Therapeutic Effect of Anti-Progranulin/GP88 Antibody AG01 in Triple Negative and Letrozole Resistant ER+ Breast Cancer Cells

Abstract

Progranulin (GP88, PCDGF, granulin/epithelin precursor, acrogranin) is a secreted autocrine growth/survival glycoprotein that functions as a biological driver of tumor cell proliferation, tumorigenesis, survival, invasiveness and drug resistance in several cancers, including breast cancer. Progranulin is found in the serum of breast cancer patients at higher levels than in healthy subjects and pathological studies have shown that in ER+ tumor biopsies, progranulin/GP88 is an independent prognostic factor of recurrence. Although TNBC represents a small percentage (15-20%) of breast cancer diagnoses, it is clinically important because of its highly aggressive nature and the fact that the disease progresses to metastasis within an exceedingly shorter period. Higher progranulin levels have also been shown to be associated with TNBC cases. Progranulin represents a therapeutic and diagnostic target in breast cancer. We have characterized a recombinant neutralizing anti-human progranulin/GP88 monoclonal antibody AG01 that inhibits progranulin biological effect in vitro and in vivo. Since GP88 is associated with poor outcomes in BC patients, we have investigated the effect of AG01 to inhibit proliferation and enhance letrozole responsiveness of letrozole resistance breast cancer cell lines as well as inhibit proliferation and migration of TNBC cells, two breast cancer areas with unmet medical needs for targeted therapy. We found that progranulin levels were sharply elevated in letrozole resistant cells as compared to the parent cell lines. Simultaneously, TNBC cells showed an increase in progranulin expression while it is undetectable in normal mammary cells. This emphasized the importance of targeting PGRN to treat letrozole resistance in ACLRTUSM as well as provide a therapeutic agent in TNBC cells. We report here that treatment of ACLRTUSM with anti-PGRN antibody (AG01) not only reduced their proliferation but increased the sensitivity of ACLRTUSM cells towards letrozole treatment. In several TNBC models, AG01 treatment reduced cell proliferation, migration, and invasion. Taken together, the research work discussed here provides new information to better understand the targeting progranulin and the effectiveness of AG01 as a potential therapeutic agent in breast cancer. Future work continuing characterization of AG01 will provide further insight into its role in regulating cancer biology.