ST. LOUIS—Women with denser breasts live with the knowledgethat they are at a higher risk of developing breast cancer, and within thatgroup, those diagnosed with breast cancer are more prone to developingaggressive tumors with a tendency to metastasize. The greater density resultsfrom an excess of collagen, and new research from the Washington UniversitySchool of Medicine in St. Louis has shed some light on why an overabundance ofthis natural protein predisposes this group to cancer and metastasis.
Researchers worked with mouse models of breast cancer aswell as tumor samples from patients and discovered that there is a protein,DDR2, found on the surface of tumor cells. This protein binds to collagen andactivates a pathway that encourages the spread of tumor cells. This sequencecontains another protein, SNAIL1, at the other end of the pathway, that isknown to play a role in cancer metastasis. Gregory D. Longmore, M.D., professorof medicine at Washington University School of Medicine in St. Louis, and hiscolleagues found that DDR2 is one of the biological factors responsible forkeeping levels of SNAIL1 high inside tumor cell nuclei, thereby priming them tospread. It is not the only protein responsible for maintaining SNAIL1 levels,according to Longmore, but it might represent the most viable target.
"We have shown how increased collagen in the breasts couldincrease the chances of breast tumors spreading and becoming more invasive,"said Longmore in a press release. "It doesn't explain why women with densebreasts get cancer in the first place. But once they do, the pathway that wedescribe is relevant in causing their cancers to be more aggressive and morelikely to spread."
To keep SNAIL levels high, DDR2 must be constantly bindingwith collagen. If that signaling is blocked, the cell, while still cancerous,is no longer invasive, which means that a drug capable of inhibiting DDR2 frombinding to collagen could reduce metastasis.
More studies need to be done on this protein, but it'spossible that DDR2 might control metastasis as a result of the alignment ofcollagen fibers. If the fibers are parallel to the tumor's surface, it is lesslikely to spread, but fibers that are perpendicular to the tumor encouragemetastasis. Tumors that lack DDR2 or SNAIL1 evince that the parallel collagenfiber alignment is protective against the spread of tumors.
Longmore noted that DDR2's functions aren't well understood,and that up to this point, it has not been implicated in cancer. Given itsreaction with collagen and its relationship with SNAIL1, however, DDR2 couldrepresent an attractive new target, as the protein is found on the surface ofthe cells and the edge of tumors, said Longmore, a physician at Siteman CancerCenter at Washington University and Barnes-Jewish Hospital and co-director ofthe Section of Molecular Oncology.
"The collagen receptor is an unusual candidate forregulating tumor cell migration, and the extent to which it did so was alsosurprising," says Longmore. "Most receptors of this nature are activated bygrowth factors or cytokines, not by structural proteins. Moreover, the locationwhere this receptor is activated makes perfect sense to explain where the SNAILprotein is stabilized in tumors."
And while many cancer subtypes are the result of geneticmutations, Longmore noted that while 70 percent of invasive ductal breast cancerspresent with DDR2, in 95 percent of those tumors, all the genes in the pathwayhave no mutations.
"If you did genomic sequencing, all of these particulargenes would be normal," said Longmore. "You have to be careful not to justfocus on mutations in cancer. This is an example of normal genes put togetherin an aberrant situation. The change in the environment — the tumor and itssurroundings — causes the abnormal expression of these proteins. It isabnormal, but it's not caused by a gene mutation."
Longmore expects this discovery to result in new answers andbenefits, noting that it will hopefully lead to "understanding how tumor cellsalter the organization of collagen fibers to facilitate their exit from primarytumors and metastasize," and that DDR2 "could be an important new target forthe development of therapeutics to treat or prevent metastatic breast cancer."
The researchers will be pursuing research into DDR2 inseveral directions, including its role in the metastasis of other cancers.Longmore says they have "an early interest in pancreatic cancer and head andneck cancers, including esophageal cancer, in particular." In addition,Longmore says they will also seek to understand more about DDR2, specificallyhow the receptor signals and how it is regulated, and whether it contributes toother tumors. They will work on developing drugs that can block DDR2's activityspecifically, and explore the function of mutations in this protein found insequencing studies of other tumors, such as those from lung or esophagealcancers.
While Longmore has noted that there are currently noinhibitors specific to DDR2, he added that work is underway at WashingtonUniversity and elsewhere for their development.
"We are currently working to discover molecules that inhibitthe binding of DDR2 to collagen," says Longmore. "Many of the existing receptortyrosine kinase drugs (e.g., imatinib) already in the clinic will inhibit thekinase activity of DDR2 as well."
The study, "The collagen receptor discoidin domain receptor2 stabilizes SNAIL1 to facilitate breast cancer metastasis," appeared online onMay 5 in Nature Cell Biology.
