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Protein protects against breast cancer recurrence in animal model
Date:6/13/2013

ch is turned on in about 20% of human breast cancers -- induces the formation of a primary mammary tumor. Subsequently, turning HER2/neu "off" in a tumor that has arisen causes it to essentially disappear, mimicking the treatment of primary human breast cancers with the anti-HER2/neu agent, Herceptin. But, as in many human patients, at some point in the weeks and months following tumor regression, tumors often return, both in the breast as well as in secondary sites such as the lungs.

By studying these paired primary and recurrent tumors, Alvarez, Chodosh, and their colleagues found that Par-4 expression was dialed down in recurrent tumors relative to primary tumors. When they examined gene expression data from human breast cancer specimens, they found that low Par-4 expression was associated with an increased risk of recurrence and a poorer response to neoadjuvant therapy -- chemotherapy prior to surgery. A poor response to neoadjuvant therapy is associated with an increased likelihood of recurrence.

Based on these findings, the team hypothesized that cells that downregulate Par-4 may be more adept at surviving chemotherapeutic treatment of the primary tumor, and that's precisely what they found. When they compared cells expressing normal levels of Par-4 with cells that had downregulated the gene, they found that it is the cells with low Par-4 levels that persist following treatment. Consequently, it is these cells that are available to give rise to recurrent tumors in the future.

The team then asked what Par-4 actually does to prevent breast cancer recurrence. They found in their mouse models that when HER2/neu is turned off and primary tumors shrink, Par-4 expression ramps up. This causes a defect in cell division, producing cells with more than one nucleus. This, in turn, leads to cell death. Cells that have downregulated Par-4 fail are able to escape this multinucleation process, allowing them to survive therapy and, eventually, gi
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Contact: Karen Kreeger
karen.kreeger@uphs.upenn.edu
215-349-5658
University of Pennsylvania School of Medicine
Source:Eurekalert

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