Bone Abstracts

Breast cancer is the most frequent malignancy in women and frequently results in osteolytic bone metastases. Amino-bisphosphonates are a standard bone protective therapy and, similarly to statins, inhibit the mevalonate pathway that is crucial for posttranslational protein modifications (farnesylation and geranylation). Direct anti-tumor effects of amino-bisphosphonates and statins have been suggested but high concentrations are necessary to achieve meaningful effects. Our study aimed to assess the potential of combining amino-bisphosphonates with statins to reach anti-tumor effects at lower doses.

We demonstrate that the expression levels of both targets of statins and amino-bisphosphonates, the 3-hydroxy-methyl-glutaryl-CoA reductase (HMGCR) and the farnesyl diphosphate synthase (FDPS), show a positive correlation in clinical samples of breast cancer (P≤0.0001) pointing to a potential benefit of simultaneously targeting both enzymes. Treating different osteotropic human cancer cell lines (MDA-MB-231, MDA-BONE, MDA-MET, MDA-453s, and PC3) with a combination of low concentrated statins (atorvastatin, simvastatin and rosuvastatin) and zoledronic acid resulted in significant anti-tumor-effects (50% reduction of cell vitality and fourfold induction of apoptosis; P<0.05). Apoptosis was the result of blocked geranylation rather than farnesylation. Rho GTPases like RhoA, Rac1, and CDC42 represent a major class of geranylated proteins. Surprisingly, the treatments with mevalonate pathway inhibitors, individually or in combination, caused an accumulation of GTP-bound RhoA and CDC42 but not of Rac1. Importantly the knockdown of RhoA and CDC42 prior to the treatment with simvastatin and zoledronic acid reduced the caspase 3/7 activation by up to 60% and the cleaved PARP accumulation by up to 80% in MDA-MB-231 human breast cancer cells (P<0.01). The observations point to a contribution of these Rho GTPases in the anti-tumor effects by statins and zoledronic acid.

Our results suggest the combination of statins and zoledronic acid as an effective approach for the adjuvant treatment of breast cancer.