Relationship between Tertiary Lymphoid Structure and the Prognosis and Clinicopathologic Characteristics in Solid Tumors

Background: An increasing number of studies had shown that tertiary lymphoid structure (TLS) plays an important role in tumor progression. However, the prognostic role of TLS in various tumors remains controversial. This meta-analysis aims to investigate the clinicopathological and prognostic values of TLS in solid tumors.Methods: A systematic search was conducted in PubMed, EMBASE and Cochrane Library undated to November 2, 2020. Odds ratios of clinical parameters, hazard ratio (HR) of overall survival (OS), relapse-free survival (RFS), disease-free survival (DFS) and relapse rate were calculated in order to evaluate the relationship between TLS expression and clinicopathological or prognostic values in different tumors.Result: 27 eligible studies including 6647 patients with different types of tumors were analyzed. High TLS expression was associated with a longer OS (HR = 0.66, 95% CI: 0.50 - 0.86, P = 0.002) and RFS (HR = 0.61, 95% CI: 0.47 - 0.79, P = 0.0001). Moreover, high TLS levels in tumor were associated with a low risk of recurrence (HR = 0.43, 95% CI: 0.32 - 0.57, P < 0.0001). However, there was no relationship between TLS expression and DFS. Meanwhile, high TLS expression was associated with smaller tumor size (P < 0.00001) and higher tumor infiltrating lymphocytes (TILs). Furthermore, the subgroup analysis showed high TLS expression that may be associated with a lower clinical grading and N stage in breast cancer and colorectal cancer.Conclusion: High TLS expression is associated with the longer OS and RFS in solid tumors, and a lower risk of cancer relapse. Meanwhile, high TLS expression is also associated with a smaller tumor size, higher infiltration of TILs, lower clinical grading and N stage in the tumor. Therefore, high TLS expression in the tumor is a favorable prognostic biomarker for solid tumor patients.     

Insulin-like growth factor receptor 1 (IGF1R) expression and survival in non-small cell lung cancer patients: a meta-analysis

The insulin-like growth factor receptor-1 (IGF1R) plays an important role in cancer progression. Previous studies have been controversial with respect to the associations between IGF1R expression and non small cell lung cancer (NSCLC) prognosis. Thus, we performed a meta-analysis to investigate the prognostic value of IGF1R expression in NSCLC patients and the relationship between the expression of IGF1R and clinical characteristics. Two independent reviewers searched PubMed, Embase, Ovid Medline and CNKI to identify eligible studies. Overall survival (OS), disease free survival (DFS) and clinicopathological characteristics were collected from included studies. Pooled hazard ratios (HRs) or odds ratios (ORs) with 95% confidence interval (95% CI) were calculated to estimate the effect. 17 studies comprising 3,294 patients were included in this meta-analysis. The results showed IGF1R positive expression was associated with an unfavorable DFS in NSCLC patients on univariate analysis (HR = 1.26, 95% CI: 1.09-1.46, P = 0.002) and multivariate analysis (HR = 1.49, 95% CI: 1.01-2.20, p = 0.045), but the relationship between IGF1R expression and OS have no significant difference on univariate analysis (HR = 0.91, 95% CI: 0.82-1.01, P = 0.157) and multivariate analysis (HR = 0.79, 95% CI: 0.45-1.41, P = 0.427). Ever smoking and smaller tumor size (T1 or T2) were associated with IGF1R positive expression: pooled OR 1.45 (1.13-1.85) and pooled OR 0.61 (0.60-0.95). Our results suggested IGF1R positive expression as an unfavorable factor for DFS in NSCLC patients, and IGF1R expression was associated with smoking status and tumor size.     

