Superconductivity in Quasi-One-Dimensional Ferromagnet CrSbSe3 under High Pressure.

Nearly a decade has passed since the discovery of superconductivity in CrAs, but until now, the discovered structure types of chromium-based superconductors are still scanty. It is urgent to expand this family to decipher the interplay between magnetism and superconductivity penetratingly. Here, we report the observation of superconductivity in ferromagnet CrSbSe3 with a quasi-one-dimensional structure under high pressure. Under compression, CrSbSe3 undergoes an insulator-to-metal transition and sequential isostructural phase transitions accompanied by volume collapse. Superconductivity emerges at 32.8 GPa concomitant with metallization in CrSbSe3. A maximum superconducting transition temperature Tc of 7.7 K is achieved at 57.9 GPa benefiting from both the phonon softening and the enhanced p-d hybridization between Se and Cr in CrSbSe3. The discovery of superconductivity in CrSbSe3 expands the existing chromium-based superconductor family and sheds light on the search for concealed superconductivity in low-dimensional van der Waals materials.

Pressure-Driven Polymorphic Transition, Emergent Insulator-To-Metal Transition, and Photoconductivity Switching in Violet Phosphorus.

Polymorphic phase transition is an essential phenomenon in condensed matter that the physical properties of materials may undergo significant changes due to the structural transformation. Phase transition has thus become an important means and dimension for regulating material properties. Herein, this study demonstrates the pressure-induced multi-transition of both structure and physical properties in violet phosphorus, a novel phosphorus allotrope. Under compression, violet phosphorus undergoes sequential polymorphic phase transitions. Concomitant with the first phase transition, violet phosphorus exhibits emergent insulator-metal transition, superconductivity, and dramatic switching from positive to negative photoconductivity. Remarkably, the resistance of violet phosphorus shows a sudden drop of around 107 along with the phase transition. In addition, piezochromism from translucent red to opaque black and suppression of photoluminescence are observed upon compression. Of particular interest is that the sample irreversibly transforms into black phosphorus with a pronounced discrepancy in physical properties from the pristine violet phosphorus after decompression. The abundant polymorphic transitions and property changes in violet phosphorus have significant implications for designing novel pressure-responsive electronic/optoelectronic devices and exploring concealed polymorphic transition materials.

Insulator-to-Superconductor Transition in Quasi-One-Dimensional HfS3 under Pressure.

Various transition-metal trichalcogenides (TMTC) show unique electronic properties, such as metal-insulator transition, topological insulator, and even superconducting transition. Currently, almost all metallic TMTC compounds can show superconductivity either at ambient pressure or at high pressure. However, most TMTC compounds are semiconductors and even insulators. Does superconductivity exist in any non-metallic TMTC compound by artificial manipulation? In this work, the electronic behavior of highly insulating HfS3 has been manipulated in terms of pressure. HfS3 undergoes an insulator-to-semiconductor transition near 17 GPa with a band gap reduction of ∼1 eV. Optical absorption, Raman spectroscopy, and X-ray diffraction measurements provide consistent results, suggesting the structural origin of the electronic transition. Upon further compression, HfS3 becomes a superconductor without further structural transition. The superconducting transition occurs as early as 50.6 GPa, and the Tc reaches 8.1 K at 121 GPa, which sets a new record for TMTCs. This work reveals that all TMTCs may be superconductors and opens a new avenue to explore the abundant emergent phenomena in the TMTC material family.

Diverse Thermal Expansion Behaviors in Ferromagnetic Cr1-δTe with NiAs-Type, Defective Structures.

