Penn researchers discover a molecular pathway that leads to recurrence of breast cancer

urning off the HER2/neu oncogene in fully formed tumors. This mimics important aspects of molecularly targeted therapies and leads to the dramatic regression of tumors to a clinically undetectable state. Nevertheless, residual tumor cells lie in a dormant state and later grow out after a month to a year in the mice.

Using microarrays, Chodosh's team compared recurrent tumors with the original tumors from which they arose. They found that a variety of genes were turned on in recurrent tumors that were not on in the original tumors, including the transcriptional regulatory protein, Snail, which was induced ten-fold. The Penn team also identified changes in the microscopic appearance of the cells in recurrent tumors, which had transformed from a cuboidal, epithelial shape to a spindle, fibroblastic shape - a change associated with more aggressive tumors in humans.

Snail was first identified in fruit flies and later in mice based on its essential role in embryogenesis during a developmental transition in which normal cells undergo a similar change in shape. "Snail controls a complex set of cellular functions that cancer cells appropriate by turning on this master regulatory gene," explains Chodosh.

To prove a cause-and-effect, the researchers added Snail back to the original tumor cells in mice and showed that Snail increased the rate of recurrence.

But could Snail expression play a similar role in women with breast cancer? When the Penn team delved into public databases of breast cancer tissue data, separating cases into those with high levels of Snail and those with low levels of Snail, they found that women whose original breast cancers expressed high levels of Snail were twice as likely to experience a recurrence within five years following surgery compared to women whose cancers expressed low levels of Snail.

The magnitude of risk associated with high Snail expression is comparable to standard prognostic factors such as

Contact: Karen Kreeger
University of Pennsylvania School of Medicine

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