Down-regulation of microRNA-124 is correlated with tumor metastasis and poor prognosis in patients with lung cancer

Introduction: MicroRNA-124 (miR-124) has been proven dysregulated in several human malignancies and correlated with tumor progression. However, its expression and clinical significance in non-small cell lung cancer (NSCLC) is still unclear. Thus, the aim of this study was to investigate the clinical significance of miR-124 expression in NSCLC. Methods: Expression levels of miR-124 in 92 pairs of NSCLC and adjacent non-tumor tissues were detected by quantitative real-time PCR (qRT-PCR). In order to determine its prognostic value, overall survival (OS) and disease-free survival (DFS) were evaluated using the Kaplan-Meier method, and multivariate analysis was performed using the Cox proportional hazard analysis. Results: miR-124 expression level was significantly lower in NSCLC tissues compared with adjacent non-tumor tissues (P < 0.05). The 5-year OS of low miR-124 expression group was significantly shorter than that of high miR-124 expression group (P < 0.05). Moreover, the 5-year DFS of low miR-124 expression group was also significantly shorter than that of high miR-124 expression group (P < 0.05). In a multivariate Cox model, we found that miR-124 expression was an independent prognostic factor for both 5-year OS and 5-year DFS in NSCLC (P < 0.05). Conclusions: Our results offer the convincing evidence that miR-124 may play key roles in the progression of lung cancer and that the down-regulated expression of miR-124 may be independently associated with shorter OS and DFS of patients, suggesting that miR-124 might be a potential marker for further risk stratification in the treatment of lung cancer.     

MFG-E8 overexpression is associated with poor prognosis in breast cancer patients

Background

MFG-E8(Milk fat globule-EGF factor 8), a secreted glycoprotein, plays an exceptional role in various diseases. MFG-E8 overexpression is found in a variety of cancers. However, it remains unclear whether MFG-E8 overexpression is associated with the clinicopathological characteristics and prognosis of human breast cancer.

Up-regulation of long non-coding RNA CCAT2 correlates with tumor metastasis and poor prognosis in cervical squamous cell cancer patients

Background: Dysregulation of long non-coding RNAs (lncRNAs) plays critical roles in tumor progression. The purpose of this study was to investigate the relationship between lncRNA CCAT2 expression and cervical squamous cell cancer susceptibility and prognosis. Methods: Expression levels of lncRNA CCAT2 in 123 cervical squamous cell tumor specimens were determined by quantitative real-time PCR (qRT-PCR), to clarify the clinical significance of lncRNA CCAT2 in cervical squamous cell cancer, we further discussed the relationship between lncRNA CCAT2 expression and overall survival (OS) and progression-free survival (PFS). Results: In the present study, we found that lncRNA CCAT2 was up-regulated in cervical squamous cell cancer tissues compared to the adjacent non-tumor tissues. In addition, the high lncRNA CCAT2 expression was significantly associated with the FIGO stage, lymph node metastasis and depth of cervical invasion (P<0.05). Furthermore, patients with high expression of lncRNA CCAT2 had poor OS (HR=2.813, 95% CI: 1.504-6.172; P=0.017), and PFS rates (HR=3.072, 95% CI: 1.716-8.174; P=0.008). Multivariate Cox proportional hazard model analysis demonstrated that high lncRNA CCAT2 expression was an independent poor prognostic factor for cervical squamous cell cancer patients. Conclusions: Our study suggested that high expression of lncRNA CCAT2 is related to the prognosis of cervical squamous cell cancer; it may be a new prognostic biomarker and potential therapeutic target for cervical squamous cell cancer intervention.     

