Protein that Turns Breast Cancers Deadly

Israeli biologists have demonstrated that a specific protein induces breast cancer cells to invade other tissues and acquire properties that are characteristic of metastatic tumor cells. The work will be published in the April 1 issue of Cancer Research.

When tumors metastasize, they can no longer be cured by surgery alone and generally kill the patient rapidly. The protein, called lysyl-oxidase-related protein 1 (LOR-1), both causes tumors to spread and induces the deposition of large amounts of collagen fibers that are a hallmark of deadly breast cancers. The team believes that chemicals that block or inhibit LOR-1 may be developed as possible treatments for breast cancer, preventing metastasis. ).

The team was led by Gera Neufeld of the Department of Cell Biology and Anatomy at the Technion-Israel Institute of Technology in Haifa, and by Michael Neeman of the Department of Biological Regulation, Weizman Institute of Science in Rehovot.

"This solves a big puzzle in breast cancer studies," says Dr. Neufeld. It is known that invasive tumor cells secrete enzymes that dissolve the barriers that separate one type of tissue from another. An important constituent of these barriers is collagen fibers. Yet in breast cancer, tumors that are about to metastasize produce large amounts of collagen. What causes the tumor to both create collagen, and then burst through it into other tissues?

Researchers have previously discovered several proteins that promote metastasis, but none of them caused breast cancer tumors to behave the way they do in patients -- creating fibrotic lumps at the same time they were metastasizing. The link between these two apparently contradictory processes was not found.

However, the new work shows that the LOR-1 protein does produce just that combination of effects -- both generating collagen and causing the tumor to metastasize. "This indicates that LOR-1 may be a key factor in the progression of breast cancer in humans," says Dr. Neufeld.

The researchers were able to demonstrate LOR-1's activity by using lines of breast cancer cells that lacked the ability to produce this protein and comparing them to breast cancer cells that had been genetically engineered to produce LOR-1. The two types of cells were then injected into mice to produce cancer tumors. They found that only the cells that produced LOR-1 became invasive and acquired the characteristics of highly malignant and metastatic cancer cells, such as an ability to migrate into blood vessels. In contrast, cells that do not make LO-1 produce benign, non-invasive tumors. The same relationship was found with the production of collagen fiber; only the LOR-1-producing cells produced excessive amounts of fiber. Curiously, the LOR-1 producing tumors grew much more slowly than those that lacked this protein, but they were far more deadly in their ability to spread.

In addition, studies of breast cancer cells taken from human patients showed that localized, benign tumors generally did not produce LOR-1 but the highly malignant, and far more deadly, tumors always produced large amounts of the protein.

"Now that we know that the product of the very same gene produces the fibers and allows the cancer to metastisize, we are closer to understanding why this happens," says Dr. Neufeld. One likely idea, he believes, is that LOR-1 causes fibers to clump together in thick cables, rather than remaining spread out in a thin sheath. "Normal collagen is like a fine sieve that keeps cells in place, but the cancer-produced fiber is more like a mesh of thick cables with holes that may be big enough for cancer cells to pass through easily," he explains.

The researchers are now turning to developing an agent that will inhibit the production of LOR-1. If such an inhibitor can prevent breast cancers from metastasizing, surgical removal of the tumors should have a better chance of success than is the case at present.

The Technion-Israel Institute of Technology is Israel's leading scientific and technological university. It commands a worldwide reputation for its pioneering work in computer science, biotechnology, water-resource management, materials engineering, aerospace and medicine. The majority of the founders and managers of Israel's high-tech companies are alumni.

Based in New York City, the American Technion Society is the leading American organization supporting higher education in Israel, with more than 20,000 supporters and 17 offices around the country.