ERBB KINASES AND NDF SIGNALING IN HUMAN PROSTATE-CANCER CELLS

Prostate carcinoma (PCA) is the most commonly diagnosed malignancy in American men. Our knowledge of PCA growth regulation lags behind that of other cancers, such as breast and colon carcinomas. Among receptor tyrosine kinases, the ErbB family is most frequently implicated in neo plasia. We report here the expression of ErbB family kinases and their ligands in PCA cell lines and a xenograft. While ErbB1/EGFR, ErbB2/NE U, and ErbB3 were always observed in a distinct pattern, ErbB4 was not observed. Interestingly, while TGF-alpha was expressed in the majorit y of PCA lines, the ligand Neu Differentiation Factor/Heregulin (NDF) was expressed only in an immortalized, non-transformed prostate epithe lial line. Concomitantly, there was a significant difference in biolog ical response to these ligands, NDF inhibited LNCaP growth and induced an epithelial-like morphological change, in contrast to TGF-alpha, wh ich accelerated cell growth. We also performed the first comprehensive analysis of NDF signaling in a prostate line, LNCaP stimulated with N DF demonstrated crosstalk between ErbB3 and ErbB2 which did not involv e ErbB1. NDF also turned on several cascades, including those of PI3-K , ERK/MAPK, mHOG/p38 and JNK/SAPK, but not those of PLC gamma or the S TAT family. This signaling pattern is distinct from that of TGF-alpha. The activation of mHOG by ErbB2 or ErbB3 has not been reported, and m ay contribute to the unusual phenotype, PI3-K activation is characteri zed by the formation of a striking 'activation complex' vith multiple tyrosine-phosphorylated species, including ErbB3. Our studies provide a framework in which to dissect the growth and differentiation signals of prostate cancer cells.