Abstract 20: Fluvastatin inhibits the development of breast cancer in SV40C3Tag mouse model of triple negative breast cancer
Authors: Bhardwaj Anjana , Embury Matthew D. , Rojo Raniv D. , Albarracin Constance , Bedrosian Isabelle 
Published: September 2020

Abstract
Introduction: Primary prevention of breast cancer that is effective at preventing both HR- and HR+ tumors, remains an important clinical need and repurposing of existing low toxicity drugs represents a low cost, efficient strategy for meeting this goal. Cholesterol pathway activation is associated with poor prognosis across all subtypes of breast cancer patients. Relevant to breast cancer prevention, the breast epithelium in women with atypical hyperplasia, a known high risk state, is known to have increase in cholesterol levels and an increase in oxidative products of cholesterol. Additionally, cholesterol pathway genes such as HMG Co A reductase (HMGCR) are deregulated in transformed cells and drive the initiation and progression of breast cancer. These observations suggest a role for the cholesterol pathway early in tumorigenesis, thus making it an attractive target for prevention.
Methods: Using SV40C3 tag mice, a transgenic mouse model of TNBC, we targeted the cholesterol pathway by fluvastatin. Fluvastatin is a cholesterol lowering drug that blocks the cholesterol pathway activation through inhibition of HMGCR, a rate limiting enzyme of the pathway. Ten mice each were treated with fluvastatin (10mg/kg body weight/ day) alone, in combination with aspirin, AMPK activator, or vehicle control for 16 weeks starting at the age of about 6 weeks. Starting at the age of 10 weeks, mice were regularly examined for the presence of mammary tumors and any palpable mass of 0.3mm or bigger was considered as a lesion. At the end of 16 weeks of treatment, all mice were euthanized and mammary glands were excised, weighed and divided in 2 parts- one was fixed in formalin for any histochemical analyses and the other half was snap frozen for RNA extractions.
Results: Fluvastatin treatment for 16 weeks reduced the tumor incidence and average tumor burden by 50%. Additionally, in animals that developed tumors, fluvastatin delayed the onset of palpable tumors by 2.5 weeks and inhibited tumor size, as indicated by a 4- fold lesser tumor weight in the fluvastatin treated group relative to vehicle control group. To our surprise, the combo group (fluvastatin and aspirin) did not inhibit tumor incidence or size. We found the growth inhibitory effects of fluvastatin to be mediated by increased programmed cell death.
Conclusions: In line with NCI's emphasis to repurpose low toxicity drugs for prevention of cancer, our pre-clinical data supports efforts to test the efficacy of fluvastatin for prevention of TNBC in clinical trials.
Citation Format: Anjana Bhardwaj, Matthew D. Embury, Raniv D. Rojo, Constance Albarracin, Isabelle Bedrosian. Fluvastatin inhibits the development of breast cancer in SV40C3Tag mouse model of triple negative breast cancer [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 20.