Par-4 protein influences breast cancer recurrence

Overexpression of the tumor suppressor protein Par-4 delays the onset of tumor recurrence in breast cancer, researchers have discovered.

Par-4 expression was found to be lower in recurrent tumors relative to primary tumors in a mouse model of recurrent breast cancer created by James V. Alvarez, PhD, of the Department of Cancer Biology at the Perelman School of Medicine, University of Pennsylvania, Philadelphia, and colleagues. When the researchers examined gene expression data from human breast cancer specimens, they learned that low Par-4 expression was associated with an increased risk of recurrence and a worse response to neoadjuvant chemotherapy.

As summarized in a statement from the University of Pennsylvania, Alvarez and associates then tested a hypothesis that cells downregulating Par-4 may be more adept at surviving chemotherapy of the primary tumor. Cells with low Par-4 levels indeed persisted following treatment, rendering them available to give rise to recurrent tumors.

Further analysis of the mouse model revealed that Par-4 expression increased when the HER2/neu oncogene was deactivated and primary tumors subsequently shrank. The overexpressed Par-4 results in the production of cells with more than one nucleus, which ultimately leads to cell death. Cells with downregulated Par-4 are able to avoid this multinucleation process and survive chemotherapy.

The authors concluded in Cancer Cell that Par-4 is downregulated during tumor recurrence, and that Par-4 downregulation is necessary and sufficient to promote recurrence. These findings suggest that strategies to increase Par-4 expression in tumors could be beneficial.

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