title: Loss of the tight junction protein claudin-7 correlates with histological grade in both ductal carcinoma in situ and invasive ductal carcinoma of the breast.
abstract: Claudins are transmembrane proteins that seal tight junctions, and are critical for maintaining cell-to-cell adhesion in epithelial cell sheets. However, their role in cancer progression remains largely unexplored. Here, we report that Claudin-7 (CLDN-7) expression is lower in invasive ductal carcinomas (IDC) of the breast than in normal breast epithelium, as determined by both RT-PCR (9/10) and Western analysis (6/8). Immunohistochemical (IHC) analysis of ductal carcinoma in situ (DCIS) and IDC showed that the loss of CLDN-7 expression correlated with histological grade in both DCIS (P<0.001, n=38) and IDC (P=0.014, n=31), occurring predominantly in high-grade (Nuclear and Elston grade 3) lesions. Tissue array analysis of 355 IDC cases further confirmed the inverse correlation between CLDN-7 expression and histological grade (P=0.03). This pattern of expression is consistent with the biological function of CLDN-7, as greater discohesion is typically observed in high-grade lesions. In line with this observation, by IHC analysis, CLDN-7 expression was lost in the vast majority (13/17) of cases of lobular carcinoma in situ, which is defined by cellular discohesion. In fact, inducing disassociation of MCF-7 and T47D cells in culture by treating with HGF/scatter factor resulted in a loss of CLDN-7 expression within 24 h. Silencing of CLDN-7 expression correlated with promoter hypermethylation as determined by methylation-specific PCR (MSP) and nucleotide sequencing in breast cancer cell lines (3/3), but not in IDCs (0/5). In summary, these studies provide insight into the potential role of CLDN-7 in the progression and ability of breast cancer cells to disseminate.
authors.affiliation: Breast Cancer Program, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
authors.forename: Scott L
authors.initials: SL
authors.lastname: Kominsky
authors.forename: Pedram
authors.initials: P
authors.lastname: Argani
authors.forename: Dorian
authors.initials: D
authors.lastname: Korz
authors.forename: Ella
authors.initials: E
authors.lastname: Evron
authors.forename: Venu
authors.initials: V
authors.lastname: Raman
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Garrett
authors.forename: Alan
authors.initials: A
authors.lastname: Rein
authors.forename: Guido
authors.initials: G
authors.lastname: Sauter
authors.forename: Olli-P
authors.initials: OP
authors.lastname: Kallioniemi
authors.forename: Saraswati
authors.initials: S
authors.lastname: Sukumar
mesh_terms: D001940:Breast / Q000166:cytology / Q000378:metabolism*; D001943:Breast Neoplasms / Q000737:chemistry* / Q000473:pathology; D018270:Carcinoma, Ductal, Breast / Q000737:chemistry* / Q000473:pathology; D002285:Carcinoma, Intraductal, Noninfiltrating / Q000737:chemistry* / Q000473:pathology; D018275:Carcinoma, Lobular / Q000737:chemistry* / Q000473:pathology; D002448:Cell Adhesion / Q000187:drug effects; D002478:Cells, Cultured / Q000737:chemistry / Q000187:drug effects; D057167:Claudins; D019175:DNA Methylation; D004847:Epithelial Cells / Q000737:chemistry; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D017228:Hepatocyte Growth Factor / Q000494:pharmacology; D006801:Humans; D008565:Membrane Proteins / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D009361:Neoplasm Invasiveness / Q000235:genetics*; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000032:analysis; D012334:RNA, Neoplasm / Q000032:analysis; D017422:Sequence Analysis, DNA; D012720:Severity of Illness Index; D019108:Tight Junctions / Q000737:chemistry*; D014407:Tumor Cells, Cultured / Q000737:chemistry / Q000187:drug effects
chemical_list: C473255:CLDN7 protein, human; D057167:Claudins; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D017228:Hepatocyte Growth Factor