Abstract
ABSTRACTEMT allows a polarized epithelium to lose epithelial integrity and acquire mesenchymal characteristics. Previously, we found that overexpression of the intracellular domain of Notch3 (N3ICD) can inhibit EMT in breast cancer cells. In this study, we aimed to elucidate the influence of N3ICD or N3ICD combined with the transmembrane domain (TD+N3ICD) on the expression and distribution of TJs/AJs and polar molecules. We found that although N3ICD can upregulate the expression levels of the above-mentioned molecules, TD+N3ICD can inhibit EMT more effectively than N3ICD alone. TD+N3ICD overexpression upregulated the expression of endogenous full-length Notch3 and contributed to correcting the position of TJs/AJs molecules and better acinar structures formation. Co-immunoprecipitation results showed that the upregulated endogenous full-length Notch3 could physically interact with E-ca in MDA-MB-231/pCMV-(TD+N3ICD) cells. Collectively, our data indicate that overexpression of TD+N3ICD can effectively inhibit EMT, resulting in better positioning of TJs/AJs molecules and cell-cell adhesion in breast cancer cells.Abbreviations: EMT: Epithelial-mesenchymal transition; TJs: Tight junctions; AJs: Adherens junctions; aPKC: Atypical protein kinase C; Crb: Crumbs; Lgl: Lethal (2) giant larvae; LLGL2: lethal giant larvae homolog 2; PAR: Partitioning defective; PATJ: Pals1-associated TJ protein
Highlights
Breast cancer is one of the leading causes of cancer-related deaths in women worldwide, with a crude incidence rate of 1.7 million cases and 521,900 deaths in 2012 [1]
Expression of Notch3 was reduced in breast cancer cell lines with relatively high malignancy, closely associated with epithelial-mesenchymal transition (EMT) We first compared the relative endogenous Notch3 expression levels by western blotting in a panel of breast cancer cell lines previously classified as four subtypes, namely MCF-7 and T47D (ERα/PgRpositive luminal mammary carcinoma cells), SKBR3 (Her2 (Neu/ErbB-2)-overexpressing human breast cancer cell line), MDA-MB-231 (G and Z indicating two strains stored in different laboratories) and BT549
We found that both the overexpression of N3ICD and TD+N3ICD can upregulate the expression levels of the tight junctions (TJs)/adherens junctions (AJs), scaffolding proteins and polar molecules, but only overexpression of TD+N3ICD can promote better 3D acinar structures formation and inhibit EMT more effectively
Summary
Breast cancer is one of the leading causes of cancer-related deaths in women worldwide, with a crude incidence rate of 1.7 million cases and 521,900 deaths in 2012 [1]. The number of younger women diagnosed with breast cancer has increased in recent years [2]. The view that EMT is a key mechanism to trigger cancer metastasis has been challenged, it is becoming increasingly clear that EMT endows epithelium with increased motility and invasiveness, stemness [6], chemoresistance and radioresistance capacities [7,8,9]. EMT is a critical biological process related to the dynamic plastic phenotype of cells during embryonic development and carcinoma progression [10,11]
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