In breast carcinoma dysadherin expression is correlated with invasiveness but not with E-cadherin

Abstract

Reduction/loss of E-cadherin is associated with the development and progression of many epithelial tumours. Dysadherin, recently characterised by members of our research team, has an anti-cell -cell adhesion function and downregulates E-cadherin in a posttranscriptional manner. The aim of the present study was to study the role of dysadherin in breast cancer progression, in association with the E-cadherin expression and the histological type. We have selected ductal carcinoma, which is by far the most common type and lobular carcinoma, which has a distinctive microscopic appearance. Dysadherin and E-cadherin expression was examined immunohistochemically in 70 invasive ductal carcinomas, no special type (NST), and 30 invasive lobular carcinomas, with their adjacent in situ components. In ductal as well as in lobular carcinoma dysadherin was expressed only in the invasive and not in the in situ component, and this expression was independent of the E-cadherin expression. Specifically, all 10 (100%) Grade 1, 37out of 45(82.2%) Grade 2 and six out of 15 (40%) Grade 3 invasive ductal carcinomas showed preserved E-cadherin expression, while 'positive dysadherin expression' was found in six out of 10 (60%) Grade 1, 34 out of 45(75.5%) Grade 2 and all 15 (100%) Grade 3 neoplasms. None of the 30 infiltrating lobular carcinomas showed preserved E-cadherin expression, while all the 30 infiltrating lobular carcinomas exhibited 'positive dysadherin expression'. Dysadherin may play an important role in breast cancer progression by promoting invasion and, particularly in lobular carcinomas, it might also be used as a marker of invasion. Recent advances into molecular pathology of breast cancer have refined diagnostic accuracy and classification systems of the most common malignant neoplasm of women, rendering personalised therapy more possible. Today, there is a plethora of molecular genetic data that indicate differences in pathogenesis between the various types of breast carcinomas and thus support their categorisation, to the patient benefit. The demonstration of lack of E-cadherin expression in lobular neoplasms has had a sound impact with practical applications (Mastracci et al, 2005) In about half of lobular carcinomas, loss of E-cadherin involves genetic changes, that is loss of heterozygosity (LOH) at 16q22.1, while in the other half epigenetic events are involved (Knudsen and Wheelock, 2005;Mastracci et al, 2005). Ductal carcinomas, on the other hand, express E-cadherin, albeit in reduced levels and/or in abnormal cellular locations (Knudsen and Wheelock, 2005). Reduction/loss of E-cadherin has been associated with the development and progression of many epithelial neoplasms. Aberrant E-cadherin expression (heterogeneous, cytoplasmic, or absent) has been detected immunohistochemically in several cancers, including head and neck carcinoma, gastric adenocarcinoma, lobular breast carcinoma, lung cancer, colorectal carcinoma, prostate adenocarcinoma, pancreatic, and bladder cancer (Becker et

Differential Expression of Dysadherin in Papillary Thyroid Carcinoma and Microcarcinoma: Correlation with E-cadherin

“…Dysadherin is a novel anti-cell-cell adhesion molecule, whose expression has been studied in several carcinomas, as well as in testicular neoplasms and cutaneous malignant melanomas [20,[22][23][24][25][26][27][28][29][30][31][32][33][34]. In all these cancer types, dysadherin expression seems to reflect tumor aggressiveness, being furthermore a marker of poor prognosis.…”

“…The dysadherin gene is upregulated in cells transformed by oncogenes, i.e., v-Ras, v-Src and neu [21]. Dysadherin expression has been detected in several neoplasms such as breast, gastric, colorectal, pancreatic, esophageal, thyroid, head and neck, testicular, and cervical carcinomas as well as in malignant melanoma and associated with tumor aggressiveness [22][23][24][25][26][27][28][29][30][31][32][33][34]. In thyroid tumors, dysadherin expression was found to be significantly higher in undifferentiated, than in papillary and follicular carcinomas and to correlate negatively with E-cadherin expression [28].…”

Adenosine 2B Receptor Expression on Cancer Cells Promotes Metastasis

“…There was also a reduction in the expression of FXYD5, Ã , P < 0.05; ÃÃ , P < 0.01; ÃÃÃ , P < 0.001; ÃÃÃÃ , P < 0.0001; unpaired t test between control and A2BR KD cells at indicated time points and cell cycle). (31) and invasiveness in breast carcinoma (40). In fact, A2BR has been suggested to negatively regulate cell adhesion by modulating the localization of Rap1 protein (41).…”

FXYD5 O-glycosylated ectodomain impairs adhesion by disrupting cell-cell trans-dimerization of Na,K-ATPase β1 subunits

“…This increase in the Na,K-ATPase activity due to the elevated expression of FXYD5 in airway epithelia results in deleterious effects in patients with cystic fibrosis (Miller and Davis, 2008), whereas such an increase in muscles is thought to provide a compensatory mechanism for the decrease in the α-β Na + pump in patients with chronic spinal cord injury (Boon et al, 2012). In different cancer types, high FXYD5 expression has been described as a predictor of metastasis and poor prognosis (Batistatou et al, 2007b;Ino et al, 2002;Shimamura et al, 2004;Tamura et al, 2005). Several lines of evidence presented here indicate that the O-glycosylated extracellular domain of FXYD5 impairs epithelial adhesion by steric hindrance of the intercellular interactions between the key amino acid residues responsible for β 1 -β 1 binding, including Y199.…”