Sources: Nature Cell Biology, May 2013; Washington University School of Medicine, St. Louis
Breast Cancer Spread (metastasis) risk is higher in women with dense breast tissue. Researchers at Washington University School of Medicine in St. Louis have discovered why breast cancer patients with dense breasts are more likely than others to develop aggressive tumors that spread. This greater density is caused by an excess of a structural protein called collagen.
“We have shown how increased collagen in the breasts could increase the chances of breast tumors spreading and becoming more invasive,” says Gregory D. Longmore, MD, professor of medicine. “It doesn’t explain why women with dense breasts get cancer in the first place. But once they do, the pathway that we describe is relevant in causing their cancers to be more aggressive and more likely to spread.”
Working in mouse models of breast cancer and breast tumor samples from patients, Longmore and his colleagues showed that a protein that sits on the surface of tumor cells, called DDR2, binds to collagen and activates a multistep pathway that encourages tumor cells to spread. “We had no idea DDR2 would do this,” says Longmore. “The functions of DDR2 are not well understood, and it has not been implicated in cancer — and certainly not in breast cancer — until now.”
At the opposite end of the chain of events initiated by DDR2 is a protein with the unfortunate acronym of “SNAIL1,” which has long been associated with breast cancer metastasis. Longmore and his colleagues found that DDR2 is one factor helping to maintain high levels of SNAIL1 inside a tumor cell’s nucleus, a necessary state for a tumor cell to spread. Though they found it is not the only protein keeping SNAIL1 levels high, Longmore says DDR2 is perhaps the one with the most potential to be inhibited with drugs. “It’s expressed only at the edge of the tumor,” says Longmore. “And it’s on the surface of the cells, which makes it very nice for developing drugs because it’s so much easier to target the outside of cells.”
The researchers emphasize that DDR2 does not initiate the high levels of SNAIL1. However, it is required to keep the level elevated. This mechanism that keeps tumor cells in a state that encourages metastasis requires constant signaling — meaning constant binding of DDR2 to collagen. If that signal is blocked, the cell remains cancerous, but it is no longer invasive. So a drug that blocks DDR2 from binding with collagen won’t destroy the tumor, but it could inhibit the invasion of these tumors into surrounding tissue and reduce metastasis. “This whole notion of fiber alignment and the tumor interface is a hot topic right now,” Longmore says. “Our co-authors at the University of Wisconsin have developed a scoring method for collagen alignment that correlates with prognosis. And the bad prognosis disappears when you take away DDR2.”
70% of invasive ductal breast cancers show DDR2. But in 95% of these tumors the genes in this pathway — from DDR2 to SNAIL1 — are entirely normal, without mutations. “Currently there are no DDR2 specific inhibitors,” Longmore says. “But there is great interest and work being done here and elsewhere to develop them.”
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