Min Sung Chung

The Glycolytic Phenotype is Correlated with Aggressiveness and Poor Prognosis in Invasive Ductal Carcinomas

Purpose Glucose uptake and glycolytic metabolism are enhanced in cancer cells, and increased expression of glucose transporter 1 (GLUT1) has also been reported. The aim of this study was to investigate GLUT1 expression in human breast tissues and invasive ductal carcinomas. Methods We used tissue microarrays consisting of normal breast tissue, ductal hyperplasia, ductal carcinoma in situ, invasive ductal carcinoma, and lymph node metastases. We examined GLUT1 expression in the microarrays by immunohistochemistry, reviewed the medical records and performed a clinicopathological analysis. Results Membranous GLUT1 expression was observed in normal and tumor cells. GLUT1 expression was higher in ductal carcinoma in situ, invasive ductal carcinoma, and lymph node metastasis than in normal tissue and ductal hyperplasia (p=0.002). Of 276 invasive ductal carcinomas, 106 (38.4%) showed GLUT1 expression. GLUT1 expression was correlated with higher histologic grade (p<0.001), larger tumor size (p=0.025), absence of estrogen receptor (p<0.001), absence of progesterone receptor (p<0.001), and triple-negative phenotype (p<0.001). In univariate survival analysis, patients with GLUT1 expression had poorer overall survival and disease-free survival (p=0.017 and p=0.021, respectively, log-rank test). In multivariate survival analysis with the Cox proportional hazards model, GLUT1 expression was an independent prognostic factor of poorer overall survival and disease-free survival (p=0.017 and p=0.019, respectively). Conclusion GLUT1 expression seems to play an important role in malignant transformation, and the glycolytic phenotype in invasive ductal carcinoma may indicate aggressive biological behavior and a worse prognosis.

Increased Expression of Forkhead Box M1 Is Associated with Aggressive Phenotype and Poor Prognosis in Estrogen Receptor-Positive Breast Cancer

Fox transcription factors play a critical role in the regulation of a variety of biological processes. While FoxM1 behaves like the oncogenic transcription factor, FoxO3a is known as a tumor suppressor by inhibiting FoxM1. This study aimed to investigate the clinicopathological significance of FoxM1 and FoxO3a expression in breast cancer. Expression of FoxM1 and FoxO3a were analyzed by immunohistochemical staining on tissue microarray sections from 236 breast cancer patients, and correlated with various clinicopathological characteristics. Overexpression of FoxM1 correlated with adverse clinicopathological features, such as larger tumor size, lymph node metastasis, advanced tumor stage, and lymphovascular invasion. The Kaplan-Meier survival curves revealed no prognostic significance of FoxM1 expression. However, in subgroup analyses with patients of estrogen receptor (ER) positive breast cancers, FoxM1 overexpression associated with poor disease free and overall survival. No association was found between FoxO3a and FoxM1 expression. Regarding clinicopathological variables, the only association between histologic grade and FoxO3a was observed. In conclusion, FoxM1 overexpression was significantly associated with aggressive phenotypes and poor prognosis of ER-positive breast cancer. These findings suggest the possible role of FoxM1 as a prognostic biomarker and putative target of anti-cancer therapy. Graphical Abstract

Clinicopathological significance of dual-specificity protein phosphatase 4 expression in invasive ductal carcinoma of the breast.

Purpose Dual-specificity protein phosphatase 4 (DUSP4), also known as mitogen-activated protein kinase phosphatase (MKP) 2 is a member of the inducible nuclear MKP group. The role of DUSP4 in cancer development and progression appears to vary with the type of malignancy. The purpose of this study was to investigate DUSP4 expression in a case series of invasive ductal carcinoma of the breast. Methods We constructed tissue microarrays consisting of 16, 14, 47, and 266 cases of normal breast tissue, usual ductal hyperplasia, ductal carcinoma in situ, and invasive ductal carcinoma, respectively. DUSP4 expression was investigated by immunohistochemistry. Results Cytoplasmic DUSP4 expression was observed. DUSP4 was more frequently expressed in malignant than in benign cases (p=0.024). The mean DUSP4 expression score was significantly higher in malignant tumors than in benign lesions (p=0.019). DUSP4 expression was significantly correlated with a larger tumor size (>2 cm, p=0.015). There was no significant correlation between overall survival or disease-free survival and DUSP4 expression in all 266 patients. We evaluated the impact of DUSP4 expression on the survival of 120 patients with T1-stage tumors. Interestingly, Kaplan-Meier survival curves revealed that DUSP4 expression had a significant effect on both overall patient survival (p=0.034, log-rank test) and disease-free survival (p=0.045, log-rank test). In early T-stage breast cancer, DUSP4 expression was associated with a worse prognosis. Conclusion DUSP4 is frequently upregulated in breast malignancy, and may play an important role in cancer development and progression. In addition, it may be a marker of adverse prognosis, especially in patients with early T1-stage cancer.

