GP88 (PCDGF, granulin-epithelin precursor) and chemoresistance in breast cancer

B37

Chemotherapy is widely used for the treatment of advanced stage breast cancer. However, after prolonged chemotherapy, breast cancer often progresses to a chemo-insensitive state. Constitutive overexpression of autocrine growth and survival factor is one possible mechanism of chemo resistance. PCDGF/GP88 (PC-Cell Derived Growth Factor, also known as progranulin or granulin-epithelin precursor) is an 88 kDa autocrine growth factor isolated in our laboratory and shown to play a critical role in breast tumorigenesis. GP88 is expressed in human breast tumors in a positive correlation with their tumorigenicity. In estrogen receptor positive (ER⁺) cells, GP88 expression is low and is stimulated by estradiol whereas it is constitutively overexpressed in ER negative cells. Inhibition of GP88 expression by antisense transfection in ER negative breast carcinoma leads to inhibition of breast tumor incidence and growth in nude mice. GP88 also increases survival, inhibits apoptosis, stimulates migration, matrix metallo-protease activities and angiogenesis. Pathological studies have shown that GP88 is expressed in 80% of human invasive ductal carcinomas and correlated with expression of markers of poor prognosis whereas normal tissues and benign breast lesions are negative. GP88 Overexpression in breast tumors conferred resistance to anti-estrogen therapy in ER⁺ breast cancer as well as doxorubicin, paclitaxel in ER^- breast cancer and Herceptin in Her-2 overexpressing breast tumors, respectively. Conversely, chemoresistant breast tumors showed an increased in GP88 expression. Based on these data, we investigated whether inhibition of GP88 action in chemo resistant breast cancer cells would restore cellular responsiveness to the chemotherapy treatment. Anti-human GP88 neutralizing monoclonal antibodies were developed. Using paclitaxel resistant breast adenocarcinoma cells as model system, we show here that administration of a neutralizing anti GP88 monoclonal antibody inhibited cell proliferation in a time and dose dependent fashion. Additionally, treatment of the cells with anti-GP88 antibody restored the ability of paclitaxel to inhibit cell proliferation and stimulate apoptosis. In contrast, treatment of the cells with unrelated isotype specific antibody had no effect. Studies carried out with breast cancer cell lines resistant to other chemotherapy will also be performed. These results demonstrate the important role of GP88 expression in the development of chemoresistant breast cancer and suggest that GP88 is a suitable molecular therapeutic target for advanced breast cancer.