E-Cadherin Loss is Characteristically Associated with Invasive Lobular Breast Cancer
Loss or mutation of E-cadherin (CDH1 gene) is the defining molecular feature of invasive lobular breast cancer (ILC), the second most common histological subtype of breast cancer. 1, 2, 3
Molecular Basis
E-cadherin is a transmembrane cell-cell adhesion protein encoded by the CDH1 gene located on chromosome 16q22.1 that maintains epithelial tissue integrity through adherens junctions. 3, 4
Invasive lobular carcinomas characteristically harbor inactivating CDH1 mutations combined with loss of heterozygosity of the wild-type allele, resulting in complete loss of E-cadherin expression. 3, 5
These mutations occur at early noninvasive stages (lobular carcinoma in situ), defining CDH1 as the tumor suppressor gene specifically for the lobular breast cancer subtype. 3, 5
Diagnostic Specificity
Complete loss of E-cadherin expression occurs in approximately 84-88% of invasive lobular carcinomas, creating the characteristic discohesive, single-file invasive growth pattern due to loss of functional adherens junctions. 6, 4
E-cadherin immunohistochemistry demonstrates high diagnostic accuracy for ILC: 97.7% specificity, 96.8% negative predictive value, 88.1% sensitivity, and 91.2% positive predictive value. 6
Negative E-cadherin staining is uncommon in non-lobular carcinomas (particularly invasive ductal carcinoma), making it a reliable biomarker to confirm ILC diagnosis in cases with indeterminate histopathologic features. 6
Associated Catenin Loss
Loss of E-cadherin in ILC is accompanied by simultaneous loss of α-catenin and β-catenin expression in all cases, reflecting complete disassembly of adherens junctions. 5
Gamma-catenin loss occurs in approximately 50% of E-cadherin-negative ILC cases. 5
This simultaneous loss of E-cadherin and catenins occurs in both invasive lobular carcinoma and adjacent lobular carcinoma in situ, indicating this is an early event in lobular breast cancer development. 5
Hereditary Context
Germline CDH1 mutations cause Hereditary Diffuse Gastric Cancer (HDGC) syndrome, which carries a 42% lifetime risk of lobular breast cancer in female carriers by age 80. 1, 2
CDH1 gene testing should be considered for patients with lobular breast cancer and diffuse gastric cancer family history. 1
Contrast with Ductal Carcinoma
Invasive ductal carcinomas (70-75% of breast cancers) generally show heterogeneous or retained E-cadherin expression, with loss typically associated with epigenetic transcriptional downregulation rather than mutation. 1, 3
E-cadherin loss in ductal carcinomas is associated with epithelial-to-mesenchymal transition at the invasive front and correlates with poor prognosis, but is not a defining feature. 3
Clinical Implications
ILC patients with E-cadherin loss demonstrate hyperactivation of growth factor receptors (particularly insulin-like growth factor 1 receptor) and anoikis resistance, creating potential therapeutic vulnerabilities. 4
Despite favorable prognostic indicators (low grade, high estrogen receptor positivity), ILC patients tend to have similar or poorer outcomes compared to invasive ductal carcinoma, highlighting the need for ILC-specific treatment strategies. 4