Breast Neoplasms ; diagnosis ; genetics ; metabolism ; Female ; Gene Amplification ; genetics ; physiology ; Humans ; Middle Aged ; Receptor, ErbB-2 ; metabolism

Breast cancer is a complex disease driven by multiple factors including both genetic and epigenetic alterations. Recent studies revealed that abnormal gene expression induced by epigenetic changes, including aberrant promoter methylation and histone modification, plays a critical role in human breast carcinogenesis. Silencing of tumor suppressor genes (TSGs) by promoter CpG methylation facilitates cells growth and survival advantages and further results in tumor initiation and progression, thus directly contributing to breast tumorigenesis. Usually, aberrant promoter methylation of TSGs, which can be reversed by pharmacological reagents, occurs at the early stage of tumorigenesis and therefore may serve as a potential tumor marker for early diagnosis and therapeutic targeting of breast cancer. In this review, we summarize the epigenetic changes of multiple TSGs involved in breast pathogenesis and their potential clinical applications as tumor markers for early detection and treatment of breast cancer.
Biomarkers, Tumor ; metabolism ; Breast Neoplasms ; diagnosis ; drug therapy ; genetics ; metabolism ; CpG Islands ; genetics ; DNA (Cytosine-5-)-Methyltransferases ; antagonists & inhibitors ; therapeutic use ; DNA Methylation ; Epigenesis, Genetic ; Female ; Gene Silencing ; Humans ; Promoter Regions, Genetic ; Tumor Suppressor Proteins ; genetics ; metabolism

Breast Neoplasms ; diagnosis ; genetics ; metabolism ; Carcinoma, Intraductal, Noninfiltrating ; genetics ; metabolism ; Chromosomes, Human, Pair 17 ; genetics ; Female ; Genetic Heterogeneity ; Humans ; Immunohistochemistry ; In Situ Hybridization, Fluorescence ; Neoplasm Metastasis ; Neoplasm Recurrence, Local ; Polyploidy ; Receptor, ErbB-2 ; genetics ; metabolism

The mitogen-activated protein kinase (MAPK) phosphatase-1 (MKP-1) belongs to the MAPK cascades which are central to cell proliferation and apoptosis. The carcinogenic role of MKP-1 has been reported in many types of cancer but it has rarely been investigated in breast cancer. The present study was designed to evaluate the MKP-1 mRNA expression and its possible regulation by methylation of MKP-1 promoter in the model of several breast cancer cell lines and tissues as well as controls. Our data demonstrate MKP-1 mRNA expression significantly decreased in five breast cancer cell lines compared to breast controls (P < 0.01). Using the methylation-specific PCR (MSP) analysis, the unmethylated reaction (U) is dominant in both normal cell lines and benign breast tumors (100% vs. 86.2%), whereas the methylated reaction (M) is dominant in both breast cancer cell lines and invasive breast tumors (100% vs. 57.2%). In terms of methylation ratio (M/M+U), methylation level in MKP-1 promoter is significantly higher in the invasive breast tumor tissues (n = 152) than in benign breast tumor tissues (n = 29) (P < 0.0001). Assessing the methylation ratio of the promoter of MKP-1 gene to diagnose the breast malignancy (invasive vs. benign), the area under the receiver-operating characteristic (ROC) curve was 0.809 (95% CI: 0.711-0.906, P < 0.001). The best performance for this prediction has a sensitivity of 76.32% and a specificity of 82.76% at the cutoff value of 0.38. Taken together, we firstly demonstrated that the promoter methylation of MKP-1 gene is a potential breast cancer biomarker for breast malignancy.
*Breast Neoplasms/diagnosis/genetics/metabolism ; Cell Line, Tumor ; DNA Methylation/*genetics ; Dual Specificity Phosphatase 1/genetics/*metabolism ; Female ; Gene Expression Regulation, Neoplastic ; Humans ; *Promoter Regions, Genetic ; ROC Curve ; Sensitivity and Specificity ; Tumor Markers, Biological

