PC cell-derived growth factor stimulates proliferation and confers Trastuzumab resistance to Her-2-overexpressing breast cancer cells.
OBJECTIVE
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.


METHODS
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.


CONCLUSIONS
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.
Kim
Wes E
WE
A&G Pharmaceutical, Inc., Columbia, Maryland 21045, USA.
Serrero
Ginette
G
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis; D020935:MAP Kinase Signaling System; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D000077153:Progranulins; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D013997:Time Factors; D000068878:Trastuzumab
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D036341:Intercellular Signaling Peptides and Proteins; D000077153:Progranulins; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; C492314:GRN protein, human