A small piece of genetic material stops the activity of an enzyme known to promote the spread of breast tumors to the brain, said a group of researchers at Baylor College of Medicine.

"We have shown that the enzyme heparanase is an important mediator of brain metastasis (breast cancer spread to the brain)," said Dr. Dario Marchetti, lead author and professor of pathology and immunology, cell and molecular biology at BCM and member of the NCI-designated Dan L Duncan Cancer Center at the College.

Little is known about how the activity of heparanase and its gene are regulated in the cell. MicroRNAs were one possibility. When Marchetti and his colleagues screened for microRNAs that regulate heparanase, they discovered microRNA-1258, which not only regulates the post-transcriptional activity (after the DNA is translated into RNA) of the heparanase gene, but also its activity in suppressing the spread or metastasis of breast cancer to the brain. A report on their work appears in the current issue of the American Association for Cancer Research journal Cancer Research.

New concepts

"Our investigations introduce new concepts that brain metastasis might be inhibited by microRNA-based strategies, and can have profound implications for the development and use of heparanase-based therapeutics in cancer metastasis in general and brain metastatic breast cancer in particular," said Marchetti and his colleagues in their manuscript.

MicroRNAs are short (about 22 nucleotides) single strands of genetic material that can bind to messenger RNA, which carries the genetic code for a protein to the cell’s organelles that make it. When the microRNA binds to the messenger RNA, it stops production of that protein.

In laboratory studies of various types of breast cancer cells in culture, laboratory animals, as well as human tissues, microRNA-1258 specifically targeted the gene for heparanase and reduced production of the enzyme. Marchetti and his colleagues also found significantly reduced levels of microRNA-1258 in breast tumor cells that have high propensity for metastasis to the brain.

"We detected the highest levels of heparanase in invasive ductal carcinoma (a form of aggressive primary breast cancer) and in brain metastatic breast cancer," said Marchetti. By contrast, the opposite was found for microRNA-1258 levels, which were lowest in human breast cancer brain metastases, he said.

Inhibition of brain metastases

Marchetti and his colleagues also found that microRNA-1258 "inhibited brain metastases by 74 percent" when it was introduced into breast cancer cells injected into animals in the laboratory.

"Of relevance, the inhibition of brain metastases correlated with the downregulation of heparanase (lower levels of the molecule) in brain metastasis of these animals," said Marchetti.

Others who took part in this work include Dr. Lixin Zhang and Dr. Jerry C. Goodman, both pathologists at BCM, Dr. Peggy S. Sullivan, a pathologist at the University of California-Los Angeles, and Dr. Preethi H. Gunaratne, a molecular biologist at the University of Houston and pathologist at BCM.

Funding for this work came from grants from the National Institutes of Health and the Special Program of Research Excellence in breast cancer from the National Cancer Institute.