Why cholesterol-lowering statins might treat cancer

Cholesterol-lowering statins seem to keep breast cancer at bay in some patients. Now researchers reporting in the January 20th issue of the journal Cell, a Cell Press publication, provide clues about how statins might yield those unexpected benefits. The findings also suggest that mutations in a single gene could be used to identify tumors likely to respond to statin therapy.

"The data raises the possibility that we might identify subsets of patients whose tumors may respond to statins," said Carol Prives of Columbia University. "Of course we can't make any definitive conclusions until we know more."

Prives said that a clinical trial of statins in breast cancer based on the mutation status of the tumor suppressor, p53, may be in order. The p53 tumor suppressor acts to regulate many aspects of cell proliferation, generally putting the brake on uncontrolled growth.

More than half of all human cancers carry mutations in the p53 gene. Many of these mutations don't simply disrupt the normal function of p53, they also endow p53 with new functions that promote, instead of inhibit, cancer formation. Mice lacking p53 develop cancer and die, Prives explained, but mice carrying tumor-derived mutant forms of the p53 gene suffer from more aggressive disease. What these mutant forms of p53 are actually doing is a big question in cancer research.

Prives' team designed experiments to sort this mystery out. By studying cancer cells grown in an artificial system that resembles the three-dimensional structures in the human breast, the researchers learned that cells carrying mutant p53 grow in a disorganized and invasive manner, characteristic of human breast cancers. When the researchers lowered the levels of mutant p53, the 3D cell cultures grew more normally.

Further studies, led by study first author William Freed-Pastor, traced the structural changes to a cholesterol-building pathway (called the mevalonate pathway). This is the same pathway targeted by cholesterol-lowering statins. When the mutant p53 cells were treated with statins, they stopped their disorganized, invasive growth, and in some cases, even died. Importantly, the effects of the drugs were erased when intermediates of the mevalonate pathway were added back in, additional proof that the drug wasn't working in some other, off-target way.

Do statins cut breast cancer recurrence? “A daily dose of drugs designed to lower cholesterol could also slash the risk of breast cancer recurring,” the Daily Mail reported today.

The news is based on the findings of a large Danish study that looked for an association between the use of statins and the recurrence of breast cancer. Researchers followed 18,769 women, for an average of 6.8 years, who had previously been diagnosed with invasive breast cancer. Of these, 17% had been prescribed statins at some point. Compared to women who did not use statins, women who took simvastatin and other “lipophilic” (fat-soluble) statins were less likely to have breast cancer that reoccurred. Those who took “hydrophilic” (water-soluble) statins did not have a reduced risk. However, this type of statin was used by only 6% of the statin users, which limits the strength of this finding.