Statins in Breast Cancer Therapy: Mechanistic Insights and Emerging Evidence

Breast cancer (BC) remains the most frequently diagnosed malignancy worldwide, with an estimated 2.3 million new cases and approximately 685,000 deaths reported in 2020. Forecasts suggest a substantial rise in global incidence, with new annual cases projected to reach 3.2 million by 2050, representing a 39% increase. Additionally, BC is expected to account for approximately 7.7% of the anticipated $25.2 trillion global economic burden associated with cancer by 2050. These trends underscore an urgent need for affordable, widely accessible and effective therapeutic strategies, particularly in low- and middle-income countries. Statins, commonly prescribed for the treatment of hypercholesterolaemia via inhibition of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, have garnered increasing interest for their potential anticancer properties. This review focuses on the mechanistic underpinnings and therapeutic implications of statin use, particularly simvastatin, in the context of BC. Statins exert their primary effect through inhibition of the mevalonate pathway, which is crucial for cholesterol and isoprenoid biosynthesis. Disruption of this pathway impairs the prenylation of key signalling proteins, including members of the Ras and Rho GTPase families, which are essential for cancer cell proliferation, survival and metastasis. Preclinical evidence has demonstrated that simvastatin can induce tumour cell apoptosis, arrest cell-cycle progression and inhibit oncogenic signalling pathways. These effects have been particularly pronounced in hormone receptor-negative and triple-negative breast cancer (TNBC) subtypes, which are often associated with poor prognosis and limited treatment options. Epidemiological and observational studies further support a potential association between statin use and reduced BC recurrence and mortality. Nevertheless, robust evidence from randomised controlled trials remains limited, and further investigation is required to establish causality and define optimal therapeutic regimens. Given their well-established safety profile, global accessibility and pleiotropic effects, statins, especially simvastatin, represent a promising class of repurposed drugs in the adjuvant treatment of BC. This review synthesises evidence from the past two decades, highlighting the need for continued clinical research to validate and optimise the use of statins as adjunctive agents in BC therapy.