In the January 27, 2013 online edition of Nature Cell Biology, UC San Francisco researchers describe how the protein GATA3 — which is abnormal or absent in many cases of human breast cancer — normally works to prevent metastasis.
The absence or loss of GATA3 can free cancerous cells to break free from their defined roles and tethers within a tumor, to move away from the tumor mass, to induce cancer-promoting inflammation, and to stimulate the development of new blood vessels that can help spreading cancerous cells regrow as tumors in new locations.
"People knew that some of these genes were turned on in some cancers, but they did not know they were turned on because GATA3 and microRNA29b were turned off," said Zena Werb, PhD, a UCSF professor of anatomy who led the research. "If you have 20 genes that are becoming less active all at once due to microRNA29b, it could have a profound effect."
Working with mice, the researchers found that restoring microRNA29b to one of the most deadly types of breast cancer stopped metastasis. But the researchers also found that if they knocked out the microRNA29b, tumors spread even in the presence of GATA3, suggesting that microRNA29b can be the driver of metastasis.
In the mouse models of breast cancer studied by Werb's team, GATA3 normally restrains cancerous cells from breaking away from the main tumor and migrating to other organs.
It might be possible, Werb said, to develop drugs that inhibit breast cancer metastasis by re-activating these controls in cancerous cells that have lost the normal protein.
Many researchers who study early stages of cancer focus on abnormal genes and proteins that cause cells to expand their numbers rapidly, a hallmark of cancer.
However, the ability to spread to distant places and to eventually cause lethal complications requires not only cell division and tumor growth, but also changes in how the cancerous cell negotiates with its surroundings. This relationship must be altered to permit cancer to spread, according to earlier research findings by Werb and others.
"Many of the key processes in cancer that GATA3 suppresses take place outside the cell, in the surrounding environment," she said.
GATA3 is a master control for luminal cells, which line the milk-carrying ducts of the breast. In essence, GATA3 dictates the defining characteristics of a normal breast cell, Werb said.
"The targeting we would like to do is to give back microRNA29b specifically to breast tumor cells to prevent metastasis," Werb said.