Negative thermal expansion (NTE) and zero thermal expansion (ZTE) properties are of great significance for the long-life stable operation of precision equipment. However, there are still existing challenges in finding new materials that exhibit NTE or ZTE over a wide temperature range. Here, we report negative, zero, and positive thermal expansion in NiAs-type, defective Cr1-δTe, containing three compounds: hexagonal CrTe, monoclinic Cr3Te4, and trigonal Cr5Te8. CrTe shows the NTE behavior from 280 to 340 K with the volume coefficient of thermal expansion αV = -27.6 × 10-6 K-1. Cr3Te4 shows the ZTE behavior over a wide temperature range of 180-320 K (αV = 0.16 × 10-6 K-1). And Cr5Te8 holds the PTE behavior over the whole temperature range (αV = 38.5 × 10-6 K-1). All of the samples show obvious anisotropic thermal expansion on heating. Combined with the magnetic measurements, it can be confirmed that the NTE and ZTE properties in ferromagnetic Cr1-δTe originate from the magnetovolume effect (MVE). Such NiAs-type, defective compounds with similar compositions but different structures provide a new perspective for tuning the NTE properties of materials and searching for new materials with ZTE over a wide temperature range.

Pressure-Induced Structural Phase Transition, Anomalous Insulator-to-Metal Transition, and n-p Conduction-Type Switching in Defective, NiAs-Type Cr1-δTe.

Cr1-δTe, as a unique series of defective compounds with a NiAs-type structure and periodic metal vacancies, has attracted intensive research interest because of its diversity in structure and property dependent on the tunable stoichiometric ratio. Another feature of these compounds is their ability to switch between NiAs- and MnP-type structures, in which there often exist composition-, temperature-, or pressure-induced phase transitions accompanied by intriguing physical property switching. Herein, we report the syntheses of a series of Cr1-δTe compounds with similar compositions but distinct crystal structures, their phase transitions, anomalous transport, and photoelectric conduction behaviors under high pressure (HP). For the three Cr1-δTe compounds with δ = 0, 0.25, 0.375, CrTe undergoes pressure-induced NiAs-to-MnP phase transition at around 15 GPa, while Cr3Te4 and Cr5Te8 undergo isostructural phase transitions at around 12 and 11 GPa, respectively. Electrical transport measurements indicate anomalous conduction behaviors: CrTe undergoes a semiconductor-to-metal transition at around 24 GPa, while Cr3Te4 and Cr5Te8 show unexpected metal-semiconductor-metal transitions sequentially upon compression. Besides, CrTe and Cr5Te8 exhibit pressure-induced n-p conduction-type switching at around 9 and 3 GPa, respectively, while Cr3Te4 shows p-type conductivity in the full pressure range. Local structure analyses based on in situ HP Raman spectra are performed to understand the structure and property evolutions of Cr1-δTe under HP. Defective transition-metal chalcogenides with pressure-induced NiAs-to-MnP phase transition and conduction-type conversion provide a potential platform for the rational design of photoelectric conversion devices.

Combined miR-486 and GP88 (Progranulin) Serum Levels Are Suggested as Supportive Biomarkers for Therapy Decision in Elderly Prostate Cancer Patients.

Our study aimed to assess the applicability of miR-486 in combination with soluble GP88 protein as a diagnostic and/or predictive biomarker for prostate cancer (PCa) patients. miR-486 and GP88 levels in serum samples from 136 patients undergoing MRI-guided biopsy of the prostate were assessed by qRT−PCR and ELISA, respectively. Of these, 86 patients received a histologically confirmed diagnosis of PCa. Neither marker showed an association with the diagnosis of cancer. PCa patients were separated based on (i) treatment into patients with active surveillance or patients with any type of curative treatment and (ii) age into elderly (>68 years) patients and younger patients (≤68 years). In elderly patients (N = 41) with the intention of curative treatment at optimized cut-off values, significantly higher GP88 levels (p = 0.018) and lower miR-486 levels (p = 0.014) were observed. The total PSA level and ISUP biopsy grade were used in a baseline model for predicting definitive therapy. The baseline model exhibited an area under the curve (AUC) of 0.783 (p = 0.005). The addition of the serum biomarkers miR-486 and GP88 to the baseline model yielded an improved model with an AUC of 0.808 (p = 0.002). Altogether, combined miR-486 and GP88 serum levels are associated with and are therefore suggested as supportive biomarkers for therapy decisions, particularly in elderly PCa patients.