High MicroRNA-370 Expression Correlates with Tumor Progression and Poor Prognosis in Breast Cancer

Purpose Deregulation of microRNA-370 (miR-370) has been reported in various cancers, in which it can act as either an oncogene or a tumor suppressor gene. However, the clinicopathologic significance of miR-370 expression in breast cancer has not been studied. Methods The expression of miR-370 was determined with quantitative real-time polymerase chain reaction in 60 formalin-fixed, paraffin-embedded primary breast cancer tissues. Additionally, the protein expression levels of previously known targets of miR-370, such as FOXM1, FOXO1, and FOXO3a, were detected using immunohistochemistry. Finally, we analyzed its correlation with target protein expression, clinicopathologic features, and clinical outcome. Results High levels of miR-370 expression correlated with lymph node metastasis (p=0.009), advanced stage (p=0.002), and frequent perineural invasion (p=0.042). Moreover, patients with high miR-370 expression had poor disease-free survival compared with the low-expression group. However, no correlation was observed between miR-370 and its target protein expression. Conclusion Our results indicate that upregulation of miR-370 in breast cancer is correlated with breast cancer progression and that it might be a potential biomarker for predicting clinical outcomes.

Clinicopathological significance of CADM4 expression in invasive ductal carcinoma of the breast

Aims Cell adhesion molecule 4 (CADM4) is a novel tumour suppressor involved in cell adhesion. Loss or decreased expression of CADM4 has been associated with the development and progression of some cancers. The purpose of this study was to investigate the clinicopathological significance of CADM4 expression in breast cancer. Methods We constructed tissue microarrays to evaluate the immunohistochemical expression of CADM4 in 256 cases of invasive ductal carcinoma (IDC) and 45 cases of ductal carcinoma in situ (DCIS). Results CADM4 was expressed in 37 (82.2%) DCIS cases, and in 173 (67.6%) IDC cases. CADM4 expression was higher in DCIS than in IDC (p=0.049). Loss or decrease of CADM4 expression was significantly correlated with higher histological grade (p=0.020), absence of oestrogen receptors (p<0.001), absence of progesterone receptors (p=0.024), and overexpression of c-erbB-2 (p=0.018). In univariable and multivariable Cox regression analyses of all 256 IDC cases, CADM4 expression was not significantly associated with overall and disease-free survival. However, it showed a significant positive association with longer disease-free survival in 187 stages I and II IDC cases (p=0.039, log-rank test). Conclusions Loss or decrease of CADM4 expression seems to play an important role in breast cancer invasiveness, and it is associated with poorer biological parameters. CADM4 can be used as a novel marker predicting risk of recurrence and disease outcomes in stages I and II IDC.

FOXO3a expression is associated with lymph node metastasis and poor disease-free survival in triple-negative breast cancer

Aims Forkhead box O (FOXO) transcription factors, consisting of FOXO1, FOXO3a, FOXO4 and FOXO6, are involved in carcinogenesis and tumour progression. Recent studies have suggested that FOXOs act as tumour suppressors in a variety of human cancers. This study investigated the clinicopathological significance of FOXOs in triple-negative breast cancer (TNBC). Methods FOXO protein expressions were assessed by immunohistochemistry in 125 TNBC tissues. Correlations between FOXO protein expression and various clinicopathological parameters, including patients’ survival, were investigated. MDA-MB-468 cell line was used for in vitro cell proliferation and migration assay. Results FOXO1 protein expression was not observed in all 125 TNBC tissues. FOXO4 and FOXO6 protein expressions were detected in 11 (8.8%) and 14 (11.2%) TNBC tissues, respectively. Loss of FOXO4 expression was significantly associated with high histological grade (P=0.014, χ2 test), and TNBCs with positive FOXO6 expression correlated with high grade (P=0.020, χ2 test). FOXO3a expression was detected in 40 (32%) TNBC cases and correlated with adverse clinicopathological features, such as lymph node metastasis (P=0.021, χ2 test), perineural invasion (P=0.013, χ2 test) and higher Ki-67 proliferation index (P=0.048, t-test). Additionally, FOXO3a expression was significantly associated with poor disease-free survival (P=0.015, log-rank test). In the in vitro study, siRNA-mediated FOXO3a knockdown in the MDA-MB-468 cell line inhibited cell proliferation and migration. Conclusion Among FOXO members, FOXO3a may have a potential role in promoting tumour cell migration and proliferation and may serve as a prognostic biomarker and a potential therapeutic target for TNBC.

