• PC cell derived growth factor (PCDGF/granulin precursor) expression, antiestrogen resistance and tumorigenesis in human breast cancer cells

      Tangkeangsirisin, Wisit; Serrero, Ginette (2004)
      Breast cancer is one of the most common malignant diseases in women. Several mechanisms have been proposed for the development and progression of breast cancer. Overexpression of growth factors or their receptors has been widely investigated as a potential pathway of breast malignancy. PCDGF is a novel growth factor characterized in our laboratory. There is significant evidence to suggest a role of PCDGF in human cancers. The purpose of this study was to investigate the role of PCDGF on tumorigenicity, estrogen dependence, endocrine therapy resistance and metastatic potential in human breast cancer. A model system to study the role of PCDGF and estrogen independence was developed by overexpressing PCDGF in human breast cancer MCF-7 cells and cultivating them in estrogen depleted condition. Results presented here show that PCDGF overexpression confers resistance to tamoxifen and fulvestrant in both in vitro and in vivo. PCDGF overexpression and estrogen depletion downregulate estrogen receptor alpha isoform, resulting in estrogen unresponsive cell growth. In addition, doxorubicin resistance was observed in PCDGF overexpressing cells. We found that PCDGF prevents apoptosis induced by tamoxifen, fulvestrant and doxorubicin. The key event in this process is that PCDGF maintains the upregulation of bcl-2 when treated with these agents. In addition, tamoxifen resistant cells express higher level of PCDGF. PCDGF transcriptionally activates estrogen inducible genes such as progesterone receptor and vascular endothelial growth factor (VEGF) via an ERa-dependent pathway. Tumors originated from PCDGF overexpressing cells express higher level of VEGF and angiopoietin-1. In addition, treatment with tamoxifen, in cooperation with PCDGF, stimulates VEGF expression in vitro and in vivo. This may explain why tamoxifen stimulates tumor growth from the PCDGF overexpressing cells but inhibits it in the wild-type cells. PCDGF induces cell migration through matrigel and stimulates matrix metalloprotease-9 secretion, suggesting an important role in metastasis. In summary, these studies provide a possible mechanism of antiestrogens and doxorubicin resistance in human breast cancer by overexpression of PCDGF. The results also show that PCDGF expression correlates with higher tumorigenicity and promotes angiogenesis and metastasis in human breast cancer.
    • Therapeutic Effect of Anti-Progranulin/GP88 Antibody AG01 in Triple Negative and Letrozole Resistant ER+ Breast Cancer Cells

      Guha, Rupa; Serrero, Ginette (2020)
      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.