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Cyclin D1, a gene that promotes the development of breast cancer, is providing clues to how breast cancer spreads, or metastasizes, in the body. By getting a better understanding of the complicated routes by which cancer cells move about, researchers at the Kimmel Cancer Center at Thomas Jefferson University in Philadelphia are finding new potential targets for drugs.

Kimmel Cancer Center director Richard Pestell, M.D., Ph.D., and his team have detailed how cyclin D1 helps regulate the migration of cells to other sites in the body by inhibiting the activity of two genes: thrombospondin 1 (TSP-1), which normally blocks cancer cells from spreading; and ROCKII, which produces a growth-promoting protein. Cell migration is an essential step by which cancer cells spread.

More specifically, the researchers showed that by knocking out the cyclin D1 gene, migration was halted. When they replaced it, the gene promoted breast cancer cell migration again. Then by analyzing mutations of the amino acids within the cyclin D1 gene, they found that a mutation of one amino acid – lysine – was enough to turn off cyclin D1’s ability to promote cancer spread. “By identifying one amino acid within the gene, we can now target drugs to that particular amino acid and we can block this pro-migratory function of cyclin D1,” says Dr. Pestell, Professor and Chair of the Department of Cancer Biology at Jefferson Medical College. They reported their findings in the journal Molecular and Cellular Biology.

The cyclin D1 gene is overexpressed in approximately 50 percent of breast cancers and its function is key to breast cancer development. Patients with breast cancer metastasis frequently have too many copies of cyclin D1. Other cancers, including prostate, colon and blood, also can be characterized by an overabundance of cyclin D1.

Dr. Pestell notes that TSP-1 protein, which is one mechanism by which cyclin D1 promotes migration, is a secreted protein. “We can target that protein with antibodies directed against it or drugs that target TSP-1,” he says. “TSP-1 also blocks angiogenesis and migration; cyclin D1 inhibits TSP-1 expression, thereby promoting both angiogenesis and migration.” The discovery, he says, links cyclin D1 to a secreted protein, which would then also be a useful target for drugs.

“The finding could be useful for a large group of women in this country,” he notes.

“This is important work,” says Andrew Arnold, M.D., Professor of Medicine and Genetics & Developmental Biology at the University of Connecticut. “Cyclin D1 is a major factor in human breast cancer. To exploit our knowledge to generate new and effective treatments, we need a deeper understanding of exactly how cyclin D1 causes a cell to develop cancerous features and malignant behavior. Dr. Pestell and colleagues have made key progress on this front, newly implicating cyclin D1 in cell migration and adhesion abnormalities that characterize cancer. Prior to their work, many authorities have favored the concept that cyclin D1 primarily increases the rate of cell division, so Dr. Pestell’s work provides a new focus for future efforts toward breast cancer therapy.”