The molecular mechanisms underlying reduced E-cadherin expression in invasive ductal carcinoma of the breast: high throughput analysis of large cohorts

Rida, Padmashree C. G.; Alsaleem, Mansour; Toss, Michael S.; Joseph, Chitra; Aleskandarany, Mohammed; Kurozumi, Sasagu; Alshankyty, Ibrahim; Ogden, Angela; Rida, Padmashree C.G.; Ellis, Ian O.; Aneja, Ritu; Green, Andrew R.; Mongan, Nigel P.; Rakha, Emad A.

Abstract

© 2019, United States & Canadian Academy of Pathology. E-cadherin is a tumor suppressor gene in invasive lobular breast cancer. However, a proportion of high-grade ductal carcinoma shows reduced/loss of E-cadherin. In this study, we assessed the underlying mechanisms and molecular implications of E-cadherin loss in invasive ductal carcinoma. This study used large, well-characterized cohorts of early-stage breast cancer-evaluated E-cadherin expression via various platforms including immunohistochemistry, microarray analysis using Illumina HT-12 v3, copy number analysis using Affymetrix SNP 6.0 arrays, and next-generation sequencing for differential gene expression. Our results showed 27% of high-grade invasive ductal carcinoma showed reduced/loss of E-cadherin membranous expression. CDH1 copy number loss was in 21% of invasive ductal carcinoma, which also showed low CDH1 mRNA expression (p = 0.003). CDH1 copy number was associated with copy number loss of TP53, ATM, BRCA1, and BRCA2 (p < 0.001). Seventy-nine percent of invasive ductal carcinoma with reduced CDH1 mRNA expression showed elevated expression of E-cadherin transcription suppressors TWIST2, ZEB2, NFKB1, LLGL2, CTNNB1 (p < 0.01). Reduced/loss E-cadherin expression was associated with differential expression of 2143 genes including those regulating Wnt (FZD2, GNG5, HLTF, WNT2, and CER1) and PIK3-AKT (FGFR2, GNF5, GNGT1, IFNA17, and IGF1) signaling pathways. Interestingly, key genes differentially expressed between invasive lobular carcinoma and invasive ductal tumors did not show association with E-cadherin loss in invasive ductal carcinoma. We conclude that E-cadherin loss in invasive ductal carcinoma is likely a consequence of genomic instability occurring during carcinogenesis. Potential novel regulators controlling E-cadherin expression in invasive ductal carcinoma warrant further investigation.

Citation

Rida, P. C. G., Alsaleem, M., Toss, M. S., Joseph, C., Aleskandarany, M., Kurozumi, S., Alshankyty, I., Ogden, A., Rida, P. C., Ellis, I. O., Aneja, R., Green, A. R., Mongan, N. P., & Rakha, E. A. (2019). The molecular mechanisms underlying reduced E-cadherin expression in invasive ductal carcinoma of the breast: high throughput analysis of large cohorts. Modern Pathology, 32(7), 967-976. https://doi.org/10.1038/s41379-019-0209-9

• Journal Article Type: Article
• Acceptance Date: Dec 28, 2018
• Online Publication Date: Feb 13, 2019
• Publication Date: Jul 1, 2019
• Deposit Date: Jan 14, 2019
• Publicly Available Date: Aug 14, 2019
• Journal: Modern Pathology
• Electronic ISSN: 0893-3952
• Publisher: Nature Publishing Group
• Peer Reviewed: Peer Reviewed
• Volume: 32
• Issue: 7
• Pages: 967-976
• DOI: https://doi.org/10.1038/s41379-019-0209-9
• Keywords: E-cadherin; mechanisms; invasive ductal carcinoma; copy number; Next generation sequence
• Public URL: https://nottingham-repository.worktribe.com/output/1450005
• Publisher URL: https://www.nature.com/articles/s41379-019-0209-9
• Contract Date: Jan 14, 2019