Combination of GP88 Expression in Tumor Cells and Tumor-Infiltrating Immune Cells Is an Independent Prognostic Factor for Bladder Cancer Patients.

Urothelial bladder cancer (BCa) is the ninth most commonly diagnosed cancer worldwide and accounts for approximately 3% of global cancer diagnoses. We are interested in prognostic markers that may characterize tumor cells (TCs) and immune cells (ICs) and their relationship in BCa. A potential candidate marker that meets these criteria is progranulin (GP88), which is expressed separately in TCs and ICs. We analyzed GP88 expression by immunohistochemistry (IHC) in 196 muscle-invasive BCa samples using a tissue microarray. The immunoreactive score for GP88 staining in TCs and the percentage of GP88-positive ICs was determined. An easy cutoff for the staining status of TCs (positive vs. negative) and ICs (0% vs. >0%) and, more generally, negative vs. positive GP88 staining could be applied. We detected 93 patients (47.4%) and 92 patients (46.9%) with GP88-positive TCs or ICs, respectively. The IHC results were correlated with clinicopathological and survival data. Positive GP88 staining in TCs appeared to be an independent poor prognostic factor for disease-specific survival (DSS) (RR (relative risk) = 1.74; p = 0.009) and recurrence-free survival (RFS) (RR = 1.92; p = 0.002). In contrast, negative GP88 staining in ICs was an independent negative predictor for overall survival (OS) (RR = 2.18; p < 0.001), DSS (RR = 2.84; p < 0.001) and RFS (RR = 2.91; p < 0.001) in multivariate Cox's regression analysis. When combining GP88 staining in TCs and ICs, a specific combination of GP88-positive TCs and GP88-negative ICs was associated with a 2.54-fold increased risk of death, a 4.21-fold increased risk of disease-specific death and a 4.81-fold increased risk of recurrence compared to GP88-negative TCs and GP88-positive ICs. In summary, GP88 positivity in TCs is a negative prognostic factor for DSS and RFS. In addition, GP88 positivity can mark ICs that are associated with a good prognosis (OS, DSS and RFS). The combination of GP88 staining in TCs and ICs appears to be a significant independent prognostic biomarker in muscle-invasive BCa.

Monoclinic EuSn_{2}As_{2}: A Novel High-Pressure Network Structure.

The layered crystal of EuSn_{2}As_{2} has a Bi_{2}Te_{3}-type structure in rhombohedral (R3[over ¯]m) symmetry and has been confirmed to be an intrinsic magnetic topological insulator at ambient conditions. Combining ab initio calculations and in situ x-ray diffraction measurements, we identify a new monoclinic EuSn_{2}As_{2} structure in C2/m symmetry above ∼14 GPa. It has a three-dimensional network made up of honeycomblike Sn sheets and zigzag As chains, transformed from the layered EuSn_{2}As_{2} via a two-stage reconstruction mechanism with the connecting of Sn-Sn and As-As atoms successively between the buckled SnAs layers. Its dynamic structural stability has been verified by phonon mode analysis. Electrical resistance measurements reveal an insulator-metal-superconductor transition at low temperature around 5 and 15 GPa, respectively, according to the structural conversion, and the superconductivity with a T_{C} value of ∼4 K is observed up to 30.8 GPa. These results establish a high-pressure EuSn_{2}As_{2} phase with intriguing structural and electronic properties and expand our understandings about the layered magnetic topological insulators.

Anti-progranulin/GP88 antibody AG01 inhibits triple negative breast cancer cell proliferation and migration.

