High levels of cholesterol in the blood, as a result of diet or disease, have been associated with an increased risk for breast cancer recurrence. Studies suggest that cancer cells may use this molecule to fuel tumor growth or to impair the immune system. But a study published this week (February 2) in Molecular Therapy reports that cholesterol synthesis can also take place within tumor cells themselves, stimulating metastatic growth. This process is mediated by communication between triple negative breast cancer (TNBC) cells and fibroblasts from the lungs. Researchers were able to inhibit this signaling cascade and reduce lung metastasis by treating mice with the most common cholesterol-lowering drugs—statins.
“This study provides a promising route through which cholesterol pathways could be targeted to treat TNBC, which is concordant with epidemiological studies that show a potential benefit to statins in patients who have been diagnosed with TNBC,” writes MD Anderson radiation oncologist and cancer epidemiologist Kevin Nead, who did not participate in the work, in an email to The Scientist.
TNBC is a particularly difficult cancer to treat. Its name reflects its lack of three cell surface receptors, found in other breast cancer subtypes, that are commonly targeted during treatment. TNBC patients a higher death rate than people with other subtypes, says Bingchen Han, a cancer researcher at the Cedars-Sinai Medical Center in Los Angeles and coauthor of the new study. Another hallmark of TNBC is its propensity to spread to other organs, especially to the lungs and the brain. Han explains that he and his colleagues were interested in better understanding the molecular basis behind this tendency to metastasize.
Han and his coauthors first looked at the gene expression profile of TNBC cells, searching for key factors secreted that may pave the way toward the colonization of the lung. Using cultured cells, they compared the profile of tumor cells with low and high levels of a biomarker that is used as a predictor of TNBC lung metastasis, and found a group of chemokines that were significantly upregulated in TNBC cells prone to metastasis. By analyzing human breast tumor samples, Han and his colleagues also found that higher expression levels of these chemokines correlated negatively with the length of time breast cancer patients survived free of metastasis in the lung. Experiments in mice showed that knocking out these signaling molecules in breast tumor cells significantly reduced the presence of cancer tissue in the animals’ lungs.
Han and his colleagues set out to unravel the details of how these chemokines end up fueling metastasis. A series of experiments in human and mouse cell lines and in mice with TNBC led them to the discovery of a signaling cascade that works as a positive feedback loop between tumor cells and lung cells. The upregulated chemokines first identified in the TNBC cells (known as CXCL1, 2, and 8) stimulate fibroblasts in the lung to secrete other chemokines (CCL2 and 7) which feedback to disseminated cancer cells in the lung metastatic site and prompt them to synthesize cholesterol. This molecule then induces the formation of new blood vessels in the lung, which is critical to metastasis.
Cholesterol’s involvement in the process was unexpected, says Han. Cholesterol has been associated with poor outcome in breast cancer patients—for instance, by impairing the immune response, selecting for cells with higher metastatic capacity, or promoting the secretion of extracellular vesicles stimulating breast cancer progression. But Han says this study is the first to report “that newly synthesized cholesterol plays a role in lung metastasis of triple negative breast cancer patients.” It’s not the cholesterol coming from food, he adds, but rather from the tumor cells themselves.
These cancer cells “have found a way to make their own cholesterol by tricking fibroblasts into secreting factors that then work on the cancer cells to start making cholesterol, among other factors involved in new blood vessel formation,” Erik Nelson, a cancer pharmacologist at the University of Illinois at Urbana-Champaign who was not involved in this study, writes in an email to The Scientist. “This reveals a novel function for cholesterol, adding to a growing list of how cancer cells can use cholesterol to their advantage,” he adds.
Han and his colleagues used simvastatin, an approved statin medication for lowering cholesterol levels, to treat TNBC in a mouse model. The drug was administered nasally to the mice using nanoparticles that specifically target tumor cells. Mice undergoing this treatment had fewer metastatic nodules and a reduced blood vessel density in the lung metastatic site compared to a control group that only received the nanoparticle without the drug.
Retrospective studies on breast cancer patients taking statins suggest that these drugs may indeed reduce breast cancer recurrence and mortality. However, “at this time, it is hard to say exactly why this is,” says Nelson, “and whether they impact the cellular communication loop described here.” But the new study does offer further support “to the potential benefit of statins in patients with TNBC,” says Nead.
Yet these results still need to be validated in humans, Nelson and Nead tell The Scientist. Han agrees, adding that his team plans to continue improving the nanoparticle-simvastatin combination they used in this study. The specificity of the nanoparticles exposes the tumor cells to higher levels of the drug compared to oral administration, and thus may enhance its effect on them, he explains. But he also acknowledges that these studies are at an early stage, and there is still “a long way to go” before the nanoparticles might be used to treat cancer patients.