Studies demonstrate that tumors are dependent on the cholesterol-forming mevalonate pathway.
Researchers have identified a pathway that is elevated in p53-mutated cancers and that points to the potential for using cholesterol-lowering statins to help hold back cancer progression. Studies on 3-D breast cancer cell cultures by a Columbia University-led team found that p53 mutations elevate the cholesterol-synthesizing mevalonate pathway, which has been implicated in multiple aspects of tumorigenesis, including proliferation, survival, invasion, and metastasis. The cancer cells then appear to become dependent on this pathway for their continued survival, cancer phenotype, and invasive properties.
Reporting in Cell, Carol Prives, Ph.D., and colleagues found that either knocking out p53 in the cell lines or treating the cultures with the lipophilic statin drugs simvastatin or metavastin, halted cancer cell growth, held back invasive morphology, and in some cases led to cancer cell death. In fact, they report, using compounds to block any one of a number of enzymes in the mevalonate pathway had similar phenotypic effects on the cultured breast cancer cells as statin therapy or mutant p53 depletion.
Even more encouragingly, the team subsequently found that simvastatin treatment significantly blocked tumor growth in mice implanted with human p53-mutated cancer cells. “This suggests that breast cancer cells bearing mutations in p53 upregulate the mevalonate pathway and eventually become dependent upon its activity for survival,” they write.
The authors moved on to compare the expression levels of 17 mevalonate pathway genes in 812 human p53-mutated and p53-wildtype breast cancer samples. They found that across all datasets, 11 of the genes were significantly upregulated specifically in the mutant p53 breast tumors. Interestingly, it was also evident that the higher the expression levels of sterol biosynthesis genes, the higher the rate of p53 mutations. And in clinical terms, the most elevated mevalonate gene-expression profiles were associated with the least favorable patient prognosis and survival.
“Because breast cancer cells bearing mutant p53 appear to be particularly sensitive to inhibition of the mevalonate pathway in the 3-D culture system, the fact that multiple members of this pathway are upregulated in mutant p53 expressing human tumors and correlate with a poor prognosis may have important therapeutic implications,” they conclude. “At a clinical level, inhibition of the mevalonate pathway, either alone or in combination with other therapies, may offer a much needed therapeutic option for tumors bearing mutant p53.