Stomatin-like protein 2 expression is associated with clinical survival in patients with cervical cancer

Aims: To investigate the prognostic role of stomatin-like protein 2 (STOML2) in cervical cancer. Methods: The expression of STOML2 in 8 pairs of cervical cancer and adjacent normal cervical tissues were detected by Real-time PCR. Immunohistochemistry was performed to evaluation of STOML2 expression in 94 paraffin-embedded cervical cancer samples. The correlation between STOML2 expression and cervical cancer progression and prognosis was analyzed statistically. Results: STOML2 expression was upregulated in cervical cancer tissues compared with adjacent normal cervical tissues. Of the 94 cervical cancer cases, high STOML2 expression was detected in 54 cases (57.4%). STOML2 expression was significantly related to tumor stage (P = 0.013) and tumor size (P = 0.025). Moreover, patients with high expression of STOML2 had a significant shorter overall survival and recurrent free survival time compared with those with low STOML2 expression in cervical cancer (P = 0.001 and P = 0.017, respectively). Multivariate analysis revealed that STOML2 was an independent prognostic factor (P = 0.022) for the overall survival in cervical cancer. Conclusion: Our study showed STOML2 was correlated to progression in cervical cancer, and implicated it as a potential predictive factor for the prognosis of cervical cancer.     

Elevated Aurora B expression contributes to chemoresistance and poor prognosis in breast cancer

Aurora-B is a major kinase responsible for appropriate mitotic progression. Elevated expression of Aurora-B has been frequently associated with several types of cancer, including breast cancer. However, it is not clear whether the alteration contributes to tumor responses to therapies and prognosis. In this study, we conducted immunohistochemistry using antibodies against Aurora-B, S1981p-ATM, Ki67, and p53 in paraffin-embedded tumor tissues from 312 invasive breast cancer patients. The correlation between disease-free-survival (DFS) and Aurora-B expression was analyzed using the Kaplan-Meier method and log-rank test. A Cox proportional hazards regression analysis was used to determine whether Aurora-B was an independent prognostic factor for breast cancer. We found that Aurora-B expression was correlated with the proliferation index (P < 0.001) and p53 expression (P = 0.014) in breast cancer tissues. Further we found that Aurora-B expression was associated with lymph node metastasis (P = 0.002) and histological grade (P = 0.001). Multivariate analyses indicated that elevated Aurora-B expression predicted a poor survival. In a subgroup of patients that received neoadjuvant chemotherapy, we found that elevated Aurora-B contributed to chemoresistance (P = 0.011). In conclusion, elevated Aurora-B expression in breast cancer patients contributes to chemoresistance and predicts poor prognosis.     

Overexpression of Rsf-1 correlates with pathological type,p53 status and survival in primary breast cancer

Aim: The incidence of breast cancer in developing countries still increasing, to identify novel molecular markers associated with carcinogenesis and prognosis of breast cancer still being implemented. The largest subunit of Remodeling and spacing factor (RSF), Rsf-1, mediates ATPase-dependent chromatin remodeling. Its oncogenic properties have been demonstrated in certain carcinomas. The aim of this study was to examine the prognostic value of Rsf-1 in patients with primary breast carcinoma. Methods: A total of 537 patients with primary breast cancer, and 54 with benign breast hyperplasia, were performed resection surgery in the same period were enrolled. Rsf-1 immunoexpression was retrospectively assessed by immunohistochemistry (IHC). As well as, it relationship with clinicopathological factors and patient survival (LRFS, DFS and OS) was investigated. Results: Compared with benign breast hyperplasia tissues, higher percentage of Rsf-1 positive expression was detected in malignant breast carcinomas. Based on IHC staining extent × intensity scores and ROC analysis, 278 of 526 cancers (52.9%) had high-expression (cut-off values 2.5) of Rsf-1, which correlated significantly to pathologic subtypes of breast cancer (DCIS vs. IDC, P < 0.001; ILC vs. IDC, P = 0.036), bigger tumor size (P = 0.030), higher TNM stage (P = 0.044), and p53-positive expression. In addition, there was a trend that high-expression of Rsf-1 associated with younger age (P = 0.053). We further prove that combined positive-expression of Rsf-1 and p53 (Rsf-1 (+)/p53 (+)) was correlated with the bigger tumor size (P = 0.018), and higher TNM stage (P = 0.024). Kaplan-Meier survival analysis showed that Rsf-1 high-expression and combined positive-expression of Rsf-1 and p53 (Rsf-1 (+)/p53 (+)) exhibited a significant correlation with poor overall survival of patients with primary breast cancer, and no association has been identified in relation to LRFS or DFS. Especially, Univariate and multivariate survival analysis demonstrated Rsf-1 expression is an independent prognostic parameter for the overall survival of patients with breast cancer. Conclusions: High-expression of Rsf-1 is associated with pathologic subtypes of breast cancer, aggressive phenotype, p53 positive and poor clinical outcome, which confers tumor aggressiveness through chromatin remodeling, and targeting Rsf-1 gene and the pathway it related may provide new therapeutic avenues for treating breast cancer.     

