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 (Po0.001, n ¼ 38) and IDC (P ¼ 0.014, n ¼ 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 ¼ 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.

Claudin-2 is selectively enriched in and promotes the formation of breast cancer liver metastases through engagement of integrin complexes

“…We observe a selection for the loss of occludin and claudins-3, -4 and -7 in the liveraggressive breast cancer cell populations. These observations are consistent with a loss of claudin-1 and -7 expression in primary breast cancers of increasing grade (Kramer et al, 2000;Kominsky et al, 2003;Sauer et al, 2005). Our results are also in agreement with a recent publication demonstrating the loss of cell adhesion molecules, including claudin-4 and claudin-7, in 4T1 sub-populations that are metastatic to the liver (Erin et al, 2009).…”

“…Some studies demonstrate the loss of specific claudins during breast cancer progression, whereas others suggest that overexpression of particular claudins are associated with poor outcome in breast cancer patients (Martin and Jiang, 2009). For example, some breast cancers exhibit a loss of claudin expression, including claudin-1, -2 and -7 (Kominsky et al, 2003;Sauer et al, 2005;Tokes et al, 2005;Kim et al, 2008), whereas claudin-3 and -4 can be overexpressed in human breast cancers, particularly in the triple-negative subtype (Kominsky et al, 2004;Blanchard et al, 2009;Kulka et al, 2009;Lanigan et al, 2009). Although these studies, which are focused on claudin expression in the primary tumor, suggest that specific claudin proteins may fulfill tumor-suppressor or tumor-promoting roles in breast cancer, little is known regarding claudin expression in breast cancer metastases.…”

Claudin-1 and claudin-5 expression patterns differentiate lung squamous cell carcinomas from adenocarcinomas

“…CLDN-3 and CLDN-4 are upregulated in ovarian and uterine cancers, 10,17,35,36 and CLDN-4 expression has been exploited for therapeutic purposes. 24 CLDN-7 expression is decreased in breast carcinomas, 13,37 but Adenocarcinoma vs bronchial cell (n ¼ 6) upregulated in gastric carcinomas. 9 With regards to other tight junction membrane proteins, we observed a statistically significant decrease in JAM-1 transcript levels in squamous cell carcinoma, when compared with normal bronchial cells, and in OCLN mRNA in squamous cell carcinoma.…”

“…Several studies have shown an altered expression of CLDNs in human tumors, including tumors of the gastrointestinal tract, 8,9 ovary, 10 pancreas, 11 breast, 12,13 epidermis, 14 liver, 15,16 uterus 17 and prostate. 18 Little information is available on the expression of cytoplasmic tight junction proteins in human cancers, [19][20][21][22] and only one study has been published about the immunohistochemical localization of a tight junction protein (occludin (OCLN)) in lung tumors.…”

Phosphorylation of claudin-4 by PKCε regulates tight junction barrier function in ovarian cancer cells

“…So far, claudin-1,3,4,5,7,10,16 have been shown altered in various cancers [5]. The functions of these proteins in tumorigenesis are still being elucidated, but they may have important roles in cell survival, motility, and invasion of cancer cells [18][19][20]. The mechanisms leading to the overexpression of claudins in cancer as well as the mechanisms of post-translational regulation/ modification of these proteins in cancer are not well understood.…”