New discovery shows how breast cancer spreads
Researchers have discovered why breast cancer patients with dense breasts are more likely than others to develop aggressive tumors that spread. The discovery, published online May 5, 2012 in Nature Cell Biology, opens the door to drug treatments that prevent metastasis.
It has long been known that women are at an increased risk for breast cancer if they have denser breasts, which is caused by a surplus of collagen.
"We have shown how increased collagen in the breasts could increase the chances of breast tumors spreading and becoming more invasive," said Gregory D. Longmore, MD, of Siteman Cancer Center at Washington University and Barnes-Jewish Hospital, who is also co-director of the Section of Molecular Oncology. "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."
Longmore and his colleagues showed that a protein sits on the surface of tumor cells, called DDR2, which binds to collagen and activates a multistep pathway that encourages tumor cells to spread.
"We had no idea DDR2 would do this," says Longmore, who is also professor of cell biology and physiology. "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 spectrum of activities initiated by DDR2 is a protein called SNAIL1, which has long been associated with breast cancer metastasis. Longmore and his team discovered that DDR2 is a part of what helps maintain high levels of SNAIL1 inside a tumor cell's nucleus – a necessary environment for a tumor cell to spread. While they found it is not the only protein keeping SNAIL1 levels high, Longmore says DDR2 may have the most potential to be inhibited with drugs.
"It's expressed only at the edge of the tumor," explained 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."
Longmore stresses that DDR2 does not initiate the high levels of SNAIL1. However, it is required to keep them elevated. This mechanism that keeps tumor cells in a state that encourages metastasis requires constant signaling, which means constant binding of DDR2 to collagen.
When that continuous signal is blocked, the cell remains cancerous, but it is no longer invasive.
SOURCE: Kun Zhang, Callie A. Corsa, Suzanne M. Ponik, Julie L. Prior, David Piwnica-Worms, Kevin W. Eliceiri, Patricia J. Keely, Gregory D. Longmore. The collagen receptor discoidin domain receptor 2 stabilizes SNAIL1 to facilitate breast cancer metastasis. Nature Cell Biology, 2013; DOI: 10.1038/ncb2743