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Genetic Evidence Links Cholesterol and Cancer
Finding could spur new approach to cancer intervention (Sept. 13)
According to a September 13 announcement from the University of Rochester Medical Center in Rochester, N.Y., researchers have discovered new genetic evidence linking cholesterol and cancer, raising the possibility that cholesterol medications could be useful in the future for cancer prevention or to augment existing cancer treatment.
The data, published in the online journal Cell Reports, support several recent population-based studies that suggest individuals who take cholesterol-lowering drugs may have a reduced risk of cancer, and, conversely, that individuals with the highest levels of cholesterol seem to have an elevated risk of cancer.
The cancer–cholesterol question has been debated since the early 20th century. Until now, however, genetic evidence directly linking cholesterol and malignancy has been lacking, said senior author Hartmut Land, PhD.
Cholesterol is a fat-like substance supplied in foods and made in cells throughout the body. Too much cholesterol is bad for the heart and vascular system. It is typically measured as serum cholesterol by routine blood tests.
Unlike serum cholesterol that is bound to proteins, however, cholesterol also hides inside cells. While locked inside cell membranes, before it is eventually exported, cholesterol has an effect on cell growth and survival. A gene, known as ABCA1, is at the crossroads of the process that shuttles intracellular cholesterol outbound.
Several years ago, Land and colleagues first noticed the importance of the ABCA1 gene. At that time, they identified a network of approximately 100 so-called “cooperation response genes” that mediate the action of cancer genes. ABCA1 was found among these genes and is frequently turned off in the presence of other mutant cancer genes. In the new investigation, Land and co-author Bradley Smith, PhD, wanted to further understand the role of the ABCA1 gene and cholesterol in cancer. They found that defective cholesterol exportation appears to be a key component in a variety of cancers.
The proper function of ABCA1 is critical for the sensing of cell stress. If ABCA1 function is lost in cancer cells, cholesterol is allowed to build up in the cells’ mitochondria, or energy centers, making their membranes more rigid. This in turn inhibits the function of cell-death triggers that normally become activated in response to cell stresses, such as cancer gene activation. Therefore, when functioning properly, ABCA1 has anticancer activity in the sense that, by keeping mitochondrial cholesterol low, it protects the functioning of cellular stress-response systems and acts as a barrier to tumor formation and progression.
Smith and Land also demonstrated that some of the relatively rare ABCA1 mutations found in human colon cancers by other investigators disabled the gene’s ability to export cholesterol. By re-establishing the cholesterol export function in human colon cancer cells, they inhibited the cells’ ability to grow as cancers when grafted onto mice.
The new study, therefore, is the first to directly show how ABCA1 loss-of-function and cholesterol may play a role in cancer.
“Our paper provides a rationale for cholesterol targeting as a potentially fruitful approach to cancer intervention or prevention strategies,” Land said.
For more information, visit the University of Rochester Medical Center Web site.