BACKGROUND: Triple negative breast cancer (TNBC) is characterized by invasiveness and short survival. Identifying novel TNBC-targeted therapies, to potentiate standard of care (SOC) therapy, is an unmet need. Progranulin (PGRN/GP88) is a biological driver of tumorigenesis, survival, and drug resistance in several cancers including breast cancer (BC). PGRN/GP88 tissue expression is an independent prognostic factor of recurrence while elevated serum PGRN/GP88 level is associated with poor outcomes. Since PGRN/GP88 expression is elevated in 30% TNBC, we investigated the involvement of progranulin on TNBC. METHODS: The effect of inhibiting PGRN/GP88 expression in TNBC cells by siRNA was investigated. The effects of a neutralizing anti-human PGRN/GP88 monoclonal antibody AG01 on the proliferation and migration of two TNBC cell lines expressing PGRN/GP88 were then examined in vitro and in vivo. RESULTS: Inhibition of GP88 expression by siRNA and AG01 treatment to block PGRN/GP88 action reduced proliferation and migration in a dose-dependent fashion in MDA-MB-231 and HS578-T cells. Western blot analysis showed decreased expression of phosphorylated protein kinases p-Src, p-AKT, and p-ERK upon AG01 treatment, as well as inhibition of tumor growth and Ki67 expression in vivo. CONCLUSION: PGRN/GP88 represents a therapeutic target with companion diagnostics. Blocking PGRN/GP88 with antibody treatment may provide novel-targeted solutions in TNBC treatment which could eventually address the issue of toxicity and unresponsiveness associated with SOC.

Association of Serum Progranulin Levels With Disease Progression, Therapy Response and Survival in Patients With Metastatic Breast Cancer.

BACKGROUND: Progranulin (GP88) is a critical player in breast tumorigenesis. GP88 tumor expression is associated with increased recurrence and mortality, whereas GP88 circulating levels are elevated in patients with breast cancer compared with healthy individuals. We examined here the correlation between serum GP88 levels in patients with metastatic breast cancer (MBC) with overall survival and disease status determined as response to therapy or progression of disease. PATIENTS AND METHODS: An institutional review board (IRB)-approved study prospectively enrolled 101 patients with MBC at the University of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer Center. GP88 serum levels were correlated with patients' disease status determined by Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 criteria and survival outcomes by Kaplan-Meier analysis and log rank statistics. RESULTS: Patients' survival was stratified by serum GP88 level. Patients with serum GP88 < 55 ng/mL had a 4-fold increased survival compared with patients with GP88 > 55 ng/mL. Examination of GP88 serum levels in association with disease status showed a statistically significant association between serum GP88 levels and disease progression or response to therapy while CA15-3 level was only associated to progression. CONCLUSION: The association of serum GP88 level with survival and disease status suggests the potential of using the serum GP88 test for monitoring disease status in patients with MBC. Measurement of serum GP88 levels in patients with MBC may have clinical value as a cost-effective adjunct to the management of patients with MBC with imaging.

Metastable oxygen vacancy ordering state and improved memristive behavior in TiO2 crystals.

Oxygen vacancy is one of the pivotal factors for tuning/creating various oxide properties. Understanding the behavior of oxygen vacancies is of paramount importance. In this study, we identify a metastable oxygen vacancy ordering state other than the well-known Magnéli phases in TiO2 crystals from both experimental and theoretical studies. The oxygen vacancy ordering is found to be a zigzag chain along the [0 0 1] direction in the (1 1 0) plane occurring in a wide temperature range of 200-500 °C. This metastable ordering state leads to a first-order phase transition accompanied by significant enhancement of dielectric permittivity and a memristive effect featuring a low driving electric field. Our results can improve oxide properties by engineering oxygen vacancies.

A simple variant selection in stress-driven martensitic transformation.

