Abstract P6-04-19: Neutralizing antibody to human GP88 (progranulin) restores sensitivity to tamoxifen and inhibits breast tumor growth in mouse xenografts

Autor: Ginette Serrero, J Dong, J Hayashi
Rok vydání: 2012
Předmět:
Zdroj: Cancer Research. 72:P6-04
ISSN: 1538-7445
0008-5472
Popis: The 88 kDa glycoprotein GP88 (Progranulin, PCDGF, acrogranin) is the largest member of the granulin/epithelin family of growth modulators characterized by 7.5 cysteine-rich granulin/epithelin repeats. Our laboratory has demonstrated that GP88 represents an ideal therapeutic and diagnostic target in breast cancer. Our published studies have demonstrated that: 1) GP88 expression increases with tumorigenesis; 2) inhibition of GP88 expression by antisense transfection in MDA-MB-468 cells inhibited by 90% tumor formation in nude mice; 3) in ER+ breast cancer cells, GP88 stimulates proliferation and its overexpression confers estrogen independence and resistance to several anti-estrogens and aromatase inhibitor; 4) In Her-2 overexpressing breast tumors, GP88 stimulated Her-2 phosphorylation and conferred trastuzumab resistance; 5) GP88 is expressed in 80% invasive ductal carcinoma and 60% of ductal carcinoma whereas it is negative in lobular carcinoma, benign lesions and normal mammary epithelial cells; 6) pathological studies with 530 cases of ER+ invasive ductal carcinoma showed that GP88 tumor expression measured by immunohistochemistry (IHC) is a prognostic indicator of recurrence in early stage breast cancer patients; High GP88 tissue expression was associated with a 4-fold increase in risk of recurrence at 5 years; 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, we developed a neutralizing anti-GP88 antibody AG1. AG1 was expressed in a high yield CHO cell line and formulated. AG1 inhibits GP88 biological effect (proliferation and migration) in a dose-dependent fashion in vitro. Here we will report the results of studies investigating 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, in tamoxifen resistant cells derived from MCF-7, the anti-GP88 antibody AG1 inhibited by more than 50% tumor formation of TamR cells in combination with tamoxifen, whereas tamoxifen only had no effect. These data suggest that inhibiting GP88 provides a novel and alternative therapeutic pathway for the restoration of tamoxifen sensitivity in ER+ breast cancer. This works is supported by grant 2R44CA124179 from the National Cancer Institute and 02–2010-010 from the Avon Foundation for Women. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-04-19.
Databáze: OpenAIRE
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