Breast Cancer Genes

woman holding autumn leaf to chest

A woman's fear of breast cancer could be reduced if doctors knew how to tell when cancer cells would metastasize.

Breast cancer is feared as the number one cancer among American women. Yet this statement ignores the fact that breast cancer is "not a single disease, but a collection of diseases," says Danny Welch of Penn State's College of Medicine. Tumors arise from different types of breast tissue and metastasize to different parts of the body, some infiltrating the bones and others the lymph nodes. Some tumors do not metastasize at all, but stay as single lumps.

"It is likely that different genes are involved in controlling development and progression of each type," Welch writes in a paper coauthored by L. L. Wei of Georgetown University. "Yet most discussions of breast cancer genetics have not, for the most part, discriminated between each type of carcinoma."

Reviewing studies of the 150 genes associated with breast cancer, Welch and Wei found that 40 of these genes play a role in a tumor's progression from benign to malignant. "The magnitude of these numbers highlights the tremendous complexity of breast cancer as a family of diseases," they note. "How, then, can one determine which changes are essential and which are ancillary?"

One way is to focus not on malignancy, but on metastasis.

"Most women succumb to breast cancer if their tumors metastasize,"they write, "but cures are more likely if the cancers remain localized." A genetic marker for metastasis could help doctors decide if removal of the cancerous lump were enough or if the patient needed more aggressive treatment. A way to suppress metastasis—either by turning on suppressor genes or by interfering with the genes that promote metastasis—could make some surgeries unnecessary.

Not all tumor cells are able to metastasize. According to a paper by Welch and Carrie Rinker-Schaeffer of the University of Chicago, "The majority of cells within a tumor cannot complete the multistep process of metastasis. Indeed, less than 0.1 percent of cells entering the bloodstream successfully form clinically detectable lesions."

In a lecture last October, Welch outlined six steps needed for metastasis: First, cells in the primary tumor must acquire all the mutations needed to migrate. Second, the tumor must provide itself with a blood supply so the cells can multiply. Third, the migrating cells must break through the basement membrane and enter the bloodstream. Fourth, while circulating in the bloodstream, the tumor cells must avoid the cells of the immune system (or perhaps co-opt them, as some research in Welch's lab suggests). Fifth, when the tumor cells reach their target site, they must direct the endothelial cells lining the blood vessel wall to open, let them through, and then close up normally again. Sixth, they must proliferate at their new site.

"For cells to metastasize successfully, they must also interact with a variety of host cells and their secreted molecules and respond appropriately," note Welch and Wei. Among these are hormones such as estrogen, which promotes breast cancer by stimulating cell division. "If a cell fails to complete any of these steps, it is nonmetastatic," Welch and Rinker-Schaeffer write. "Thus, it takes only one gene to block metastasis, whereas it takes the coordinated expression of many genes to allow metastasis."

Welch and his colleagues have been studying one metastasis-blocking gene, labelled KAI1. Located on chromosome 11, this gene was found to suppress metastasis in prostate cancer, while similar genes showed the same effects in lung cancer and melanoma. Welch and his colleagues measured the activity of KAI1 in a variety of human breast cell lines, from nearly normal ones to highly metastatic cells. They found that KAI1 was expressed less and less as a cell's malignancy and metastatic potential increased. They then introduced a normal chromosome 11 into a metastatic breast-cell line. While the cells' ability to form tumors was not affected, their ability to metastasize was "significantly reduced," Welch and Wei reported.

Of the 150 genes associated with breast cancer, five have been shown to suppress metastasis, but how they do it is far from understood.

Danny R. Welch, Ph.D., is associate professor of pathology, Jake Gittlen Cancer Research Institute, College of Medicine, 500 University Dr., Box 850, Hershey PA 17033; 717-531-8521; drw9@psu.edu. This work was published in the Journal of the National Cancer Institute (August 18, 1999) and in Endocrine-Related Cancer (Society for Endocrinology, 1998). Funding came from the National Institutes of Health, the U.S. Army Medical Research and Materiel Command, the National Foundation for Cancer Research, the American Cancer Society, the Latham Fund, the Jake Gittlen Memorial Golf Tournament, and the University of Chicago's RESCUE Fund.

Last Updated May 01, 2000