Breast cancer is a major health problem that affects more than 24% of women in Bangladesh. Further- more, among low-income countries including Bangladesh, individuals have a high risk for developing breast cancer. This study aimed to identify candidate mitochondrial DNA (mtDNA) biomarkers for breast cancer diagnosis in Bangladeshi women to be used as a preventive approach. We screened the blood samples from 24 breast cancer patients and 20 healthy controls to detect polymorphisms in the D-loop and the ND3- and ND4-coding regions of mtDNA by direct sequencing. Among 14 distinct mutations, 10 polymorphisms were found in the D-loop, 3 were found in the ND3-coding region, and 1 was found in the ND4-coding region. The frequency of two novel polymorphisms in the D-loop, one at position 16290 (T-ins) and the other at position 16293 (A-del), was higher in breast cancer patients than in control subjects (position 16290: odds ratio = 6.011, 95% confidence interval = 1.2482 to 28.8411, P = 0.002; position 16293: odds ratio = 5.6028, 95% confidence interval = 1.4357 to 21.8925, P = 0.010). We also observed one novel mutation in the ND3-coding region at position 10316 (A > G) in 69% of breast cancer patients but not in control subjects. The study suggests that two novel polymorphisms in the D-loop may be candidate biomarkers for breast cancer diagnosis in Bangladeshi women.
Adult ; Aged ; Bangladesh ; Biomarkers, Tumor ; metabolism ; Breast Neoplasms ; diagnosis ; genetics ; DNA Primers ; genetics ; DNA, Mitochondrial ; genetics ; Female ; Humans ; Middle Aged ; Mutation ; Odds Ratio ; Polymerase Chain Reaction ; Polymorphism, Genetic

OBJECTIVETo investigate the expression of a novel metastasis-inducing protein human anterior gradient-2 (AGR2) in breast cancer and its clinical and prognostic significance.

METHODSAGR2 expression was assessed in 160 cases of breast cancer and 20 cases of benign breast diseases by immunohistochemistry using tissue chip technology. In addition the expression of ERa, PR and c-erbB-2 in breast cancer was also evaluated. Follow-up information of 5-year duration was available in 127 patients with breast cancer. Kaplan-Meier analysis and COX regression model were used to analyze the correlation between AGR2 expression and the follow-up clinical data.

RESULTSThe expression of AGR2 was significantly higher in breast cancers than that in benign diseases (68.3% vs. 25.0% , P < 0.01). There was a negative correlation between AGR2 expression and the histological grade of breast cancer (P <0.05) , whereas positive correlations was found between the expression of AGR2 and ERalpha (P <0.05), and between the expression of AGR2 and PR (P <0.01). In the subgroup of ERalpha-positive breast cancer, Logistic regression model demonstrated AGR2 and TNM stage were important factors affecting lymph node metastasis (both P < 0.01). Kaplan-Meier analysis demonstrated that a positive expression of AGR2 was associated with poor overall survival and relapse-free survival (both P <0.01). Moreover, COX regression model confirmed the expression of AGR2 as an independent prognostic factor among patients with ERa-positive breast cancer (P <0.01).

CONCLUSIONSThe abnormal expression of AGR2 may play a role in the pathogenesis and progression of breast cancer. The metastasis-inducing capability of AGR2 may be partly regulated through the ER pathway. Therefore, AGR2 may be a useful molecular marker for prognostication for patient with hormone-responsive breast cancer.

Antineoplastic Agents, Hormonal ; analysis ; BRCA2 Protein ; genetics ; metabolism ; Biomarkers, Tumor ; analysis ; Breast Neoplasms ; diagnosis ; genetics ; metabolism ; Estrogen Receptor alpha ; metabolism ; Female ; Gene Expression Regulation, Neoplastic ; genetics ; Humans ; Immunohistochemistry ; Neoplasm Metastasis ; diagnosis ; Neoplasm Staging ; Prognosis ; Proteins ; genetics ; metabolism ; Receptor, ErbB-2 ; analysis ; metabolism