Association of pancreatic adenocarcinoma up-regulated factor expression in ovarian mucinous adenocarcinoma with poor prognosis

Pancreatic adenocarcinoma up-regulated factor (PAUF) expression is elevated in both ovarian tumors and pancreatic adenocarcinoma. However, PAUF expression in ovarian tumors according to histologic subtype and grade has not been investigated. In this study, we examined various clinicopathologic features of 24 patients with mucinous cystadenoma (MCA), 36 with mucinous borderline tumors (MBTs), and 46 with mucinous adenocarcinomas (MACs) according to PAUF expression status assessed using immunohistochemistry. We found that MACs more frequently stained positive for PAUF than did MCAs and MBTs (P < 0.0001). Although there was no significant differences with respect to other clinicopathologic characteristics of MACs according to PAUF expression status, patients with PAUF-weakly positive and PAUF-strongly positive MACs tended to have a shorter overall survival (OS) than those with PAUF-negative MAC, determined using a Kaplan–Meier analysis (P = 0.1885). After adjusting for various clinicopathologic parameters, PAUF positivity of MACs was a significant predictive factor for disease-free survival (DFS) (negative vs. weakly positive: P = 0.045, hazard ratio [HR] = 57.406, 95% confidence interval [CI]: 1.090-3022.596; and negative vs. strongly positive: P = 0.034, HR = 97.890, 95% CI: 1.412-6785.925). In conclusion, PAUF was more frequently expressed in MAC than in its benign and borderline counterparts, and was associated with a poor OS and DFS in MAC patients. Therefore, we suggest that PAUF may be a practical biomarker for histopathological categorization and a prognostic marker for patients with an ovarian mucinous tumor.     

Decreased HCRP1 expression is associated with poor prognosis in breast cancer patients

Background: Downregulation of hepatocellular carcinoma related protein 1 (HCRP1) has been reported to be associated with a poor prognosis in a variety of malignant tumors. The purpose of this study was to assess HCRP1 expression in breast cancer and to examine its possible correlation with commonly used prognostic factors, particularly epidermal growth factor receptor (EGFR). Methods: Immunohistochemical analysis was performed on tumors from 194 patients with primary breast cancer. HCRP1 expression was analyzed along with major clinicopathological variables. Results: HCRP1 protein expression was shown to be correlated with age (P = 0.001), histological grade (P = 0.005), tumor progression (P = 0.013), and death (P = 0.001), but not with tumor size, lymph-node metastasis, or Ki67 status. Kaplan-Meier survival curves showed that lower HCRP1 expression was significantly correlated with increased short-term survival (P < 0.001), and both univariate and multivariate analyses revealed that HCRP1, tumor size, lymph-node metastasis, and human epidermal growth factor receptor-2 (HER-2) were independent prognostic factors (all P < 0.05). In addition, low HCRP1 expression was much more frequent in triple negative breast cancer (TNBC; 63.89%) than in luminal (16.95%) and HER-2 overexpression phenotypes (7.5%; P < 0.001), and significant correlations between HCRP1 and survival time were observed for the TNBC group (P < 0.004). Furthermore, an inverse relationship between HCRP1 and EGFR expression was found both for the complete set of all cases (P < 0.001), and for each phenotype analyzed individually (P < 0.05). Conclusion: Our results suggest that HCRP1 may play an important role in EGFR regulation and that its decreased expression is an independent predictor of breast cancer, especially in TNBC patients.     

