Abstract
Loss of E-cadherin expression due to mutation of the CDH1 gene is a characteristic feature of invasive lobular breast cancer (ILBC). Beta-catenin, which binds to the cytoplasmic domain of E-cadherin, is simultaneously downregulated, reflecting disassembly of adherens junctions (AJs) and loss of cell adhesion. E-cadherin to P-cadherin expression switching can rescue AJs and cell adhesion. However, P-cadherin has not been implicated in ILBC, so far. We aimed to characterize 13 ILBCs with exceptional histomorphology, which we termed ILBCs with tubular elements. The CDH1 mutational status was determined by next generation sequencing and whole-genome copy number (CN) profiling. Expression of cadherins was assessed by immunohistochemistry. ILBCs with tubular elements were ER-positive (13/13) and HER2-negative (13/13) and harbored deleterious CDH1 mutations (11/13) accompanied by loss of heterozygosity due to deletion of chromosome 16q22.1 (9/11). E-cadherin expression was lost or reduced in noncohesive tumor cells and in admixed tubular elements (13/13). Beta-catenin expression was lost in noncohesive tumor cells, but was retained in tubular elements (11/13), indicating focal rescue of AJ formation. N-cadherin and R-cadherin were always negative (0/13). Strikingly, P-cadherin was commonly positive (12/13) and immunoreactivity was accentuated in tubular elements. Adjacent lobular carcinoma in situ (LCIS) was always P-cadherin-negative (0/7). In a reference cohort of LCIS specimens, P-cadherin was constantly not expressed (0/25). In a reference cohort of invasive mammary carcinomas, P-cadherin-positive cases (36/268, 13%) were associated with triple-negative nonlobular breast cancer (P < 0.001). Compared with ILBCs from the reference cohort, P-cadherin expression was more common in ILBCs with tubular elements (12/13 versus 7/84, P < 0.001). In summary, E-cadherin to P-cadherin switching occurs in a subset of ILBCs. P-cadherin is the molecular determinant of a mixed-appearing histomorphology in ILBCs with tubular elements.
Highlights
Supplementary information The online version of this article contains supplementary material, which is available to authorized users.Classical cadherins are transmembrane proteins that mediate homotypic adhesive cell–cell contacts by formation of adherens junctions (AJs) [1, 2]
We aimed to characterize a series of 13 invasive lobular breast cancer (ILBC) with unusual histomorphology (Table 1)
Cases selected for this study were defined by noncohesive tumor cells arranged in conventional ILBC growth pattern admixed with well-defined cancerous tubular elements (Fig. 1)
Summary
Classical cadherins are transmembrane proteins that mediate homotypic adhesive cell–cell contacts by formation of adherens junctions (AJs) [1, 2]. They are implicated in a variety of cellular processes, such as cell polarization and differentiation [3]. Classical cadherins include epithelial (E-) and placental (P-) cadherin, which are encoded by the genes CDH1 and CDH3, respectively [2]. Both map to chromosome 16q22.1 and share 66% homology [4, 5]. P-cadherin is associated with poor prognosis in BC [7, 15]
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