PC cell-derived growth factor mediates tamoxifen resistance and promotes tumor growth of human breast cancer cells.
PC cell-derived growth factor, also known as progranulin, is an M(r) 88,000 growth factor (referred as PCDGF/GP88) overexpressed in human breast cancer. Antisense inhibition of PCDGF/GP88 expression in MDA-MB-468 cells inhibited tumor formation in nude mice. In estrogen receptor-positive cells, PCDGF/GP88 was expressed in response to estradiol and shown to mediate its mitogenic effect. Pathologic studies indicated that PCDGF/GP88 was expressed in 80% of invasive ductal carcinomas in correlation with parameters of poor prognosis. In the present article, the relationship between PCDGF/GP88 expression and tamoxifen resistance was examined in MCF-7 cells. PCDGF/GP88 overexpression rendered MCF-7 cells able to proliferate in the absence of estrogen and in the presence of tamoxifen. The PCDGF/GP88-overexpressing cells formed tumors in ovariectomized nude mice in the absence of estradiol and in its presence, in contrast to MCF-7 cells. Tumor growth of the overexpressing cells was increased significantly when the mice were treated with tamoxifen. PCDGF/GP88 blocked tamoxifen-induced apoptosis by preventing down-regulation of bcl-2 expression and poly(ADP-ribose) polymerase cleavage. In addition, PCDGF/GP88-overexpressing cells presented higher level of the angiogenic factors vascular endothelial growth factor and angiopoietin-1 than MCF-7 control cells. Tamoxifen treatment additionally increased the level of vascular endothelial growth factor. These studies suggest that PCDGF/GP88 plays a critical role in breast cancer tumorigenesis and in the transition to estrogen independence and tamoxifen resistance, a hallmark of poor prognosis. On the basis of the in vivo studies, it is postulated that tamoxifen treatment of patients with estrogen receptor-positive breast tumors overexpressing PCDGF/GP88 could have adverse clinical consequences.
Tangkeangsirisin
Wisit
W
A and G Pharmaceutical, Columbia, Maryland 21045, USA.
Hayashi
Jun
J
Serrero
Ginette
G
D000818:Animals; D017209:Apoptosis; D001943:Breast Neoplasms / Q000188:drug therapy / Q000473:pathology*; D002455:Cell Division / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D005260:Female; D006023:Glycoproteins / Q000502:physiology*; D006133:Growth Substances / Q000502:physiology*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000502:physiology*; D051379:Mice; D009389:Neovascularization, Pathologic / Q000209:etiology; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000032:analysis; D013629:Tamoxifen / Q000494:pharmacology*
D006023:Glycoproteins; D006133:Growth Substances; D036341:Intercellular Signaling Peptides and Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D013629:Tamoxifen; D011065:Poly(ADP-ribose) Polymerases