Overexpression of matriptase correlates with poor prognosis in esophageal squamous cell carcinoma

Matriptase is one of the type II transmembrane serine proteases and is known to be involved in cancer progression. Increased matriptase expression has been reported in a variety of human cancers, and its association with poor prognosis has been highlighted in some cancer types. However, its exact role in cancer progression and its effect on patient survival in esophageal squamous cell carcinoma (ESCC) are still unclear. We performed immunohistochemical staining of matriptase in 171 ESCC samples after antibody validation and evaluated the association of its expression with clinicopathological parameters and prognosis. High matriptase expression was observed in 38.6 % (66/171) of ESCC samples and more frequently in N3 stage and in poorly differentiated tumors. Both overall survival (OS) and disease-free survival (DFS) were significantly lower for patients with high expression of matriptase than for patients with low expression (5-year OS rate, 38.6 vs 55.3 %; p?=?0.034 and 5-year DFS rate, 30.5 vs 49.4 %; p?=?0.007). High matriptase expression was an independent prognostic factor for OS [hazard ratio (HR), 1.65 (95 % confidence interval (CI), 1.01–2.68); p?=?0.045] and for DFS [HR, 1.79 (95 % CI, 1.14–2.81); p?=?0.012]. In conclusion, higher expression of matriptase is an independent prognostic factor involved in the progression of ESCC, which suggests that matriptase is a factor in ESCC tumor progression and also a potential molecular therapeutic target.     

Increased expression of microRNA-196a predicts poor prognosis in human ovarian carcinoma

Objective: Overexpression of MicroRNA-196a (miR-196a) has recently been reported in different types of human cancers. However, the prognostic value of miR-196a in ovarian carcinoma remains unknown. In this study, we investigated the expression of miR-196a in ovarian carcinoma and its relationship with tumor progression and clinical prognosis. Methods: The expression level of miR-196a was examined by quantitative Real-time PCR (qRT-PCR) in surgically removed ovarian cancer tissues and ovarian cancer cell lines. The correlation between miR-196a expression and clinical features and prognosis were statistically analyzed. Results: The results showed that the miR-196a expression was significantly upregulated in tumor tissues and ovarian cancer cell lines compared with that in normal ovarian surface tissues and normal ovarian epithelial cells. Moreover, miR-196a expression was positively correlated with FIGO stage (P <0.001), tumor size (P =0.020), and lymph nodes metastasis (P =0.019). Kaplan-Meier analysis demonstrated that high levels of miR-196a expression was associated with poorer overall survival (P <0.001) and recurrent-free survival (P =0.003), especially in patients with advanced disease (P =0.002). Multivariate analysis suggested that miR-196a expression was an independent prognostic factor for overall survival of patients with ovarian carcinoma. Conclusions: In conclusion, miR-196a may play an important role in the progression of ovarian carcinoma, and could be used as an independent prognostic biomarker for patients with ovarian carcinoma.     

Expression of Yes-associated protein (YAP) in breast phyllodes tumor

This study aimed to identify expression profiles of Yes-associated protein (YAP) and its phosphorylated form (pYAP) in phyllodes tumor (PT) of human breast and verify the clinical implications. We selected PTs from the pathologic archive and reviewed the histologic features (141 benign, 27 borderline, and 15 malignant). We made tissue microarray (TMA) block from the formalin-fixed paraffin-embedded (FFPE) tissue corresponding to the representative section. Using TMA block, we performed immunohistochemical staining of YAP and pYAP. In the stromal component, expressions of YAP and pYAP were increased in borderline/malignant PT with comparison of benign PT (P = 0.002, and P < 0.001, respectively). In the epithelial component, cytoplasmic expression of YAP was highest in borderline PT (P = 0.001). Stromal YAP expression (P < 0.001) and stromal pYAP expression (P = 0.042) were associated with shorter disease-free survival (DFS) and stromal pYAP expression (P = 0.001) was associated with shorter overall survival (OS) in univariate Cox analysis. In multivariate Cox analysis, stromal YAP expression was an independent prognostic factor associated with shorter DFS (Hazard ration: 3.206, 95% CI: 1.000-10.27, P = 0.050). In conclusion, expression level of YAP in stromal component was increased along with histologic grade of PT and YAP expression in PT was related to tumor progression and poor prognosis.     