The study of orientation variant selection helps to reveal the mechanism and dynamic process of martensitic transformations driven by temperature or pressure/stress. This is challenging due to the multiple variants which may coexist. While effects of temperature and microstructure in many martensitic transformations have been studied in detail, effects of stress and pressure are much less understood. Here, an in situ variant selection study of Mn2O3 across the cubic-to-orthorhombic martensitic transformation explores orientation variants at pressures up to 51.5 GPa and stresses up to 5.5 GPa, using diamond anvil cells in radial geometry with synchrotron X-ray diffraction. The diamonds not only exert pressure but also impose stress and cause plastic deformation and texture development. The crystal orientation changes were followed in situ and a {110} c 〈001〉 c // (100) o 〈010〉 o relationship was observed. Only the {110} c plane perpendicular to the stress direction was selected to become (100) o , resulting in a very strong texture of the orthorhombic phase. Contrary to most other martensitic transformations, this study reveals a clear and simple variant selection that is attributed to structural distortions under pressure and stress.

Expression of GP88 (Progranulin) Protein Is an Independent Prognostic Factor in Prostate Cancer Patients.

Prostate cancer, the second most common cancer, is still a major cause of morbidity and mortality among men worldwide. The expression of the survival and proliferation factor progranulin (GP88) has not yet been comprehensively studied in PCa tumors. The aim of this study was to characterize GP88 protein expression in PCa by immunohistochemistry and to correlate the findings to the clinico-pathological data and prognosis. Immunohistochemical staining for GP88 was performed by TMA with samples from 442 PCa patients using an immunoreactive score (IRS). Altogether, 233 cases (52.7%) with negative GP88 staining (IRS < 2) and 209 cases (47.3%) with positive GP88 staining (IRS ≥ 2) were analyzed. A significant positive correlation was found for the GP88 IRS with the PSA value at prostatectomy and the cytoplasmic cytokeratin 20 IRS, whereas it was negatively associated with follow-up times. The association of GP88 staining with prognosis was further studied by survival analyses (Kaplan-Meier, univariate and multivariate Cox's regression analysis). Increased GP88 protein expression appeared as an independent prognostic factor for overall, disease-specific and relapse-free survival in all PCa patients. Interestingly, in the subgroup of younger PCa patients (≤65 years), GP88 positivity was associated with a 3.8-fold (p = 0.004), a 6.0-fold (p = 0.008) and a 3.7-fold (p = 0.003) increased risk for death, disease-specific death and occurrence of a relapse, respectively. In the PCa subgroup with negative CK20 staining, GP88 positivity was associated with a 1.8-fold (p = 0.018) and a 2.8-fold increased risk for death and disease-specific death (p = 0.028). Altogether, GP88 protein positivity appears to be an independent prognostic factor for PCa patients.

Expression of GP88 (progranulin) in serum of prostate cancer patients is associated with Gleason scores and overall survival.

BACKGROUND: GP88/Progranulin is a well-recognized cell growth promoter in different cancers, and elevated serum GP88 levels have been described as negative prognostic factor in breast cancer. However, serum levels in prostate cancer (PCa) patients have not yet been studied. MATERIAL AND METHODS: We analyzed serum GP88 levels by enzyme immunosorbent assay and correlated them with clinicopathological parameters in PCa patients. PCa patients were separated into two groups based on the serum GP88 median level (low ≤44.56 ng/mL or high >44.56 ng/mL) and according to their median age (younger ≤66 years or elder patients >66 years). RESULTS: Low serum GP88 levels were more often detected in younger patients and high levels in elder patients (P=0.018; Fisher's exact test). PCa patients were separated into three groups, Gleason score (GS) ≤6; GS=7; and GS≥8. In receiver operating characteristic analyses, we could distinguish GS≤6 from GS=7 [area under the curve (AUC): 0.646; P=0.018] and GS≤6 from GS≥8 (AUC: 0.629; P=0.048) but not GS=7 from GS≥8. For survival analysis, GP88 levels were separated into two groups by an optimized cutoff value of 36.92 ng/mL. Using this GP88 stratification, all PCa patients and younger patients with a low serum GP88 level had a significantly better overall survival compared with patients with higher serum GP88 levels (log-rank test P=0.010 and P=0.024). CONCLUSION: Serum GP88 levels are significantly different depending on age and GS, and they are associated with the prognosis of PCa patients.

