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 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."
The results appear online May 5 in Nature Cell Biology.
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, 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 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 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, a physician at Siteman Cancer Center at Washington University and Barnes-Jewish Hospital and co-director of the Section of Molecular Oncology. "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 emphasizes that DDR2 does not initiate the high levels of SNAIL1. But it is required to keep them 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 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 tumor, but it could inhibit the invasion of these tumors into surrounding tissue and reduce metastasis.
One possible way DDR2 may govern metastasis is its influence on the alignment of collagen fibers. If fibers are aligned parallel to the tumor's surface, the tumor is less likely to spread. While fibers aligned perpendicular to the surface of the tumor provide a path for the tumor cells to follow and encourage spreading. Tumors without DDR2 or SNAIL1 tend to show the parallel fiber alignment that is protective against spreading.
"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."
With the current emphasis on genetic mutations in cancer, Longmore is careful to point out that 70 percent of invasive ductal breast cancers show DDR2. But in 95 percent of these tumors the genes in this pathway – from DDR2 to SNAIL1 – are entirely normal, without mutations.
"If you did genomic sequencing, all of these particular genes would be normal," Longmore says. "You have to be careful not to just focus on mutations in cancer. This is an example of normal genes put together in an aberrant situation. The change in the environment -- the tumor and its surroundings -- causes the abnormal expression of these proteins. It is abnormal, but it's not caused by a gene mutation."
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.
"Currently there are no DDR2 specific inhibitors," Longmore says. "But there is great interest and work being done here and elsewhere to develop them."
This work was funded by the National Institutes of Health (NIH) grants P50CA94056 to the Imaging Core of the Siteman Cancer Center at Washington University and Barnes-Jewish Hospital, GM080673, CA143868 and F31CA165729, and by Susan G. Komen for the Cure.
Zhang K, Corsa CA, Ponik SM, Prior JL, Piwnica-Worms D, Eliceiri KW, Keely PJ, Longmore GD. The collagen receptor discoidin domain receptor 2 stabilizes SNAIL1 to facilitate breast cancer metastasis. Nature Cell Biology. Online May 5, 2013.
Washington University School of Medicine's 2,100 employed and volunteer faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Children's hospitals. The School of Medicine is one of the leading medical research, teaching and patient care institutions in the nation, currently ranked sixth in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children's hospitals, the School of Medicine is linked to BJC HealthCare.
Julia Evangelou Strait | EurekAlert!
First time-lapse footage of cell activity during limb regeneration
25.10.2016 | eLife
Phenotype at the push of a button
25.10.2016 | Institut für Pflanzenbiochemie
Ultrafast lasers have introduced new possibilities in engraving ultrafine structures, and scientists are now also investigating how to use them to etch microstructures into thin glass. There are possible applications in analytics (lab on a chip) and especially in electronics and the consumer sector, where great interest has been shown.
This new method was born of a surprising phenomenon: irradiating glass in a particular way with an ultrafast laser has the effect of making the glass up to a...
Terahertz excitation of selected crystal vibrations leads to an effective magnetic field that drives coherent spin motion
Controlling functional properties by light is one of the grand goals in modern condensed matter physics and materials science. A new study now demonstrates how...
Researchers from the Institute for Quantum Computing (IQC) at the University of Waterloo led the development of a new extensible wiring technique capable of controlling superconducting quantum bits, representing a significant step towards to the realization of a scalable quantum computer.
"The quantum socket is a wiring method that uses three-dimensional wires based on spring-loaded pins to address individual qubits," said Jeremy Béjanin, a PhD...
In a paper in Scientific Reports, a research team at Worcester Polytechnic Institute describes a novel light-activated phenomenon that could become the basis for applications as diverse as microscopic robotic grippers and more efficient solar cells.
A research team at Worcester Polytechnic Institute (WPI) has developed a revolutionary, light-activated semiconductor nanocomposite material that can be used...
By forcefully embedding two silicon atoms in a diamond matrix, Sandia researchers have demonstrated for the first time on a single chip all the components needed to create a quantum bridge to link quantum computers together.
"People have already built small quantum computers," says Sandia researcher Ryan Camacho. "Maybe the first useful one won't be a single giant quantum computer...
14.10.2016 | Event News
14.10.2016 | Event News
12.10.2016 | Event News
25.10.2016 | Earth Sciences
25.10.2016 | Power and Electrical Engineering
25.10.2016 | Process Engineering