To evaluate the relationship between p27Kip1 low expression in breast cancer and its prognostic implication in breast carcinoma patients. Methods All data that were associated with the study of the relationship between p27Kip1 and the prognosis for breast cancer was pooled from Cochrane library, PubMed, Embase and Medlinebase. The outcome was measured using the risk ratio (RR). Data pooling was performed by RevMan 4. 2. Results 6457 patients from 20 studies were included in this meta-analysis. RR estimate of overall survival (OS) for patients with low level p27Kip1 was 2.07 [1.66,2.60] (P<0.01). For disease free survival (DFS), the pooled RR was 1.27 [1.10,1.47] (P<0.05). The combined RR estimate of relapse free survival (RFS) for patients with low level of p27Kip1 was 1.49 [0.92, 2.42] (P >0.05). In patients with lymph node negative breast carcinoma, the combined RR for OS and RFS were 1.98 [1.34,2.91] (P <0.01) and 1.28 [0.45,3.65] (P > 0.05), respectively. Among the patients with lymph node positive breast carcinoma, the combined RR for OS and RFS was 1.92 [1.31, 2.82] (P=0.0009) and 1.35 [0.96,1.89] (P>0.05) respectively. Conclusions Low level of p27Kip1 appears to be an independent prognostic factor to OS and DFS of breast cancer patients but not to RFS. Additional studies with large patient number and widely accepted practical methods are required to derive the precise prognostic significance of p27Kip1 expression in breast cancer patients.
Biomarkers, Tumor ; analysis ; Breast Neoplasms ; diagnosis ; genetics ; metabolism ; pathology ; Carcinoma ; diagnosis ; genetics ; metabolism ; Cyclin-Dependent Kinase Inhibitor p27 ; genetics ; metabolism ; Disease-Free Survival ; Female ; Gene Expression Regulation, Neoplastic ; genetics ; Humans ; Lymphatic Metastasis ; diagnosis ; physiopathology ; Neoplasm Staging ; methods ; Prognosis

OBJECTIVEThe study was designed to investigate the expression patterns of metalloproteinase (MMP)-13 protein in invasive breast carcinoma and to determine the clinicopathological and prognostic values of its various localization and relation to the tumor phenotypes.

METHODSImmunohistochemistry was performed on paraffin-embedded tissue array from 263 invasive breast carcinomas to investigate the protein expressions of MMP-13, estrogen receptor, progesterone receptor, HER2, MMP-2, MMP-9 and tissue inhibitor of matrix metalloproteinases (TIMP)-1, TIMP-2.

RESULTSMMP-13 protein was detected in the cytoplasm of carcinoma cells and peritumoral fibroblasts. High level expression of MMP-13 protein in tumor cells was associated with more lymph node involvement and higher tumor grade (both P < 0.01), and positively correlated with HER2 (P = 0.015) and TIMP-1 protein (P < 0.01) expression in carcinoma cells. Moreover, high expression of MMP-13 was associated with shortened overall survival for the entire patient population and the patient group with positive lymph node. Tumor cell derived MMP-13 had different impact on patients with different HER2 status. Peritumoral fibroblasts derived MMP-13 protein, although correlated with tumor cell derived MMP-13 and associated with lymph node stage and HER2 expression, was found having less prognostic impact. Univariate survival analysis showed that the tumor size, grade, lymph node status, PR status, HER2 expression, tumors TIMP-1 and MMP-13 expression were prognostic factors. However, multivariate survival analysis showed that only tumor size, lymph node status, HER2 expression, tumors TIMP-1 and MMP-13 were independent prognostic factors.

CONCLUSIONMMP-13 protein expressed by tumor cells correlates with the invasion and metastasis of breast carcinoma, and therefore, may serve as a poor prognostic marker for the patient.

Biomarkers, Tumor ; metabolism ; Breast Neoplasms ; metabolism ; pathology ; physiopathology ; Female ; Gene Expression Regulation, Neoplastic ; Humans ; Immunohistochemistry ; Lymph Nodes ; pathology ; Matrix Metalloproteinase 13 ; analysis ; genetics ; Matrix Metalloproteinase 9 ; analysis ; Neoplasm Invasiveness ; diagnosis ; physiopathology ; Neoplasm Staging ; classification ; Prognosis ; Receptor, ErbB-2 ; analysis ; Receptors, Estrogen ; Receptors, Progesterone ; analysis

Biopsy, Fine-Needle ; methods ; Breast ; metabolism ; pathology ; Breast Neoplasms ; diagnosis ; genetics ; pathology ; Female ; Humans ; In Situ Hybridization, Fluorescence ; Lymph Nodes ; metabolism ; pathology ; Lymphoma ; diagnosis ; genetics ; pathology ; Pancreas ; metabolism ; pathology ; Pancreatic Neoplasms ; diagnosis ; genetics ; pathology

Carcinoembryonic Antigen ; metabolism ; Carcinoma in Situ ; immunology ; pathology ; virology ; Carcinoma, Ductal, Breast ; immunology ; pathology ; virology ; Cervical Intraepithelial Neoplasia ; immunology ; pathology ; virology ; DNA, Viral ; analysis ; Diagnosis, Differential ; Female ; Human papillomavirus 16 ; genetics ; isolation & purification ; Humans ; Ki-67 Antigen ; metabolism ; Uterine Cervical Dysplasia ; immunology ; pathology ; virology ; Uterine Cervical Neoplasms ; immunology ; pathology ; virology