Format

Send to

Choose Destination
Mod Pathol. 2019 Feb 13. doi: 10.1038/s41379-019-0209-9. [Epub ahead of print]

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

Author information

1
Nottingham Breast Cancer Research Centre, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, Nottingham, UK.
2
Faculty of Applied Medical Sciences, Onizah Community College, Qassim University, Qassim, Saudi Arabia.
3
Faculty of Medicine, Menoufyia University, Shebin El Kom, Egypt.
4
Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia.
5
Department of Biology, Georgia State University, Atlanta, GA, USA.
6
Cancer Biology and Translational Research, Faculty of Medicine and Health Sciences, University of Nottingham, Nottingham, UK.
7
Department of Pharmacology, Weill Cornell Medicine, New York, USA.
8
Nottingham Breast Cancer Research Centre, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, Nottingham, UK. Emad.Rakha@nottingham.ac.uk.
9
Faculty of Medicine, Menoufyia University, Shebin El Kom, Egypt. Emad.Rakha@nottingham.ac.uk.

Abstract

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.

PMID:
30760857
DOI:
10.1038/s41379-019-0209-9

Supplemental Content

Full text links

Icon for Nature Publishing Group
Loading ...
Support Center