Enzyme presents therapeutic target in breast cancer brain metastasis
The enzyme heparanase plays a critical role in the spread of breast cancer cells to the brain, and, as such, is a promising target for future treatment, said researchers from Baylor College of Medicine and the University of California – Los Angeles, in a report in the current issue of the American Association of Cancer Research journal Molecular Cancer Research.
Allows cells to enter circulation, increases proliferation
The activity of this enzyme, which degrades the extracellular matrix to allow cells to escape into the surrounding tissue and circulation, is associated with the activation of HER2/epidermal growth factor receptor, said Dr. Dario Marchetti, the senior author of the report that elucidates the enzyme's role in spreading cancer cells to the brain. The extracellular matrix is the tissue framework that holds cells together.
Marchetti's experiments show that after cells are treated with epidermal growth factor, heparanase moves to the cell's nucleolus, the site of ribosome production in the nucleus. In that structure, high levels of heparanase activate an enzyme called topoisomerase 1, which is essential for DNA replication and transcription (translation of the genetic message into protein). Heparanase–induced activation of topoisomerase 1 results in a significant increase of cell proliferation.
"This occurs only in metastatic breast cancer cells that have high levels of HER2 and target the brain," said Marchetti. "These findings help us to determine how heparanase works and how it affects the activity of topoisomerase 1 in the life cycle of these cells.
"It also opens an entire treatment spectrum in terms of the clinical application of this enzyme as a promising drug target for the treatment of brain metastasis," said Marchetti.
In the future, he said, it will be important to determine how and where cellular location of heparanase affects its activity with regard to cell differentiation and growth.
"As we try to understand how heparanase goes into the cell's nucleus and/or nucleolus, we will also better understand its role in metastatic events," said Marchetti.
Others who took part in this work include Lixin Zhang and Julie Suyama, also of BCM, and Peggy Sullivan of the University of California – Los Angeles.
Funding for this work came from the National Institutes of Health.