Abstract B057: Treatment with anti-human GP88/progranulin antibody restores tamoxifen sensitivity to tamoxifen-resistant breast cancer cells

The 88 kDa glycoprotein GP88 (Progranulin, PCDGF, acrogranin) is the largest member of the granulin/epithelin family consisting of 7.5 repeats of a highly conserved 12-cysteine granulin/epithelin motif. Our laboratory demonstrated the role of GP88 as an autocrine growth and survival factor in breast cancer: 1) GP88 expression increases with tumorigenesis; 2) inhibition of GP88 expression by antisense transfection in MDA-MB-468 cells inhibited tumor formation in nude mice by 90%; 3) in ER+ breast cancer cells, GP88 stimulates proliferation and its overexpression confers estrogen independence; 4) GP88 is a strong survival factor that confers resistance to anti-estrogen and aromatase inhibitors in ER+ breast cancer; 5) GP88 is expressed in 80% invasive ductal carcinoma and 60% of ductal carcinoma whereas it is negative in benign lesions and normal mammary epithelial cells; 6) pathological studies with 530 cases of ER+ invasive ductal carcinoma (ER+ IDC) showed that GP88 tumor expression is a prognostic indicator of recurrence and death in early stage breast cancer patients with high GP88 tissue expression associated with a 4-fold increase in the risk of recurrence; 7) GP88 is secreted and can be detected in the serum of breast cancer patients at an increased level when compared to healthy subjects. Based on these results GP88 represents an ideal therapeutic and diagnostic target in breast cancer. We have characterized a neutralizing anti-GP88 monoclonal antibody that has been expressed in recombinant form and named AG1. AG1 inhibits GP88 biological effect such as migration and invasion of breast cancer cells in a dose-dependent fashion. Since GP88 is a prognostic factor of recurrence in ER+ IDC, the present study investigates the effect of AG1 on the tumor development and tamoxifen responsiveness of tamoxifen resistant ER+ breast cancer cell line (TamR) injected in nude mice. We show that AG1 alone inhibited tumor growth of TamR cells injected into nude mice while tamoxifen alone had moderate effect. Interestingly, AG1 administered in combination with tamoxifen, inhibited by more than 50% tumor formation of TamR cells. These data suggest that inhibiting GP88 provide a novel and alternate pathway for restoration of tamoxifen sensitivity in ER+ breast cancer. This works is supported by grant 2R44CA124179 and contract HHSN261201200060C from the National Cancer Institute. Citation Format: Ginette Serrero, Jianping Dong, Binbin Yue, David Hicks, Jun Hayashi. Treatment with anti-human GP88/progranulin antibody restores tamoxifen sensitivity to tamoxifen-resistant breast cancer cells. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research: Genetics, Biology, and Clinical Applications; Oct 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2013;11(10 Suppl):Abstract nr B057.