Efficacy of fluvastatin and aspirin for prevention of hormonally insensitive breast cancer

Anjana Bhardwaj,Raniv D Rojo,Isabelle Bedrosian,Matthew D Embury,Constance Albarracin

doi:10.1007/s10549-021-06229-0

Abstract

PurposePrimary prevention of hormonally insensitive breast cancers remains an important clinical need and repurposing existing low-toxicity drugs represents a low-cost, efficient strategy for meeting this goal. This study targeted the cholesterol pathway using fluvastatin, a cholesterol-lowering drug, and aspirin, an AMPK activator that acts as a brake in the cholesterol pathway, in a transgenic mouse model of triple-negative breast cancer (TNBC).MethodsUsing SV40C3 TAg mice, the efficacy and mechanism of fluvastatin, aspirin, or both in combination were compared with vehicle alone.ResultsSixteen-weeks of fluvastatin treatment resulted in significant delay in onset of tumors (20 weeks vs. 16.8 weeks in vehicle treatment, p = 0.01) and inhibited tumor incidence and tumor multiplicity by 50% relative to the vehicle control. In animals that developed tumors, fluvastatin treatment inhibited tumor weight by 75% relative to vehicle control. Aspirin alone did not significantly affect tumor latency, tumor incidence or tumor burden compared to vehicle control. Fluvastatin and aspirin in combination delayed the onset of tumors but failed to inhibit tumor incidence and tumor multiplicity. The growth-inhibitory effects of fluvastatin were mediated through increased FAS/FASL mediated apoptotic cell death that was characterized by increased cleaved PARP and driven in part by depletion of an isoprenoid, geranyl geranyl pyrophosphate (GGPP).ConclusionsIn line with NCI’s emphasis to repurpose low-toxicity drugs for prevention of cancer, fluvastatin was effective for prevention of TNBC and warrants further clinical testing. Aspirin did not provide chemopreventive benefit.

Highlights

Statins, drugs that target the cholesterol biosynthesis pathway, have become among the most widespread drugs used in medical practice
We report that fluvastatin was confirmed as an effective strategy for breast cancer prevention, aspirin, alone or in combination with fluvastatin, did not show efficacy in this transgenic mouse model
To investigate the effect of fluvastatin treatment alone or in combination with aspirin on the development of mammary tumors, SV40C3 TAg mice were treated with these agents for 16 weeks, and tumor incidence, tumor burden, and tumor latency were assessed between treatment groups (Fig. 1)

Summary

Introduction

Drugs that target the cholesterol biosynthesis pathway, have become among the most widespread drugs used in medical practice. Studies that followed showed that statins were not associated with increased cancer risk, and may reduce the risk of several cancers, including breast cancer [2]. This finding that statins may reduce incidence of breast cancer is aligned with the corollary observation that the cholesterol synthesis pathway has been shown to be activated in the breast epithelium of women with high-risk breast lesions [3], and targeting the cholesterol pathway with statins inhibited breast cancer growth in mouse models [4,5,6,7].

Objectives

Methods

Results

Conclusion