Progranulin (GP88) tumor tissue expression is associated with increased risk of recurrence in breast cancer patients diagnosed with estrogen receptor positive invasive ductal carcinoma

Serrero, Ginette; Hawkins, Douglas M.; Yue, Binbin; Ioffe, Olga B.; Bejarano, P.A.; Phillips, Jeffrey T.; Head, Jonathan F.; Elliott, Robert L.; Tkaczuk, Katherine; Godwin, Andrew K.; Weaver, Jo Ellen; Kim, Wes E.

doi:10.1186/bcr3111

Cited by 52 publications

(53 citation statements)

References 30 publications

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“…This study revealed that preoperative serum PGRN levels are clinically significant for predicting recurrence in patients with hormone receptor-positive tumors; however, these data have several limitations that are important to consider when interpreting the study’s results [80]. Serrero et al [81] also analyzed PGRN expression by immunohistochemistry in paraffin-embedded breast tumor sections from patients with estrogen receptor-positive invasive ductal carcinoma. Their results showed that high PGRN expression was associated with a decrease in disease-free and overall survival as well as a 5.9-fold higher hazard of disease recurrence and a 2.5-higher mortality risk compared to patients with low PGRN expression in the tumor tissue.…”

Section: Progranulin As Cancer Biomarkermentioning

confidence: 99%

Progranulin and its biological effects in cancer

et al. 2017

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Cancer cells have defects in regulatory mechanisms that usually control cell proliferation and homeostasis. Different cancer cells share crucial alterations in cell physiology, which lead to malignant growth. Tumorigenesis or tumor growth requires a series of events that include constant cell proliferation, promotion of metastasis and invasion, stimulation of angiogenesis, evasion of tumor suppressor factors, as well as avoidance of cell death pathways. All these events in tumor progression may be regulated by growth factors produced by normal or malignant cells. The growth factor progranulin has significant biological effects in different types of cancer. This protein is a regulator of tumorigenesis because it stimulates cell proliferation, migration, invasion, angiogenesis, malignant transformation, resistance to anticancer drugs, and immune evasion. This review focuses on the biological effects of progranulin in several cancer models and provides evidence that this growth factor should be considered as a potential biomarker and target in cancer treatment.

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Section: Progranulin As Cancer Biomarkermentioning

confidence: 99%

Progranulin and its biological effects in cancer

et al. 2017

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“…Progranulin has been reported to activate many of the typical cell proliferation signaling pathways, including ERK, PI3K, and Akt pathways (48,50,51), not only in tumor cells but also in neurons (52,53). Progranulin may be a prognostic marker (54) or a therapeutic target in cancer: progranulin overexpression confers an aggressive phenotype to adenocarcinoma (46), immortalized ovarian epithelial cells (55), breast cancer (49,56), and hepatocellular carcinoma (57), and anti-progranulin treatment reduces in vivo tumorigenicity of teratoma (58) and breast cancer cell lines (59). However, it should be emphasized that although these early studies strongly linked progranulin to cancer, no cell surface receptor has been shown to mediate these effects.…”

Section: What Does Progranulin Do?mentioning

confidence: 99%

Progranulin: A Proteolytically Processed Protein at the Crossroads of Inflammation and Neurodegeneration

Sephton

Cenik

Herz

et al. 2012

Journal of Biological Chemistry

207

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GRN mutations cause frontotemporal lobar degeneration with TDP-43-positive inclusions. The mechanism of pathogenesis is haploinsufficiency. Recently, homozygous GRN mutations were detected in two patients with neuronal ceroid lipofuscinosis, a lysosomal storage disease. It is unknown whether the pathogenesis of these two conditions is related. Progranulin is cleaved into smaller peptides called granulins. Progranulin and granulins are attributed with roles in cancer, inflammation, and neuronal physiology. Cell surface receptors for progranulin, but not granulin peptides, have been reported. Revealing the cell surface receptors and the intracellular functions of granulins and progranulin is crucial for understanding their contributions to neurodegeneration. Progranulin: The BasicsProgranulin (encoded by GRN) is widely expressed in epithelia, bone marrow, immune cells, solid organs, and the nervous system both during development and in adulthood (1-5). In the brain, intracellular expression is highest in neurons and activated microglia (6 -8). At the subcellular level, progranulin colocalizes with the endoplasmic reticulum and Golgi markers in the secretory pathway and the lysosomal marker Lamp1 (9, 10). Progranulin is a secreted glycoprotein and is readily detected in blood and cerebrospinal fluid (11)(12)(13).Progranulin is evolutionarily conserved in Animalia: homologs exist in vertebrates and Caenorhabditis elegans (14), but seemingly not in Drosophila. It has no robust sequence homology to any other known protein family. Biological activities attributed to progranulin are numerous; the protein is made up of several granulin domains, which can be individually liberated by neutrophil proteases (see Fig. 1). These "granulins" were discovered first, before the cloning of the full-length gene. Whether the biological activities of progranulin are mediated by the full-length protein, individual granulins, or both is not clear. We begin our discussion with the consequences of progranulin deficiency. Progranulin Haploinsufficiency Causes Frontotemporal Lobar Degeneration with Ubiquitinated TDP-43-positive InclusionsIn 2006, mutations in GRN were discovered to be a cause of frontotemporal lobar degeneration (FTLD) 3 with ubiquitinated TDP-43-positive inclusions (FTLD-TDP) (15,16). FTLD is the second most common presenile dementia disorder after Alzheimer disease, representing 5-15% of all dementias (17,18). More than 70 mutations in GRN, almost all of which result in null alleles, have been identified in FTLD patients. A few causative missense mutations also result in reduced levels of progranulin (19).Clinical manifestations of heterozygous loss-of-function GRN mutations include variants of the FTLD spectrum, parkinsonism, and the corticobasal syndrome (20). Neuropathologically, atrophy of the brain parenchyma (most severe in the frontal cortex) is usually observed. The atrophy can be asymmetrical, and different brain regions are affected with varying frequency. Loss of pigmentation of the substantia nigra, hippocam...

