April 6, 2003

“This solves a big puzzle in breast cancer studies,” says Gera Neufeld, team leader from the Department of Cell Biology and Anatomy at the Technion.In an important breakthrough, Israeli biologists have demonstrated that a specific protein causes breast cancer cells to invade other tissues and acquire properties that are characteristic of metastatic tumor cells.

They hope that chemicals that block or inhibit this protein may be developed in the near future could be developed into possible treatments for preventing the spread of breast cancer.

Metastatic tumor cells are the most dangerous and life-threatening type, spreading rapidly to other organs. When tumors metastasize, they can no longer be cured by surgery alone and generally kill the patient rapidly.

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

Called lysyl-oxidase-related protein 1 (LOR-1), this protein causes tumors to spread and creates 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 work was published in the April 1 issue of Cancer Research. According to the National Breast Coalition Fund, an estimated 3 million women in the U.S. are living with breast cancer: 2 million who have been diagnosed and an estimated 1 million who do not yet know they have the disease. More than 180,000 women are diagnosed with breast cancer each year. Breast cancer also affects more than 1,000 men in the U.S. each year.

“This solves a big puzzle in breast cancer studies,” said Neufeld.

It has been 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. The research focused on looking at 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,” said 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 metastasic 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.

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 metastasize, we are closer to
understanding why this happens,” said 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 explained.

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.

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Jason Harris

Jason Harris

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