Abstract P5-09-05: Progranulin (GP88) expression and letrozole resistance in breast cancer
Authors: Serrero G , Dong J , Yue B , Tkaczuk KR , Chumsri S , Hayashi J 
Published: August 2014

The 88 kDa glycoprotein GP88 (Progranulin, PCDGF, acrogranin) is the largest member of the granulin/epithelin family of growth modulators. GP88 was originally characterized in our laboratory through a biological screen to identify drivers of tumorigenesis. Published studies have established that GP88 represents an ideal therapeutic and diagnostic target in breast cancer (BC) leading to the development of validated tools to measure GP88 in tumor biopsies and biological fluids as well as blocking its action. It was shown that: 1) GP88 expression increases with tumorigenesis; 2) in ER+ breast cancer cells, GP88 stimulates proliferation and its overexpression confers estrogen independence and resistance to several anti-estrogens and aromatase inhibitor; 3) inhibition of GP88 expression by antisense transfection inhibited proliferation in vitro and in vivo; 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 (IDC) and 60% of ductal carcinoma whereas it is negative in lobular carcinoma, benign lesions and normal mammary tissues; 6) GP88 is secreted and can be detected in the serum of BC patients at an increased level when compared to healthy subjects; 7) Pathological studies with 530 cases of ER+ IDC with clinical outcomes showed that GP88 tumor expression was an independent prognostic indicator of recurrence in early stage BC patients. Training study followed by an independent validation study demonstrated that high GP88 tissue expression (GP88 3+) was associated with a 4-fold increase in risk of recurrence at 5 years.

Since GP88 displays not only diagnostic but also therapeutic potentials, we developed a neutralizing anti-GP88 antibody AG1 that inhibited GP88 biological effect (proliferation and migration) in a dose-dependent fashion in vitro. AG1 was expressed in a high yield CHO cell line and formulated. We have shown that in tamoxifen resistant cells, treatment with AG1 would inhibit tumor growth and restore tamoxifen sensitivity. The present study examined the effect of AG1 in letrozole resistant cells. We have developed from a letrozole sensitive cell ER+ BC cell line, a letrozole-resistant cell line by long term selection in letrozole-supplemented medium. This cell line (LetR) shows also decreased letrozole responsiveness in vivo and therefore constitutes an excellent model for investigating letrozole resistance in vivo as well as in vivo. Here we investigated the effect of various doses of AG1 on LetR tumor development alone or in combination with letrozole. Treatment with AG1 (10 mg/kg i.p.) in combination with letrozole was efficient to maintain long term responsiveness to letrozole and inhibited tumor growth. In addition to the mouse xenografts study, an IRB approved clinical study examines changes in GP88 circulating levels in patients with resistance to aromatase inhibitors. Preliminary data will be presented.

In conclusion, inhibiting GP88 could provide a novel and alternative therapeutic strategy for patients with resistance to anti-estrogen therapy, being tamoxifen or letrozole.

This work is supported by 2R44CA124179 and HHSN 261201200060C from NCI and 02- 2013-018 from the Avon Foundation for Women.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P5-09-05.