p140Cap modulates the mevalonate pathway decreasing cell migration and enhancing drug sensitivity in breast cancer cells

p140Cap is a protein encoded by the SRCIN1 gene and is naturally present in neurons and various epithelial tissues, including the breast. Its primary function is to form multi-protein complexes that influence a wide range of cellular processes, from synaptic plasticity to modulation of the tumour microenvironment. Previous research suggests that p140Cap acts as a tumour suppressor in breast cancer (BC) and neuroblastoma (NB) patients. The expression of p140Cap is associated with a better prognosis and a delay in the spread of metastasis to other parts of the body. Although p140Cap has been recognised to have a counteracting role in cancer progression through various mechanisms, its impact on tumor metabolism has not been extensively studied. Recent evidence has highlighted the critical role of cancer cell metabolism in tumor progression. The aim of this study is to investigate the effect of p140Cap on the metabolism of BC cells, with a particular focus on its role in modulating the mevalonate (MVA) pathway. This pathway is critical for the synthesis of cholesterol and non-steroidal isoprenoids and is often dysregulated in cancer. Our results indicate that cells and tumors expressing p140Cap exhibit increased flux through the MVA pathway, both in cells and in living organisms. The up-regulation of this route is attributed to the positive regulation of the key enzyme in this pathway, 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR), by both transcriptional and post-translational mechanisms. The study also found that increased cholesterol synthesis is associated with augmented cholesterol efflux. Furthermore, p140Cap contributes to higher cholesterol localisation in the cell membrane, leading to an increase in lipid raft formation. This alteration has a negative effect on cell membrane fluidity and cell migration, especially in a cholesterol-dependent manner. Moreover, BC cells expressing p140Cap exhibit reduced viability when treated with statins, either alone or in combination with low concentrations of chemotherapeutic agents, indicating a synergistic effect. These findings provide a new perspective on tumor suppression in BC and reveal a previously unrecognized role for the MVA pathway in tumors expressing p140Cap. This finding indicates that p140Cap has the potential to be a powerful biomarker for grouping patients for more precise therapeutic interventions.