GP88 Serum Level Is Increased in Breast Cancer Patients with Disease Progression.

Abstract

Abstract GP88 (progranulin) is an 88-kDa glycoprotein autocrine growth factor that plays a critical role in breast tumorigenesis. GP88 is expressed in human BC tumors in a positive correlation with their tumorigenicity. In estrogen receptor positive (ER+) cells, GP88 expression is low and is stimulated by estradiol whereas in ER negative (ER-) cells, it is constitutively overexpressed. In ER+ cells, increased GP88 expression was found to be associated with resistance to anti-estrogen therapy. In Her-2 overexpressing breast tumors, increased GP88 expression was associated with Herceptin resistance. Inhibition of GP88 expression in human breast adenocarcinoma cells resulted in a drastic reduction of tumor incidence and tumor growth in nude mice. Immunohistochemical studies carried out with 206 paraffin-embedded human breast biopsies have shown that GP88 is expressed in invasive ductal carcinomas in correlation with expression of markers of poor prognosis whereas normal tissues and benign breast lesions were negative. Importantly, high GP88 expression in tissue biopsies was accompanied by decreased disease-free and overall survival. Since GP88 contains a signal peptide for secretion, we have shown that GP88 can be found in serum. An IRB approve blood sampling study of 189 patients (Race: Caucasian- 91, African American-92, Asian-6; median age- 51 with a range from 26 to 81) established at the University of Maryland demonstrated that GP88 was measurable in serum and that GP88 serum level was statistically elevated in breast cancer patients when compared to healthy individuals. Median level of GP88 was 40.7 ng/ml (range 6.4-80) in early stage (stage 1 –3) BC pts (p- value = 0.007) and 45.3 ng/ml (range 9.8 to 158.4) in stage 4 metastatic BC patients (p-value= 0.0007). Statistically significant increase in circulating GP88 level was found in early stages as well as in metastatic disease when compared to healthy individuals.Since we have shown that GP88 tissue expression was associated with increased disease recurrence, the present study was focused on examining whether GP88 serum level was also increased in disease progression and could be used to monitor disease recurrence. Our data show that patients with disease recurrence or progression presented a 5 to 10 fold increase in their GP88 serum levels.This study identifies GP88 as a measurable biomarker for recurrence or disease progression not only at the tissue but also at the serum level.This study is supported by grants from MIPS, the Avon Foundation and from the National Cancer Institute. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 6040.