Breast cancer, while scary, is a highly treatable disease, thanks both to clinical advances and to the work of advocates. Indeed, the five-year survival rate after diagnosis of a primary breast tumor now is more than 80 percent.

But in contrast to other types of cancer, which most likely will not recur at all if they have not done so within five years of diagnosis, breast cancer can recur even decades after the original tumor has been vanquished. And it is such recurrence that accounts for many breast cancer deaths, as well as the fear.

The molecular mechanisms of that recurrence have been elusive to date. But in the September 2005 issue of Cancer Cell, scientists at the University of Pennsylvania School of Medicine and the University of California at Davis report on one protein that appears to underlie such recurrences, at least in an animal model: Snail, an inhibitor of transcription already known to play a role in cancer metastasis. (See BioWorld Today, Nov. 2, 2004.)

The difference between recurrence and metastasis, said senior author Lewis Chodosh, vice chair of the cancer biology department at the University of Pennsylvania's Abramson Family Cancer Research Institute, is that for recurrent cancer, there is a period in which the patient is symptom-free. In contrast, "you can have metastasis where there's no break in the action."

The scientists first created a mouse model that can overexpress Her2/neu. That tyrosine kinase is overexpressed in 20 percent to 30 percent of breast tumors and is one characteristic signaling of an aggressive form of the disease. In the animal model, the mice carry a transgene for Her2/neu that is controlled by an antibiotic-inducible promoter. When the mice are given antibiotic, the Her2/neu gene is expressed, and the mice develop tumors; antibiotic withdrawal leads to tumor regression, as Her2/neu is no longer expressed. However, about 85 percent of the mice will develop recurrent tumors within one year of remission.

The scientists first ascertained, through xenograft experiments, that the recurrences were indeed true recurrences of the original tumors rather than new tumors at the same site. While cells from the primary tumor had the characteristics of epithelial cells, the recurrent tumors showed characteristics of another cell type (mesenchymal cells) both in terms of histology and marker expression. Because Snail is prominently involved in the epithelial-to-mesenchymal transition, the researchers further investigated whether it plays a role in the recurrence they observed.

In a series of animal experiments, they demonstrated that Snail is up-regulated in recurrent breast tumors, and that it promotes tumor recurrence. They also showed in cell culture that Snail induced an epithelial-to-mesenchymal transition like that seen in the transition from primary to recurrent breast tumors in their animal model.

In a final analysis, the scientists investigated several microarray expression data sets of human breast cancer tissue samples that reported both Snail expression levels and clinical outcomes. They found that high levels of Snail expression predicted decreased relapse-free survival, and that the increased risk was independent of other known prognostic factors such as estrogen receptor expression and lymph node involvement.

To Chodosh, that direct validation of the findings of the mouse model in human samples is one of the most remarkable aspects of the paper.

"I could list 30 reasons why this experiment wouldn't work even if [Snail] is involved," he told BioWorld Today. "The fact that it worked this robustly is remarkable."

In the clinic, Her2/neu is the target of South San Francisco-based Genentech Inc.'s Herceptin (trastuzumab), approved for the treatment of metastatic breast cancer in 1998 and, as the first humanized monoclonal antibody to be approved by the FDA, one of biotechnology's success stories.

Herceptin is effective at reducing the risk of disease recurrence; earlier this year, two Phase III studies in early stage breast cancer patients were halted prematurely when patients receiving Herceptin showed a more than 50 percent reduction in disease recurrence, compared to those receiving only chemotherapy. And last week, the results of another study were released, again showing significant improvements in disease-free survival for patients who received Herceptin in addition to chemotherapy.

However, Snail is not up-regulated only in Her2/neu overexpressing cancers; indeed, in the animal model, though the primary tumors are induced by Her2/neu overexpression, recurrence also occurs in the absence of overexpression. The human tissue analyses in the Cancer Cell paper also confirmed that tumors expressing high levels of Snail have a higher level of recurrence, whether they express Her2/neu or not.

Chodosh and his colleagues are conducting experiments to determine whether it is the epithelial-to-mesenchymal transition itself that causes recurrence, or whether Snail somehow allows residual neoplastic cells to survive. They also are investigating the Snail pathway to determine whether there are targets in it, such as kinases, that might be more tractable drug targets.

"Snail is a transcriptional repressor, and that's a tough nut to crack pharmacologically," Chodosh said.

He and his colleagues are interested in developing industrial partnerships to bring his research to the clinic. He hopes that "in 10 years, disease-free women will be taking a cocktail of drugs to prevent recurrence by wiping out these residual neoplastic cells."

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