Scientists show gene reverts cancer genes to normal, predicts breast cancer prognosis

The gene, Dachshund, normally regulates eye development and development of other tissues, in essence playing a role in determining the fate of some types of cells. Richard Pestell, M.D., Ph.D., director of the Kimmel Cancer Center at Jefferson and professor and chair of cancer biology at Jefferson Medical College, and co-workers looked at cancer cells from more than 2,000 breast cancer patients and found that this commandeering or “organizing” ability is increasingly lost in cancer cells and associated with the progression of disease. The more the gene is expressed in breast cancer, the researchers saw, the better the patient did. The scientists report their findings in October in the journal Molecular and Cellular Biology.

“This is a new type of gene in cancer that commandeers the cancerous genes and returns them to normal,” says Dr. Pestell. “The standard cancer treatment strategy has been to block the proliferation of cancer cells or cause them to die. This is quite different. We've shown that the Dachshund gene reverts the cancerous phenotype and turns the cell back to a pre-malignant state. Cells don't die, but rather, they revert.

“It's a bad prognostic feature if you lose this organizer gene,” he says, adding that it could be used as a prognostic marker for breast cancer.

In the work, the researchers showed that Dachshund could block breast cancer growth in mice and also could halt breast cancer from invading other tissues in cell culture. They also found that the gene inhibits the expression of the cyclin D1 gene, a cancer-causing gene that is overexpressed in about half of all breast cancers.

The group used microarray technology – silicon chips containing ordered selections of genetic material upon which sample material can be tested – to analyze Dachshund expression during the development of breast cancer. The scientists compared normal breast cells, pre-cancerous “in situ” cells and more than 2,100 breast cancer cell samples. Dachshund gene expression was “significantly reduced” in breast cancer.

The average survival was almost 40 months better in women in whom their breast cancer continued to express Dachshund.

Dr. Pestell notes that the expression of Dachshund correlates with tumor size, stage and metastasis, with its expression greatly reduced in metastatic breast cancer cells. Dr. Pestell's team is examining other cell fate-determining genes in an attempt to identify new therapeutics for breast cancer and metastasis.