May 11, 2009

Genes Help Breast Cancer Cells Invade the Brain

Close-up photo of a breast cancer cell A breast cancer cell up closeNCI

Scientists have identified 3 genes that help breast cancer cells gain access and take root in the brain. The finding points to potential new strategies for blocking the often-deadly spread of cancer to the brain and other parts of the body.

About 90% of all cancer deaths are caused by metastatic cancer, when tumor cells break away from their original location and invade healthy tissues elsewhere. When breast cancer metastasizes, it often settles in the bones, lungs, liver or brain. But brain metastasis may not appear until years after the original breast tumor's been removed. The delay suggests that circulating breast cancer cells must undergo a slow transformation to be able to cross the brain's protective blood-brain barrier and invade brain tissues.

In previous studies, Dr. Joan Massagué of the Memorial Sloan-Kettering Cancer Center and his colleagues identified several genes that help breast cancer cells infiltrate the lungs and bone. In their latest investigation, published in the May 6, 2009, online edition of Nature, the scientists searched for genes that help cancer cells cross the blood-brain barrier and become established in the brain. Their research was funded in part by NIH's National Cancer Institute (NCI).

The scientists first isolated human breast cancer cells that could readily infiltrate the brains of mice. They searched across the genome for genes that were active, or expressed, at different levels in these cells compared to other breast cancer cells. An analysis of the resulting 243 genes in more than 300 human breast tumors narrowed the search to 17 genes whose expression correlated with brain metastasis in patients.

The investigators focused on 2 of these genes—called cyclooxygenase-2 (COX2) and heparin-binding epidermal growth factor (HB-EGF)—that were previously linked to lung metastasis. By treating mice with compounds that block the functions of these 2 genes, the scientists showed that they could reduce the ability of breast cancer cells to invade the brain. Earlier research showed that COX2 influences the growth of tumor-feeding blood vessels, and HB-EGF increases cancer cell motility and invasiveness. These 2 genes likely help cultivate the growth of breast cancer cells in the brain.

The scientists next searched for genes that help the cancerous cells cross the blood-brain barrier in the first place. They found several genes whose expression was increased more than threefold in brain-invasive breast cancer cells but not in cells that metastasize to bone or lungs. One of these genes, called ST6GALNAC5, produces an enzyme that is normally active only in brain tissue.

When ST6GALNAC5 is expressed in breast cancer cells, the researchers showed, it helps produce a coating on the cell surface that allows the cells to slip through the blood brain barrier and infiltrate brain tissue. By co-opting production of cell-surface molecules normally found only in the brain, the breast cancer cells essentially masquerade as brain cells to gain entry and become established in brain tissue.

"Our results draw attention to the role of the cell-surface coating as a previously unrecognized participant in brain metastasis, and to the possibility of using drugs to disrupt its interactions," says Massagué. "Further study is necessary to explore the role of these genes in brain metastasis and their interest as therapeutic targets."

—by Vicki Contie

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