Intense RKIP staining was observed in normal milk duct epithelial cell, whereas RKIP expression was downregulated in primary breast carcinomas. The consistent yet cystine variable downregulation of RKIP expression in primary breast carcinomas prompted us to examine whether there was a correlation between the reduction of RKIP expression and the Captopril propensity to metastasize and weakly positive in of, weakly positive in of cases. This distribution of RKIP downregulation is statistically not significant but suggestive of a trend that primary tumors with reduced levels of RKIP expression have a higher tendency to metastasize.Raf kinase inhibitor protein expression is significantly diminished in metastatic breast cancer.RKIP expression in the nodepositive tumors was predominantly moderate in intensity. By contrast, in the matched lymph node metastases obtained from the same patients, RKIP expression was considerably diminished were weakly positive for RKIP expression, of cases were moderately positive, and RKIP was entirely absent in a significant number of cases. This decrease of RKIP expression in metastases was found to be A.RKIP expression in primary tumors versus lymph node metastases RKIP expression NOTE: A, RKIP staining in the nodenegative versus nodepositive tumors.Node positive primary tumors show a statistically nonsignificant trend to reduced RKIP expression.B, RKIP expression is significantly reduced in lymph node metastases compared with primary tumors. No correlation was found between RKIP expression and established clinical and pathologic breast cancer markers, including histologic type, tumor differentiation grade, size, or estrogen receptor status, suggesting that RKIP is independent of other markers for breast cancer progression and prognosis.Extracellular signalregulated kinase activation in breast cancer.As RKIP can interfere with ERK activation, we assessed the levels of phosphoERK in the primary tumors and in metastases.ERK activation can be conveniently and quantitatively determined using phosphospecific antibodies that detect the activating phosphorylation sites.All tumors expressed easily detectable and rather uniformly distributed levels of total ERK. In contrast, phosphoERK staining revealed that activated ERK was not homogeneously distributed, often only found in few tumor cells, interestingly often in cells at the invasive edges of the tumors. for most tumors, which were thus deemed negative for phosphoERK staining.In immunopositive tumor cells, phosphoERK distribution was specific and predominantly nuclear, with occasional cytoplasmic staining. Immunohistochemical staining shows moderate RKIP immunoreactivity in the primary tumor. Phospho ERK was typically limited to a fraction of the tumor cells. No significant association between RKIP expression and phosphoERK staining was noted for nodepositive tumors or for matched lymph node metastases.Curiously, RKIP and phosphoERK levels showed a significant association in nodenegative tumors. Raf kinase inhibitor protein enhances apoptosis in nodenegative tumors.RKIP can sensitize prostate and breast carcinoma cells to druginduced apoptosis. Therefore, we assessed the levels of apoptosis in a subset of tumors from nodenegative and nodepositive groups, including paired lymph node metastases, and compared them with RKIP expression. No significant difference between RKIP expression and apoptosis was noted for nodepositive tumors or for paired lymph node metastases.However, a statistically significant weak association between RKIP expression and apoptosis was found in nodenegative tumors. This suggests that the role of RKIP to prevent metastasis may be associated with the ability to promote apoptosis.

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