Abstract 1775: Anti-tumor effects of statins in triple-negative breast cancer: Apoptosis, chemosensitization and degradation of mutant-p53

Abstract

Abstract Background: Despite many advances in recent years, therapeutic options for triple-negative breast cancer (TNBC) remain limited by a lack of defined molecular targets. Many studies have found that cholesterol-lowering statins possess significant anti-tumor effects, including against TNBC. Statins influence several key signaling pathways and have recently been shown to degrade mutant p53, a common oncogenic driver. We aim to further evaluate the efficacy of statins in the treatment of TNBC and examine links with the p53 pathway. Methods: The anti-proliferative effect of two different statins, atorvastatin and simvastatin was tested on a panel of 15 breast cancer cell lines (8 TNBC & 7 non-TNBC). Viability was measured using the MTT assay at 5 days incubation and colony formation assays at 10 days. Induction of apoptosis was analyzed by flow cytometry following annexin V staining. Western blotting was used to assess levels of mutant-p53. Results: Both atorvastatin and simvastatin significantly reduced proliferation in a panel of breast cancer cell lines (IC50 values: atorvastatin 0.3 - 49.1 µM, simvastatin 0.2 - 40.8 µM). Simvastatin was selected for further study due to its significantly lower mean IC50 values (11.85 v 17.69 µM, p<0.05). IC50 values were significantly lower in TNBC cell lines than non-TNBC for atorvastatin (7 v 31 µM, p < 0.01) and was borderline-significantly lower for simvastatin (6 v 19 µM, p = 0.054). Simvastatin was also found to be more potent in cell lines with mutated-p53 versus those with wild-type (p < 0.05). Western blotting also revealed that simvastatin reduced levels of mutated-p53 in two cell lines investigated. Addition of the cholesterol-precursor compound MVA negated the anti-proliferative effect of statins, suggesting the crucial nature of this pathway in TNBC cell survival. Combination treatment of simvastatin and the chemotherapeutic agents, doxorubicin or docetaxel showed synergistic growth inhibition. Finally, analysis of apoptosis by annexin-V staining found significant increases in statin treated cells (p<0.0001 at 48H, 10 µM), further highlighting the efficacy of statins in TNBC cell lines. Conclusions: Our results suggest that statins may be a new treatment for patients with breast cancer especially those with TNBC. Preliminary results also suggest the presence of mutant-p53 may be both a marker of statin response and a mediator by which the statins act. Future work will aim to further clarify the precise signaling pathways affected by these drugs and the mechanism by which they induce cell death. Citation Format: Shane O'Grady, John Crown, Michael J. Duffy. Anti-tumor effects of statins in triple-negative breast cancer: Apoptosis, chemosensitization and degradation of mutant-p53 [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1775.