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Background  The E-Cadherin gene ( CDH1, Cadherin 1 ), located at 16q22.1 encodes for a calcium-dependent membranous glycoprotein with an important role in cellular adhesion and polarity maintenance.    Methods  To systematically determine E-Cadherin protein expression in normal and cancerous tissues, 14,637 tumor samples from 112 different tumor types and subtypes as well as 608 samples of 76 different normal tissue types were analyzed by immunohistochemistry in a tissue microarray format.    Results  E-Cadherin was strongly expressed in normal epithelial cells of most organs. From 77 tumor entities derived from cell types normally positive for E-Cadherin, 35 (45.5%) retained at least a weak E-Cadherin immunostaining in ≥99% of cases and 61 (79.2%) in ≥90% of cases. Tumors with the highest rates of E-Cadherin loss included Merkel cell carcinoma, anaplastic thyroid carcinoma, lobular carcinoma of the breast, and sarcomatoid and small cell neuroendocrine carcinomas of the urinary bladder. Reduced E-Cadherin expression was linked to higher grade ( p  = 0.0009), triple negative receptor status ( p  = 0.0336), and poor prognosis ( p  = 0.0466) in invasive breast carcinoma of no special type, triple negative receptor status in lobular carcinoma of the breast ( p  = 0.0454), advanced pT stage ( p  = 0.0047) and lymph node metastasis in colorectal cancer ( p  < 0.0001), and was more common in recurrent than in primary prostate cancer ( p  < 0.0001). Of 29 tumor entities derived from E-Cadherin negative normal tissues, a weak to strong E-Cadherin staining could be detected in at least 10% of cases in 15 different tumor entities (51.7%). Tumors with the highest frequency of E-Cadherin upregulation included various subtypes of testicular germ cell tumors and renal cell carcinomas (RCC). E-Cadherin upregulation was more commonly seen in malignant than in benign soft tissue tumors ( p  = 0.0104) and was associated with advanced tumor stage ( p  = 0.0276) and higher grade ( p  = 0.0035) in clear cell RCC, and linked to advanced tumor stage ( p  = 0.0424) and poor prognosis in papillary RCC ( p  ≤ 0.05).    Conclusion  E-Cadherin is consistently expressed in various epithelial cancers. Down-regulation or loss of E-Cadherin expression in cancers arising from E-Cadherin positive tissues as well as E-Cadherin neo-expression in cancers arising from E-Cadherin negative tissues is linked to cancer progression and may reflect tumor dedifferentiation.    Supplementary Information  The online version contains supplementary material available at 10.1186/s40364-021-00299-4.

E-Cadherin expression in human tumors: a tissue microarray study on 10,851 tumors