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PC Cell–Derived Growth Factor Stimulates Proliferation and Confers Trastuzumab Resistance to Her-2-Overexpressing Breast Cancer Cells

Authors' Affiliations: ¹ A&G Pharmaceutical, Inc., Columbia, Maryland and ² Department of Pharmaceutical Sciences and ³ Program in Oncology, Greenebaum Cancer Center, University of Maryland, Baltimore, Maryland

Requests for reprints: Ginette Serrero, A&G Pharmaceutical, Inc., 9130 Red Branch Road, Suite U, Columbia, MD 21045. Phone: 410-884-4100; Fax: 410-884-1607; E-mail: gserrero{at}agrx.net.

Purpose: Trastuzumab is only effective in 25% to 30% of the administered breast cancer patients who overexpress the erbB2/Her-2 oncoprotein. PC cell–derived growth factor (PCDGF/GP88) is an 88-kDa glycoprotein growth factor overexpressed in 80% invasive ductal carcinomas. Our objective was to determine whether the increased levels of PCDGF/GP88 confers Trastuzumab resistance in erbB2-overexpressing breast cancer cells.

Experimental Design: The ability of PCDGF to induce erbB2 phosphorylation and to confer Trastuzumab resistance was studied in erbB2-overexpressing MCF-7 and SKBR3 breast cancer cell lines.

Results: PCDGF/GP88 added exogenously induced the phosphorylation of erbB2 in a dose-dependent and time-dependent manner in erbB2-overexpressing breast cancer cells. In addition, the overexpression of PCDGF/GP88 conferred Trastuzumab resistance in erbB2-overexpressing cells. Furthermore, overexpression of PCDGF/GP88 in erbB2-overexpressing cells provided a growth advantage over erbB2-overexpressing cells that do not have increased levels of PCDGF/GP88. Lastly, PCDGF/GP88 induced the phosphorylation of mitogen-activated protein kinase in a time-dependent manner in erbB2-overexpressing cells, and pretreatment with Trastuzumab was not able to attenuate the phosphorylation levels of mitogen-activated protein kinase induced by PCDGF/GP88.

Conclusion: These data suggest that PCDGF/GP88 confers Trastuzumab resistance in erbB2-overexpressing cells. Thus, the increase in PCDGF/GP88 levels may indicate Trastuzumab unresponsiveness in breast cancer patients.