U-M researchers link pathway to breast cancer stem cells

ANN ARBOR, Mich. -- A gene well known to stop or suppress cancer plays a role in cancer stem cells, according to a new study from the University of Michigan Comprehensive Cancer Center. The researchers found that several pathways linked to the gene, called PTEN, also affected the growth of breast cancer stem cells.

Further, by using a drug that interferes with that pathway, the researchers produced an up to 90 percent decrease in the number of cancer stem cells within a tumor.

The study appears in the June issue of PLoS Biology, a journal from the Public Library of Science.

PTEN is the most frequently inactivated tumor suppressor gene in several cancers, including breast cancer, where it is inactivated in about 40 percent of patients. PTEN is linked to poor outcomes and is associated with aggressive cancers resistant to chemotherapy and current targeted therapies.

The U-M researchers deleted PTEN in tumors grown in cell cultures and in mice, and found an increase in the number of stem cells. They also looked at pathways associated with PTEN and reported that a pathway called PI3-K/Akt regulated the cancer stem cell population by activating another stem cell pathway, Wnt, which is also implicated in multiple cancer types.

"Although there has been considerable progress in identifying cancer stem cells in a variety of tumor 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., research investigator in internal medicine at the U-M Medical School.

Researchers at U-M were the first to identify stem cells in breast cancer. These cells represent fewer than 5 percent of the cells in a tumor but are believed to be responsible for fueling a tumor's growth and spread. Researchers believe that the ultimate cure of cancer will require killing these cancer stem cells.

In the current study, researchers looked at a drug called perifosine, which inhibits the Akt pathway. Tumors in mice were treated with perifosine or docetaxel, a standard chemotherapy drug. The docetaxel alone showed no effect on the number of cancer stem cells in the tumor. But adding perifosine reduced the cancer stem cell population by up to 90 percent.

What's more, the cells treated with perifosine -- either with or without docetaxel -- were less likely to grow a secondary tumor, compared to the cells treated with just docetaxel.

"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 tumor 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 U-M Comprehensive Cancer Center.

Breast cancer statistics: 194,280 Americans will be diagnosed with breast cancer this year and 40,610 will die from the disease, according to the American Cancer Society

Additional authors: Amanda Paulson, Christophe Ginestier, Marty Brown, Julie Dutcher and Shawn G. Clouthier, all from the U-M Comprehensive Cancer Center; and Emmanuelle Charafe-Jauffret from the Laboratory of Molecular Oncology at the Marseille Cancer Research Institute in France

Funding: National Institutes of Health and the A. Alfred Taubman Medical Research Institute at U-M

Reference: PLoS Biology, Vol. 7, No. 6, June 1, 2009

Resources:

U-M Cancer AnswerLine, 800-865-1125

U-M Comprehensive Cancer Center, www.mcancer.org

June 1, 2009