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 nor...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.展开更多
Background:The Fn14 fibroblast growth factor-inducible 14(Fn14)can stimulate cell migration and promote cancer lessions.Progranulin(GP88)protein has been identified as an epidermal growth factor and participates in ma...Background:The Fn14 fibroblast growth factor-inducible 14(Fn14)can stimulate cell migration and promote cancer lessions.Progranulin(GP88)protein has been identified as an epidermal growth factor and participates in many biological processes.The aim of the present work was to investigate the immunohistochemical expression of Fn14 and GP88 proteins in relation to the clinical parameters in women's invasive ductal carcinoma(IDC)and to explore their role as novel prognostic biomarkers.Methods:The qualitative and quantitative immunohistochemical techniques were used to evaluate the expression levels of Fn14 and GP88 in 100 fresh samples of Egyptian women who had breast lesions.They were divided into three groups:control healthy tissues(10 samples from woman lesions),benign group(30 cases),and IDC group(60 cases).Results:The histopathological results of 60 cases with IDC have been reported with 45 cases being gradeⅡand 15 cases being gradeⅢ.The immunohistochemical results showed that the degree of strong positive staining for both markers was increased in gradeⅢcompared to that in gradeⅡ.The integrated optical density was significantly increased in gradeⅢ(p<0.05).Also,the result revealed a highly significant correlation between the two markers and the tumor size,grades,and lymph node metastasis,as well as a correlation to normal and benign breast lesions.Conclusion:The quantitative immunohistochemistry of Fn14 and GP88 proteins revealed the correlation between the two markers and clinical parameters.Therefore,the two markers may be serviceable as prognostic and therapeutic markers in IDC patients.展开更多
文摘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.
文摘Background:The Fn14 fibroblast growth factor-inducible 14(Fn14)can stimulate cell migration and promote cancer lessions.Progranulin(GP88)protein has been identified as an epidermal growth factor and participates in many biological processes.The aim of the present work was to investigate the immunohistochemical expression of Fn14 and GP88 proteins in relation to the clinical parameters in women's invasive ductal carcinoma(IDC)and to explore their role as novel prognostic biomarkers.Methods:The qualitative and quantitative immunohistochemical techniques were used to evaluate the expression levels of Fn14 and GP88 in 100 fresh samples of Egyptian women who had breast lesions.They were divided into three groups:control healthy tissues(10 samples from woman lesions),benign group(30 cases),and IDC group(60 cases).Results:The histopathological results of 60 cases with IDC have been reported with 45 cases being gradeⅡand 15 cases being gradeⅢ.The immunohistochemical results showed that the degree of strong positive staining for both markers was increased in gradeⅢcompared to that in gradeⅡ.The integrated optical density was significantly increased in gradeⅢ(p<0.05).Also,the result revealed a highly significant correlation between the two markers and the tumor size,grades,and lymph node metastasis,as well as a correlation to normal and benign breast lesions.Conclusion:The quantitative immunohistochemistry of Fn14 and GP88 proteins revealed the correlation between the two markers and clinical parameters.Therefore,the two markers may be serviceable as prognostic and therapeutic markers in IDC patients.