Correlations between Tumor to Background Ratio on Breast-Specific Gamma Imaging and Prognostic Factors in Breast Cancer

The purpose of this study was to investigate the correlations between tumor-to-background ratio (TBR) obtained from breast-specific gamma imaging (BSGI) and the prognostic factors of breast cancer. Sixty-seven patients with invasive ductal carcinoma who underwent preoperative BSGI were enrolled. The BSGI images were visually scored from 1 to 5 according to a breast imaging reporting and data system (BIRADS). The TBR results obtained from positive BSGI images were compared according to the following prognostic factors: tumor size; axillary lymph node metastasis; nuclear grade (NG); histologic grade (HG); subtype; Ki-67; and the expression profile of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). Among 67 images, 60 were classified as a positive finding (sensitivity 89.6%). A higher TBR value was significantly correlated with tumor size ≥ 2 cm (P = 0.001), axillary lymph node metastasis (P = 0.007), high HG (P = 0.029), negative PR status (P = 0.036), and Ki-67 ≥ 14% (P = 0.007). The TBR showed a significant difference between the luminal A and non-luminal A subtypes (P = 0.007). On multivariate analysis, TBR had a high correlation with tumor size ≥ 2 cm, axillary lymph node metastasis, and negative PR status (P = 0.003, 0.048, and 0.030, respectively). A high TBR on BSGI was significantly correlated with poor prognostic factors of breast cancer. Luminal A subtype, a breast cancer subtype with more favorable prognosis, was associated with a low TBR on BSGI.

Wnt7a Deficiency Could Predict Worse Disease-Free and Overall Survival in Estrogen Receptor-Positive Breast Cancer

Purpose Wnt7a is a glycoprotein involved in embryonic development and the progression of different types of malignant tumors. This study aimed to detect the level of Wnt7a expression in breast cancer and explore its role in the disease progression and prognosis. Methods A total of 258 patients diagnosed with invasive ductal carcinoma of the breast were included in this study. Using tissue microarray and immunohistochemical staining, we evaluated the association between Wnt7a expression and clinicopathological parameters, and the prognostic value of Wnt7a. Results Wnt7a expression was significantly correlated with estrogen receptor (ER) expression (odds ratio, 3.95; 95% confidence interval [CI], 1.99–7.80; p<0.001). On univariate and multivariate analyses, loss of Wnt7a expression was associated with poor disease-free survival (DFS) (multivariate hazard ratio [HR], 9.12; 95% CI, 1.80–46.09; p=0.008), but not with poor overall survival (OS). In the ER-positive group (n=114), loss of Wnt7a expression was an independent prognostic factor for shorter DFS (multivariate HR, 13.54; 95% CI, 1.11–165.73; p=0.042) and OS (multivariate HR, 4.76; 95% CI, 1.29–17.61; p=0.019) on univariate and multivariate analyses. However, in the ER-negative group, there was no significant difference in DFS and OS according to Wnt7a expression. Conclusion The loss of Wnt7a expression might be a meaningful factor in assessing DFS and OS, especially in ER-positive breast cancer.

Bilateral granulomatous mastitis with a different etiology

Idiopathic granulomatous mastitis (IGM) and Tuberculosis mastitis (TM) are rare inflammatory diseases of the breast that can clinically mimic malignancy causing misdiagnosis as breast cancer. We present a rare case of bilateral granulomatous mastitis with a different etiology. An initial lesion developed in the right breast was diagnosed as IGM, which was treated with antibiotics and surgery. A subsequent lesion developed in the contralateral breast 5 months later and was diagnosed as TM, which also completely responded to antituberculosis medication without surgical excision. Differential diagnosis was made using the results of the polymerase chain reaction for tuberculosis (TBC-PCR) of both of the breast lesions in addition to typical pathologic findings of IGM in the right breast and an antituberculosis medication response in the left breast. To the best of our knowledge, this is the first case of bilateral granulomatous mastitis with a different etiology.