Interestingly, we found that exogenous PEDF failed to induce apoptosis in MCF 7 breast cancer cells in vitro, however, it significantly inhib ited the growth of MCF 7 tumors in athymic mice, which was due to its anti angiogenic activity. The anti tumor activity of PEDF, however, was more pronounced in the endocrine resistant breast cancer cells compared with Brefeldin A mw the endocrine sensitive cells. We should note that a similar finding was reported by Konson and coworkers in which they showed that exogenous PEDF preferentially induced apoptosis in endothelial cells compared with MDA MB 231, HCT116, and U87 MG cancer cells, however, PEDF efficiently inhibited the growth rate of xenografts generated from these cancer cells.

While the reason for this cell type specific effect of PEDF is not known, there is evidence for multiple PEDF receptors at the cell surface Inhibitors,Modulators,Libraries including the recently identified non integrin 67 37 kDa laminin receptor, extracellular matrix components, and a phospholipase linked membrane protein. Differential expression of these receptors on neuronal, endothelial, and cancer cells may provide a partial expla nation for the differential effects on these cell populations. Identification of which of these PEDF receptors are present on cancer cells, as well as further elucidation of signaling downstream of PEDF, could lead to the identifi cation of new pharmacologic targets for both anti cancer and neuronal Inhibitors,Modulators,Libraries survival therapies. We are currently trying to determine whether there is a specific PEDF receptor expressed in breast cancer cells and whether the functional activity of the receptor is altered by the endocrine respon siveness of the cells.

Apart from its ability to inhibit to angiogenesis, we also found that PEDF suppressed Inhibitors,Modulators,Libraries RET expression in endo crine resistant breast cancer cells and that this suppression was associated with the reversal of tamoxifen resistance. Specifically, we found that basal RET, p RET, ERa, and pSer167 ERa Inhibitors,Modulators,Libraries protein levels were markedly increased in endocrine resistant MCF 7,5C cells compared with endo crine sensitive MCF 7 cells and stable expression of PEDF in MCF 7,5C cells or treatment of these cells with rPEDF suppressed RET, p RET, and pSer167 ERa protein in these cells. Furthermore, we found that suppression of RET expression using siRNA knockdown also reversed tamoxi fen resistance in MCF 7,5C cells, which suggests a role for RET in tamoxifen resistance.

This finding is important because recent studies have indicated that RET is involved in the biology of ERa positive breast cancers and in the response to endocrine treatment. Two indepen dent studies have Inhibitors,Modulators,Libraries identified RET overexpression in a sub set of ERa positive breast cancers, suggesting an important selleck chemicals Imatinib role of RET in this subset. By in situ hybridiza tion, in a cohort of 245 invasive breast cancers, RET mRNA was detected in 29. 7% of the tumors and preferen tially expressed in ER positive cases.