Reduction of the cancerous phenotype of breast cancer cells by RNAi-mediated reduction of the PRL-2 tyrosine phosphatase.

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PRL-1 and PRL-2 tyrosine phosphatases, like PRL-3 phosphatase, are overexpressed in human cancer. PRL-1 and PRL-2 are present at higher levels in breast, ovarian, pancreatic, and a number of other cancer types in comparison to normal tissues. To test the hypothesis that PRL phosphatases are required to maintain the cancerous phenotype of cells, we undertook siRNA experiments to knock down the expression of these proteins. We hypothesized that reduction of native PRL proteins in cancer cell lines would reduce the cancerous phenotype of those cells. Although the sequences of PRL-1, PRL-2, and PRL-3 are very similar, there are several potential siRNA sequences that are likely to target one family member but not the other two. These studies describe the targeted reduction of PRL-2 and the subsequent reversal of several key cancerous characteristics in transfected human breast carcinoma cells. The RNAi-mediated reduction of PRL-2 in three separate human breast cancer cell lines, T47D, ZR75-1, and BT549, results in a significant decrease in the cancerous phenotype, namely a 50% reduction in DNA synthesis, a 55% decrease in the proportion of the cell population in S-phase, and decreased cell proliferation. Interestingly, while cells with increased PRL-2 expression have been shown to have similar apoptotic levels to control cells, cells with decreased expression of PRL-2 exhibited a 48% increase in apoptosis. Together, these results suggest that PRL-2 is required in part for maintenance of the cancerous phenotype in human breast cancer cells, and it is a viable molecular target for the chemoprevention and chemotherapy of breast and possibly other cancers.