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ErbB2/Her2 is a receptor tyrosine kinase that is overexpressed in approximately 25% of all breast cancer patients. Herceptin is the most common choice for therapy in patients with erbB2 overexpressing tumors. However, only 20-25% will respond to this treatment. PC-Cell Derived Growth Factor (PCDGF/GP88) is an 88 kDa autocrine growth factor, characterized in our laboratory, which is the largest member of the epithelin-granulin family of polypeptides conatining a unique cysteine rich motif. PCDGF/GP88 plays a critical role in breast tumorigenesis. Its expression is increased in breast cancer cells in a positive correlation with their tumorigenesis. Inhibition of PCDGF/GP88 action or expression in human breast carcinoma cells blocked proliferation as well as lead to a 98% reduction in tumor incidence and growth rate in vivo. Immunohistochemistry studies of paraffin embedded human breast cancer biopsies showed that PCDGF/GP88 is expressed in 80% of infiltrating ductal carcinoma in correlation with parameters of poor prognosis such as tumor grade, p53 expression and Ki67 proliferation index. Even though PCDGF/GP88 expression was independent of Her2, about 20% of Her-2 overexpressing breast cancer biopsies also displayed a high GP88expression. We investigated whether PCDGF/GP8 played a role in cell proliferation of erbB2 overexpressing tumors. In vitro and in vivo studies showed that PCDGF/GP88 expression conferred a growth advantage in erbB2 expressing breast cancer cells as shown by an increase in colony formation in soft agar and larger tumors in nude mice. In addition, PCDGF/GP88 conferred Herceptin resistance in these cells. Studies presented here explored the signaling pathways stimulated by PCDGF in erbB2 overexpressing cells. We demonstrate that PCDGF/GP88 activates erbB2, c-Src and ultimately c-myc by utilizing ERK1/2 and Akt pathways, when compared to breast cancer cells having a basal level of erbB2. In particular, PCDGF/GP88 stimulated the levels of c-myc, and induced c-myc phosphorylation of in MCF-7/erbB2 cells, but not in MCF-7/EV cells. The c-myc activation by PCDGF/GP88 was inhibited by LY294002 and U0126 indicating the involvement of both MAPK and PI3 Kinase activities. Thus, we propose a novel signaling mechanism for PCDGF/GP88 in erbB2-overexpressing cells, where PCDGF/GP88 activates Src, leading to the activation of ERK1/2 and PI3-Kinase/Akt, and ultimately phosphorylation of c-myc, leading to increased proliferation in erbB2 overexpressing breast tumors.

[Proc Amer Assoc Cancer Res, Volume 47, 2006]