Expression of cyclin kinase subunit 2 in human breast cancer and its prognostic significance

Cyclin kinase subunit 2 (CKS2) protein is a small cyclin-dependent kinase-interacting protein, which is essential for the first metaphase/anaphase transition of mammalian meiosis. CKS2 is up-regulated in various malignancies, suggesting that CKS2 maybe an oncogene. However, data on its expression pattern and clinical relevance in breast cancer are unknown. The aim of this study is to investigate CKS2 expression and its prognostic significance in breast cancer. The CKS2 expression was examined at mRNA and protein levels by real-time quantitative polymerase chain reaction (RT-PCR) and Western blotting analysis in paired breast cancer tissues and the adjacent normal tissues. The expression of CKS2 protein in 126 specimens of breast cancer was determined by immunohistochemistry assay. The relations between CKS2 expression and clinicopathological features were analyzed. The result show the expression of CKS2 mRNA and protein was higher in breast cancer than the adjacent normal tissues. Compared with adjacent normal breast tissues, Overexpression of CKS2 was detected in 56.3% (71/126) patients. Overexpression of CKS2 was significantly associated with large tumor size (P = 0.035), poor cellular differentiation (P = 0.016), lack expression of progesterone receptor (P = 0.006), and decreased overall survival (P = 0.001). In multivariate analysis, CKS2 expression was an independent prognostic factor for overall survival (Hazard ratio [HR] = 3.404, 95% confidence interval [CI] 1.482-7.818; P = 0.004). CKS2 is up-regulated in breast cancer and associated with large tumor size, lack expression of progesterone receptor, poor tumor differentiation and survival. CKS2 may serve as a good prognostic indicator for patients with breast cancer.     

S4646 polymorphism in CYP19A1 gene is associated with the efficacy of hormone therapy in early breast cancer

Purpose: The aim was to verify the potential association between CYP19A1 genetic polymorphisms and clinical outcome of hormone therapy in hormone receptor (HR)-positive early breast cancer. Methods: Genotyping for CYP19A1 rs4646 (C/A) polymorphism was performed on 287 women with HR-positive early breast cancer. Associations were evaluated between CYP19A1 rs4646 genotypes and disease-free survival (DFS). Results: Totally, women with the minor allele (AA or AC) had an improved DFS when compared with those carrying the homozygous common allele (CC) (AA or AC vs. CC: 62.7 months versus 55.6 months; Hazard ratio (HR), 0.745; 95% CI, 0.562-0.988; P = 0.04). The difference was further demonstrated by multivariate analyses (HR, 0.681; 95% CI, 0.506-0.917; P = 0.011). In premenopausal women, AA genotype was associated with a prolonged DFS (AA versus CC or AC: 98.2 months versus 56.2 months; HR, 0.425; 95% CI, 0.198-0.914; P = 0.024). In addition, women with the A allele had an improved DFS when compared with those carrying the homozygous C allele (AA or AC vs. CC: 62.7 months versus 55.6 months; HR, 0.709; 95% CI, 0.516-0.975; P = 0.033). These findings were further confirmed by the Cox regression model (HR, 0.336, 0.670; 95% CI, 0.160-0.836, 0.479-0.938; P = 0.017, 0.019). In postmenopausal women, rs4646 genotypes were significantly associated with DFS (AA versus AC versus CC: 32.7 months versus not reached versus 56.3 months; P = 0.011). Women carrying AA variant had a poorer DFS than those with CC or AC genotypes (32.7 months versus 70.6 months; HR, 3.613; 95% CI, 1.380-9.457; P = 0.005). Furthermore, being adjusted by the patients features in multivariate analyses, AA genotype remained an independent prognostic factor for DFS (HR, 3.614; 95% CI, 1.308-9.991; P = 0.013). Conclusions: The homozygous minor allele (AA) of CYP19A1 rs4646 is significantly associated with improved clinical outcome of hormone therapy in premenopausal HR-positive early breast cancer patients, but with a worse impact on postmenopausal women. The findings are novel, if confirmed, genotyping for CYP19A1 rs4646 polymorphism may provide predictive information for better selection of endocrine treatment.     