Progranulin levels in blood in Alzheimer's disease and mild cognitive impairment.

OBJECTIVE: Changes in progranulin (GRN) expression have been hypothesized to alter risk for Alzheimer's disease (AD). We investigated the relationship between GRN expression in peripheral blood and clinical diagnosis of AD and mild cognitive impairment (MCI). METHODS: Peripheral blood progranulin gene expression was measured, using microarrays from Alzheimer's (n = 186), MCI (n = 118), and control (n = 204) subjects from the University of California San Francisco Memory and Aging Center (UCSF-MAC) and two independent published series (AddNeuroMed and ADNI). GRN gene expression was correlated with clinical, demographic, and genetic data, including APOE haplotype and the GRN rs5848 single-nucleotide polymorphism. Finally, we assessed progranulin protein levels, using enzyme-linked immunosorbent assay, and methylation status using methylation microarrays. RESULTS: We observed an increase in blood progranulin gene expression and a decrease in GRN promoter methylation in males (P = 0.007). Progranulin expression was 13% higher in AD and MCI patients compared with controls in the UCSF-MAC cohort (F2,505 = 10.41, P = 3.72*10-5). This finding was replicated in the AddNeuroMed (F2,271 = 17.9, P = 4.83*10-8) but not the ADNI series. The rs5848 SNP (T-allele) predicted decreased blood progranulin gene expression (P = 0.03). The APOE4 haplotype was positively associated with progranulin expression independent of diagnosis (P = 0.04). Finally, we did not identify differences in plasma progranulin protein levels or gene methylation between diagnostic categories. INTERPRETATION: Progranulin mRNA is elevated in peripheral blood of patients with AD and MCI and its expression is associated with numerous genetic and demographic factors. These data suggest a role in the pathogenesis of neurodegenerative dementias besides frontotemporal dementia.

Significant improvement in Mn2O3 transition metal oxide electrical conductivity via high pressure.

Highly efficient energy storage is in high demand for next-generation clean energy applications. As a promising energy storage material, the application of Mn2O3 is limited due to its poor electrical conductivity. Here, high-pressure techniques enhanced the electrical conductivity of Mn2O3 significantly. In situ synchrotron micro X-Ray diffraction, Raman spectroscopy and resistivity measurement revealed that resistivity decreased with pressure and dramatically dropped near the phase transition. At the highest pressure, resistivity reduced by five orders of magnitude and the sample showed metal-like behavior. More importantly, resistivity remained much lower than its original value, even when the pressure was fully released. This work provides a new method to enhance the electronic properties of Mn2O3 using high-pressure treatment, benefiting its applications in energy-related fields.

Reversal in the Size Dependence of Grain Rotation.

The conventional belief, based on the Read-Shockley model for the grain rotation mechanism, has been that smaller grains rotate more under stress due to the motion of grain boundary dislocations. However, in our high-pressure synchrotron Laue x-ray microdiffraction experiments, 70 nm nickel particles are found to rotate more than any other grain size. We infer that the reversal in the size dependence of the grain rotation arises from the crossover between the grain boundary dislocation-mediated and grain interior dislocation-mediated deformation mechanisms. The dislocation activities in the grain interiors are evidenced by the deformation texture of nickel nanocrystals. This new finding reshapes our view on the mechanism of grain rotation and helps us to better understand the plastic deformation of nanomaterials, particularly of the competing effects of grain boundary and grain interior dislocations.

Deformation Behavior across the Zircon-Scheelite Phase Transition.

