TITLE:
GP88 (Progranulin) Confers Fulvestrant (Faslodex, ICI 182,780) Resistance to Human Breast Cancer Cells
AUTHORS:
Wisit Tangkeangsirisin, Ginette Serrero
KEYWORDS:
Progranulin (GP88), Fulvestrant, Faslodex, Breast Cancer, Anti-Estrogen Resistance
JOURNAL NAME:
Advances in Breast Cancer Research,
Vol.3 No.3,
June
25,
2014
ABSTRACT: The 88 kDa glycoprotein
known as GP88, Progranulin or PC cell derived growth factor is an autocrine
growth factor with a unique cysteine rich motif that is over expressed in
breast cancer whereas it is negative in normal mammary epithelial cells. It has
been shown to play a major role in estrogen independence, tamoxifen resistance
and tumorigenesis of breast cancer cells. In the present study, we investigated
the effect of GP88 overexpression on the response of the human breast cancer
MCF-7 cells to the pure estrogen receptor antagonist fulvestrant (ICI 182,780).
While fulvestrant effectively inhibited cell proliferation of empty vector
transfected cells, it had no inhibitory effect on the proliferation of GP88
overexpressing breast cancer cells. Mouse xenograft experiments in athymic
ovariectomized nude mice showed that GP88 over expressing cells were
fulvestrant resistant in vivo in contrast to low GP88 expressing
cells. We show that the ability of fulvestrant to induce apoptosis determined
by measuring cleavage of poly (ADP-ribose) polymerase was inhibited by GP88.
Anti-apoptotic activity of GP88 was associated with sustained expression of
bcl-2 and bcl-xL after
fulvestrant treatment. In contrast, fulvestrant was still able to inhibit the
ability of estrogen to stimulate ERE-luciferase reporter gene activity as well
as vEGF expression in GP88 over expressing MCF-7 cells similarly to control
MCF-7 cells. Collectively, our data suggest that GP88 prevents apoptosis
induced by faslodex and contributes to antiestrogen resistance in human breast
cancer.