Increased HIF-1alpha expression in tumor cells and lymphocytes of tumor microenvironments predicts unfavorable survival in esophageal squamous cell carcinoma patients

The expression of hypoxia-induced factor (HIF)-1α is up-regulated in tumor microenvironments under hypoxia condition. However, the prognostic significance of HIF-1α in esophageal squamous cell carcinoma (ESCC) is still elusive. We measured the HIF-1α expression by immunochemistry in tumor specimens from 136 resected ESCC; in the current study, the HIF-1α expression in tumor cells was significantly associated with tumor stage (P = 0.003) and lymph node metastasis (P = 0.006); whereas the HIF-1α expression in tumor-infiltrating lymphocytes (TILs) had no relationship with patients’ clinicopathological parameters. Patients with high HIF-1α expression in tumor cells or in TILs showed worse survival related to those with low HIF-1α expression. Multivariate analysis demonstrated that expression of HIF-1α in TILs was an independent factor for DFS (P = 0.007) and OS (P = 0.013). Additionally, the expression of HIF-1α in tumor cells was an independent factor for DFS (P = 0.037) and OS (P = 0.033) in locoregional ESCC patients, whereas the expression of HIF-1α in TILs was an independent factor for DFS (P = 0.048) and OS (P = 0.039) in metastatic ESCC patients. Correlation analysis revealed that expressions of HIF-1α in tumor cells and in TILs were positively correlated, and patients with combined high HIF-1α in both tumor cells and TILs had the worst survivals (P < 0.05). These findings suggest that the HIF-1α expressions in different cell populations of ESCC microenvironments have different clinical relevance and prognostic impact on patients.     

High expression of REGγ is associated with metastasis and poor prognosis of patients with breast cancer

REGgamma (REGγ) has been recently found in several types of human cancer, however, its clinical significance in metastasis and prognosis of breast cancer remains unknown. In this study, immunohistochemical staining and western blot analysis were performed to evaluate REGγ expression in both mouse and human breast cancer specimens. We found that in MMTV-PyMT mice, 14 out of 20 (70%) mouse mammary carcinomas were REGγ positive, which was significantly higher than control (0/20, 0%, P < 0.001) and lower than metastatic lung tumour (20/20, 100%, P = 0.027). Further investigation for REGγ expression in 136 human breast cancer tissues with the paired peritumoural normal breast tissues and 140 breast benign disease tissue samples showed that REGγ was undetectable in normal breast tissues and nonmetastatic axillary lymph nodes (ALNs), whereas 111 out of 136 (81.6%) breast cancer tissue samples were REGγ positive, which was significantly higher than breast benign disease tissues (9/140, 6.4%, P < 0.001) and lower than metastatic ALNs (116/116, 100%, P < 0.001). The 5-year disease-free and overall survivals of patients with negative/low level of REGγ were significantly higher than those of patients with high level of REGγ (P < 0.05). Cox regression analyses further indicated that REGγ could serve as a novel independent prognostic factor for breast cancer (OR = 4.369, P = 0.008). Our results suggest that the high expression of REGγ might predict metastasis and poor prognosis in breast cancer.