Why women with dense breasts have high risk of cancer metastasis

This greater breast density is caused by an excess of a structural protein called collagen.

Washington: In a new study, 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 tumours that spread.

The finding opens the door to drug treatments that prevent metastasis. It has long been known that women with denser breasts are at higher risk for breast cancer. 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 tumours spreading and becoming more invasive," said 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," he stated. Working in mouse models of breast cancer and breast tumour samples from patients, Longmore and his colleagues showed that a protein that sits on the surface of tumour cells, called DDR2, binds to collagen and activates a multistep pathway that encourages tumour cells to spread. "We had no idea DDR2 would do this. The functions of DDR2 are not well understood, and it has not been implicated in cancer-and certainly not in breast cancer-until now," said Longmore, also professor of cell biology and physiology. At the opposite end of the chain of events initiated by DDR2 is a protein called 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 tumour cell`s nucleus, a necessary state for a tumour 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 tumour. 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," asserted Longmore, a physician at Siteman Cancer Center at Washington University and Barnes-Jewish Hospital and co-director of the Section of Molecular Oncology. Longmore emphasizes that DDR2 does not initiate the high levels of SNAIL1. But it is required to keep them elevated. This mechanism that keeps tumour cells in a state that encourages metastasis requires constant signalling - meaning constant binding of DDR2 to collagen. If that continuous 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 tumour, but it could inhibit the invasion of these tumours into surrounding tissue and reduce metastasis. One possible way DDR2 may govern metastasis is its influence on the alignment of collagen fibres. If fibres are aligned parallel to the tumour’s surface, the tumour is less likely to spread. While fibres aligned perpendicular to the surface of the tumour provide a path for the tumour cells to follow and encourage spreading. Tumours without DDR2 or SNAIL1 tend to show the parallel fibre alignment that is protective against spreading. In early drug development efforts, Longmore and his colleagues have done some preliminary work looking for small molecules that may inhibit DDR2 binding to collagen. The results appear online in Nature Cell Biology. ANI