Abstract 2515: Anti- GP88 (progranulin) antibody to GP88 (progranulin) inhibits breast tumor growth and restores sensitivity to tamoxifen

GP88 (Progranulin, PCDGF, acrogranin) is an 88 kDa glycoprotein that is the largest member of the granulin/epithelin family of growth modulators characterized by 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 showed that GP88 tumor expression is a prognostic indicator of recurrence in early stage breast cancer patients; 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 developed a neutralizing anti-GP88 antibody AG1. AG1 inhibits GP88 biological effect in a dose-dependent fashion. In the present study, we investigated the effect of AG1 on the tumor development of tamoxifen sensitive (MCF-7) and resistant (TamR) estrogen receptor positive breast cancer cells lines injected in nude mice. We show that AG1 alone (5mg/kg) inhibited tumor growth of MCF-7 cells injected into nude mice in a similar efficacy as tamoxifen. Interestingly, AG1 in combination with tamoxifen inhibited by more than 50% tumor formation of TamR cells, whereas tamoxifen only had no effect. 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 from the National Cancer Institute. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2515. doi:1538-7445.AM2012-2515