The pressure effects on plastic deformation and phase transformation mechanisms of materials are of great importance to both Earth science and technological applications. Zircon-type materials are abundant in both nature and the industrial field; however, there is still no in situ study of their deformation behavior. Here, by employing radial x-ray diffraction in a diamond anvil cell, we investigate the dislocation-induced texture evolution of zircon-type gadolinium vanadate (GdVO_{4}) in situ under pressure and across its phase transitions to its high-pressure polymorphs. Zircon-type GdVO_{4} develops a (001) compression texture associated with dominant slip along ⟨100⟩{001} starting from 5 GPa. This (001) texture transforms into a (110) texture during the zircon-scheelite phase transition. Our observation demonstrates a martensitic mechanism for the zircon-scheelite transformation. This work will help us understand the local deformation history in the upper mantle and transition zone and provides fundamental guidance on material design and processing for zircon-type materials.

Determination of GP88 (progranulin) expression in breast tumor biopsies improves the risk predictive value of the Nottingham Prognostic Index.

BACKGROUND: The Nottingham Prognostic Index (NPI), which combines numerical values for nodal status, tumor size and histological grade, is used in the standard of care to provide predictive value information on post-surgery survival for patients with primary breast cancer. Attempts to improve the performance of the NPI algorithm have been carried out by testing the inclusion of other biomarker expression and morphological features such as vascular invasion. In the present study, we investigated whether expression of the autocrine growth and survival factor GP88 (progranulin), known to be overexpressed in breast cancer, would improve NPI's predictive value. METHODS: We examined by immunohistochemistry (IHC) the GP88 expression in 508 cases of estrogen receptor positive invasive ductal carcinoma with known clinical outcomes and for which NPI had been determined. GP88 IHC expression was scored by two board certified pathologists and classified into two score groups of GP88 <3+ (0, 1+, 2+) and GP88 = 3+. The correlation between GP88 scoring, NPI and disease-free (DFS) or overall survival (OS) outcomes was then examined by Kaplan-Meier analysis, Cox proportional Hazard (CPH) ratio and Pearson's X (2) test. RESULTS: Kaplan-Meier survival graphs of cases categorized by their NPI scores (<3.4, 3.4-5.4, >5.4) and GP88 expression showed that for patients within the same NPI subgroup, patients having tumors with a high GP88 expression (GP88 IHC score of 3+) had a worse DFS than patients with tumors that had a low GP88 expression (GP88 IHC score <3+). When adjusted for NPI, high GP88 score was significantly associated with recurrence with a hazard ratio of 3.30 (95 % CI 2.12 to 5.14). CONCLUSIONS: The data suggest that the determination of GP88 tumor expression at time of diagnosis for early stage breast cancer patients can provide additional survival information to that provided by NPI alone and thus may be useful for risk management of patients diagnosed with breast cancer.

Signaling Pathway of GP88 (Progranulin) in Breast Cancer Cells: Upregulation and Phosphorylation of c-myc by GP88/Progranulin in Her2-Overexpressing Breast Cancer Cells.

Her2 is a receptor tyrosine kinase overexpressed in 25% of breast tumors. We have shown that the 88 kDa autocrine growth and survival factor GP88 (progranulin) stimulated Her2 phosphorylation and proliferation and conferred Herceptin resistance in Her2-overexpressing cells. Herein, we report that GP88 stimulates c-myc phosphorylation and upregulates c-myc levels in Her2-overexpressing cells. c-myc phosphorylation and upregulation by GP88 were not observed in non-Her2-overexpressing breast cancer cells. c-myc activation was inhibited upon treatment with ERK, PI3 kinase, and c-src pathway inhibitors, U0126, LY294002, and PP2. GP88 also stimulated c-src phosphorylation, a known upstream regulator of c-myc. Thus, we describe here a signaling pathway for GP88 in Her2-overexpressing cells, with GP88 stimulating Src phosphorylation, followed by phosphorylation and upregulation of c-myc. These data would suggest that targeting GP88 could provide a novel treatment approach in breast cancer.