating WTp53 and destabilizing p53α in BC cells. Overall, our study provides preclinical evidence to show the functional implication of ketogenic signaling in the regulation of p53 and its relevance to BC prevention and treatment. Citation Format: SONIA BATAN, Nanditi Thangaraju, Jabuneesa Khanom, Kunal Kumar, Snigdha Ganjikunta, Subash Sundaram, Nikhil Patel, Santhakumar Manicassamy, Puttur D. Prasad, Muthusamy Thangaraju. HCAR2 activation limits tumor growth by the activation of p53 signaling in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3304.