A Gene Known for Its Role in Heart Disease Also Drives Metastasis in Breast Cancer

Replicating good luck

While the discovery of a lump evokes an existential dread, initial or “primary” tumors are rarely fatal. Instead, these tumors often kill indirectly, by seeding new growths elsewhere — via the lymphatic system, breast cancer can spread to bone, the lungs, the liver, or the brain, and an analysis in Norway found that at least two-thirds of all cancer deaths result from metastasis.

But this process isn’t a given; the body has mechanisms in place to prevent the spread of cancer. Scientists have long suspected that so-called driver mutations, genetic abnormalities that arise over the course of life and fuel a primary tumor’s emergence and growth, may also empower cancer to overcome these barriers. But so far, researchers haven’t identified any mutations that arise anew in tumors to propel metastasis.

After Mei joined his lab in 2019, Tavazoie saw an opportunity to look for more metastasis-controlling variants like those in APOE. Rather than relying on molecular experiments and good luck, this time they would take advantage of Mei’s background in computational biology to examine patients’ genetic data. They also shifted their focus from melanoma to breast cancer.

Researchers often turn to genomes collected from members of various populations to divine genetic links to disease. Depending on the circumstances, these studies can draw on data from thousands or even a million or more participants. Mei, however, was limited to a much smaller set of 1,099 patients, whose information he pulled from two databases. Within it, he searched for genes linked to how long the patients had lived after being diagnosed — a proxy for metastasis.

But to find meaningful results from within this relatively tiny data set, he needed to narrow his search. He did so by focusing on common genetic changes with established links to diseases of any type, an approach that guaranteed he was looking only at variants with known significant effects on the physiology of those who carried them.

This analysis yielded eight gene candidates, and he and Tavazoie recognized one of them quickly: PCSK9.

The cholesterol connection

PCSK9’s potential as a target for lowering cholesterol came to light two decades earlier through a similar, though larger, analysis of genetic and health-related data.

In 2000, Helen Hobbs, a physician–scientist with a long-running interest in cholesterol metabolism, co-founded the Dallas Heart Study to look for rare genetic variations that influence cardiovascular health. Drawing upon data from several thousand Dallas County residents, she and her collaborator Jonathan Cohen looked for abnormal versions of PCSK9 in people who had unusually low levels of low-density lipoprotein (LDL), the “bad” cholesterol known for clogging arteries and contributing to heart disease.

The PCSK9 protein increases LDL levels by binding to and initiating the removal of receptors on the surface of liver cells that would otherwise take this fatty, waxy substance out of the blood.

Hobbs and Cohen found what they sought: alterations, present primarily in African-American study participants, that interfered with PCSK9’s function and depressed LDL levels. Although this reduction in cholesterol was relatively moderate, it substantially lowered the risk of heart disease, paving the way for the development of LDL-lowering PCSK9 inhibitor drugs now used by many patients.

Interestingly, in addition to its newly discovered role in breast cancer metastasis, the version of PCSK9 that turned up in Mei’s search has an opposing, if less pronounced, effect. A difference of just a single letter in its DNA code boosts the PCSK9 protein’s LDL receptor–removing activity, leading to a slight increase in LDL and heart disease risk.

A new way to fight metastasis?

After the initial analysis implicated PCSK9, Mei acquired more patient data from Europe and collaborated with Swedish researchers who confirmed these findings in Scandinavian women with early-stage breast cancer. Mei also turned to the lab to explore the mechanisms underlying the effect on metastasis and to untangle this from the gene’s known role in cholesterol control. In experiments in mice whose genomes included the PCSK9 variant, breast tumors metastasized aggressively to the lungs. However, altering PCSK9 in tumors alone did not encourage metastasis. And while high cholesterol levels can promote cancer, feeding the animals high-cholesterol diets indicated that high LDL levels on their own also did not explain the increase in metastasis.

The team then began looking for another explanation.

Further work showed that, in addition to acting on the receptor that removes LDL from the blood, PCSK9 acts on another, related molecule called LRP1. Unlike the specialized LDL receptor, LRP1 participates in many physiological processes, including preventing the spread of malignancies.

Positioned on the surface of cancer cells, LRP1 inhibits their ability to attach to foreign tissue, preventing cells from breast cancer tumors from establishing themselves in lung, bone, or elsewhere. Unable to land, the circulating cells eventually die.

But as with the LDL receptor, PCSK9 reduces LRP1’s presence on cells. The researchers determined that the PCSK9 gene’s hyperactive version eliminates LRP1 more quickly and potently, activating genes that help cancer cells establish a new colony.

And, in another round of experiments, they turned a cholesterol-lowering medication on the cancer. Working with mice, tissue, and cell lines, they found that a PCSK9-blocking antibody slowed the progression of metastasis. It had an even more pronounced effect preventing these new tumors from forming in the first place.

“It tells us it’s possible that inhibiting the PCSK9 pathway could reduce metastatic relapse,” Tavazoie says, referring to a deadly phenomenon in which cancer returns, but in places it didn’t exist before treatment.

He envisions combining a PCSK9 inhibitor, one already approved to lower cholesterol, with conventional breast cancer therapies for those at high risk of such a relapse, and Mei and others in his lab have begun preliminary studies using this approach. In future searches for metastasis-controlling genes, Tavazoie plans to use the same strategy that led to PCSK9 — searching patient data with a focus on genes already linked to disease.

‘Surprising science’

Although she hasn’t worked on PCSK9 for more than a decade, Hobbs, a member of the Chan Zuckerberg Initiative’s Scientific Advisory Board and a professor at UT Southwestern Medical Center, still keeps tabs on the field. So the discovery by the Rockefeller group caught her eye while she was reading Cell. That this minor difference has a major effect on metastasis, specifically in breast cancer, is “striking,” she says. It is also further evidence of the secrets hidden in genetic data, whether from patients or the general population.

“Genetics hands you these unexpected observations that can form the basis of really surprising science,” Hobbs says. “That certainly happened to me with PCSK9, and I think that is also true in this case.”