The Growth Factor GP88 (Progranulin) Confers Aromatase Inhibitor Resistance to Breast Cancer Cells.

Abstract

The development of aromatase inhibitors has provided novel therapeutic strategies for post-menopausal patients with estrogen receptor positive (ER+) breast tumors. Aromatase inhibitors, such as letrozole, inhibit ER+ breast cancer cell growth by blocking the synthesis of estrogen by the enzyme aromatase in the tumor stroma. However, ER+ breast cancer cases can sometimes fail or cease to benefit from such therapy. Several mechanisms have been proposed for aromatase inhibitor resistance. Here, we investigate the role of the 88 kDa autocrine growth factor PC-Cell Derived Growth Factor, also known as GP88 or progranulin on the acquisition of aromatase inhibitors resistance by ER+ breast cancer cells. GP88 is the largest member of the epithelin-granulin family characterized by a unique cysteine rich motif. GP88 has been shown to play a role in breast tumorigenesis. GP88 expression increased in breast cancer cells in a positive correlation with tumorigenesis whereas inhibition of GP88 expression lead to a 98% reduction in tumor incidence and growth rate in vivo. Pathological studies of paraffin embedded breast cancer biopsies have shown that GP88 is expressed in infiltrating ductal carcinoma (IDC) in correlation with expression of parameters of poor prognosis but was independent from Her-2 expression. Most importantly, increased GP88 expression in ER+ IDC was associated with increased recurrence and decreased overall survival. The present study investigated the effect of GP88 on the proliferation and letrozole responsiveness of ER+ breast cancer cells that express high aromatase activity (MCF-7 CA and MCF-7 AC1 cells). For both cell types, GP88 added exogenously conferred letrozole resistance in a time and dose-dependent fashion. GP88 also stimulated survival and soft agar colony formation of MCF-7-CA and AC1 cells in the presence of letrozole. GP88 overexpressing cells displayed higher basal levels of phosphorylated ERK1/2 and AKT, both known to be activated in GP88 mitogenic signaling pathways. In addition, naturally letrozole resistant breast tumors displayed a 10-fold increase in GP88 expression when compared to letrozole sensitive cells. Treatment of these letrozole resistant cells with GP88 SiRNA lead to a dose dependent inhibition of proliferation and restoration of letrozole sensitivity indicating that GP88 is regulating the ability of the cells to respond to letrozole.These data show the importance of GP88 as a target for the development of diagnostic and therapeutic products for aromatase inhibitor resistant breast cancer. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 4171.