Targeting breast cancer stem cells

Researchers from the University of Michigan Comprehensive Cancer Center have identified roles for the gene PTEN and for several pathways linked to PTEN in the growth of stem cells that give rise to breast cancer.

Cancer develops when these special cancer stem cells begin to divide in an uncontrolled manner. Stem cells in breast cancer represent fewer than 5 percent of the cells in a tumour but are believed to be responsible for fuelling a tumour's growth and spread. Researchers believe that the ultimate cure of cancer will require killing these cancer stem cells.

PETN, which is already well known for its ability to suppress tumour growth, is the most frequently inactivated tumour suppressor gene in several cancers, including breast cancer, where it is inactivated in about 40 percent of patients. PTEN inactivation is associated with poor patient outcomes, aggressive tumour growth, and resistance to chemotherapy and current targeted therapies.

Researchers first deleted PTEN from tumour cells grown in cell culture and from tumours in mice, and found an increase in the number cells able to form new tumours, which suggests that PTEN influences the cancer stem cell population. They also looked at pathways associated with PTEN and reported that the activity of the PI3-K/Akt pathway also regulates the size of the tumour-forming cell population by activating the Wnt pathway, another pathway previously implicated in multiple cancer types.

"Although there has been considerable progress in identifying cancer stem cells in a variety of tumour types, the pathways that drive the transformation of these cells are not well understood," says lead study author Hasan Korkaya, D.V.M., Ph.D., a research investigator in internal medicine at the University of Michigan Medical School.

In the study, researchers looked at a drug called perifosine, which inhibits the Akt pathway. Tumours in mice were treated with perifosine or docetaxel, a standard chemotherapy drug. The docetaxel alone treatment showed no effect on the number of tumour-forming cells, but the addition of perifosine reduced the tumour-forming cell population by up to 90 percent. Additionally, cells treated with perifosine – either with or without docetaxel – were less likely to form tumours when reintroduced into mice when compared to cells treated with docetaxel alone. These results suggest that perifosine specifically targets the breast cancer stem cell population.

"This is most exciting since perifosine and other drugs that target this pathway are currently in clinical development. If cancer stem cells do contribute to tumour relapse, then adding drugs that target these cells may help to make our current therapies more effective," says study senior author Max S. Wicha, M.D., Distinguished Professor of Oncology and director of the University of Michigan Comprehensive Cancer Center.

The work is published in this week's issue of the open-access journal PLoS Biology, and also reports that a drug that interferes with the activity of one of these pathways leads to a 90 percent decrease in the number of cells able to form tumours in mice.