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“…Analysis of GP88 tissue expression in 600 cases of estrogen receptor positive, invasive ductal carcinoma in relation with clinical outcomes demonstrated that high GP88 expression was statistically associated with a 5.9-fold higher hazard of disease recurrence (p< 0.0001) and a 2.5-fold higher mortality hazard (p=0.0002) compared to patients with no or low expression of tumor GP88 (14). GP88 remained an independent risk predictor after considering age, ethnicity, nodal status, tumor size, tumor grade, disease stage, progesterone receptor expression and treatments (14).…”

Section: Introductionmentioning

confidence: 99%

“…GP88 remained an independent risk predictor after considering age, ethnicity, nodal status, tumor size, tumor grade, disease stage, progesterone receptor expression and treatments (14). Since GP88 is a secreted protein, a prospective longitudinal clinical study to measure circulating level of GP88 with an Enzyme Immunoassay (EIA) developed in our laboratory demonstrated the performance of the serum GP88 EIA by establishing a basal range for GP88 in serum from healthy volunteers of 28 ng/ml and showing that serum GP88 levels in breast cancer patients was elevated to 40 ng/ml in early stage and over 100 ng/ml in later stages of breast cancer (15).…”

Section: Introductionmentioning

confidence: 99%

GP88 (progranulin): a novel tissue and circulating biomarker for non–small cell lung carcinoma

et al. 2014

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GP88 (progranulin) is a growth and survival factor implicated in tumorigenesis and drug resistance. Previous studies showed that GP88 was expressed in breast cancer tissue in inverse correlation with survival. This study evaluates GP88 tissue expression in localized/locally advanced lung cancer and GP88 serum levels in advanced disease. GP88 expression was determined by immunohistochemistry in tumor tissue from non-small cell carcinoma (NSCLC) patients, 85 with localized (Stage I-II) and 40 with locally advanced disease (Stage IIIa) and correlated with clinical outcome. Serum GP88 levels from Stage IIIb/IV patients, quantified by Enzyme Immunoassay (EIA) were compared to GP88 levels from patients with Chronic Obstructive Pulmonary Disease (COPD) and healthy individuals. GP88 was expressed in >80% adenocarcinoma and squamous cell carcinoma in contrast to normal lung or small cell lung cancer. There was a statistically significant inverse association of GP88 expression (GP88 Immunohistochemistry score 3+ vs. <3+) with survival for patients with localized resected NSCLC with Hazard Ratio (HR)=2.28 (p=0.0076) for DFS and HR=2.17 (p=0.014) for OS. A statistically significant decrease in progression-free survival (HR=2.9, p=0.022) for GP88 scores of 3+ vs. <3+ was observed for Stage IIIa after chemoradiotherapy. In addition, serum GP88 was significantly elevated in Stage IIIb/IV NSCLC compared to control subjects (49.9ng/ml vs. 28.4ng/ml, p<0.0001). This is the first study demonstrating GP88 tissue and serum expression as a prognostic biomarker in localized and advanced disease. Future research will determine utility of monitoring GP88 and the potential of GP88 expression as a predictive marker for anti-GP88 therapeutics.

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Progranulin (GP88) tumor tissue expression is associated with increased risk of recurrence in breast cancer patients diagnosed with estrogen receptor positive invasive ductal carcinoma

Cited by 52 publications

References 30 publications

Progranulin and its biological effects in cancer

Progranulin and its biological effects in cancer

Progranulin: A Proteolytically Processed Protein at the Crossroads of Inflammation and Neurodegeneration

GP88 (progranulin): a novel tissue and circulating biomarker for non–small cell lung carcinoma

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