Abstract

Background: The Rho/Rho-Associated Coiled-Coil Containing Protein Kinase (ROCK) pathway is involved in breast cancer metastasis via its role in regulating cancer cell migration and proliferation, making it a potential target therapy. Cholesterol is implicated in cancer metabolism, both as energy source and as building blocks for lipid rafts formation in cell membrane that harbors oncogenic receptors. By inhibiting HMG-CoA Reductase (HMGCR), statins reduce cholesterol biosynthesis and decrease the formation of isoprenoid intermediates, which are essential for Rho/ROCK signalling. This study aimed to determine the antimetastasis (migration and proliferation) effect of simvastatin on breast cancer through the Rho/ROCK pathway.

Methods: In an interventional perioperative "window", randomized, doubleblinded and placebo-controlled trial, Simvastatin 40 mg/d were administered to 30 breast cancer subjects for 4-6 weeks followed by mastectomy. Changes in migration (migration index, ROCK activity, and mRNA levels of RhoC, Chemokine Receptor type 4 (CXCR4) and CD44) and proliferation (Ki67 expression) from biopsy and surgical specimen were obtained before and after intervention. The relationships of significant factors with blood cholesterol, grade, ER/PR and HER-2 status were analyzed.

Results: Simvastatin 40 mg/d significantly reduced migration index (p=0.006), ROCK activity (p=0.002), mRNA levels of CXCR4 (p=0.045) and Ki67 expression (p<0.001). Decrease was also observed in mRNA levels of RhoC (p=0.163) and CD44 (p=0.094). Reduced ROCK activity was related to hypercholesterolemia (p=0.008), low grade (p=0.019) and HER-2 amplification (p=0.009). Meanwhile, mRNA levels of CXCR4 reduction was related to hypercholesterolemia (p=0.024), positive ER/PR (p=0.013) and HER-2 amplification (p=0.018). Ki67 expression was related to hypercholesterolemia (p=0.001), low (p=0.017) or high grade (p=0.018), with (p=0.002) or without HER-2 amplification (p=0.034), and positive (p=0.007) or negative ER/PR (p=0.042).

Conclusion: Simvastatin inhibits migration and proliferation in breast cancer through Rho/ROCK pathway, hence holds a promising potential as prophylaxis for breast cancer metastasis.

Keywords: Breast cancer, metastasis, Rho/ROCK, simvastatin