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Open Access Highly Accessed Research article

Notch activation stimulates migration of breast cancer cells and promotes tumor growth

Victoria Bolós1, Emilia Mira2, Beatriz Martínez-Poveda1, Guillermo Luxán1, Marta Cañamero3, Carlos Martínez-A2, Santos Mañes2 and José Luis de la Pompa1*

  • * Corresponding author: José L de la Pompa jlpompa@cnic.es

  • † Equal contributors

Author Affiliations

1 Program of Cardiovascular Developmental Biology, Department of Cardiovascular Development and Repair, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Melchor Fernández Almagro 3, E-28029 Madrid, Spain

2 Department of Immunology and Oncology, Centro Nacional de Biotecnología/CSIC, Darwin 3, Campus de Cantoblanco, E-28049 Madrid, Spain

3 Comparative Pathology Unit, Biotechnology Program, Centro Nacional de Investigaciones Oncológicas, E-28029 Madrid, Spain

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Breast Cancer Research 2013, 15:R54  doi:10.1186/bcr3447

Published: 4 July 2013

Abstract

Introduction

Dysregulated NOTCH receptor activity has been implicated in breast cancer but the mechanisms by which NOTCH contributes to transformation are not yet clear, as it has context-dependent effects on the properties of transformed cells.

Methods

We have used various in vitro and in vivo carcinogenic models to analyze the impact of Notch signaling in the onset and progression of breast tumors.

Results

We found that ectopic expression of the Notch1 intracellular domain (N1ICD) in MCF-7 breast adenocarcinoma cell line caused reduction and delocalization of E-CADHERIN levels and increased migratory and invasive abilities. Notch inhibition in the invasive breast cancer cell line MDA-MB-231 resulted in increased E-CADHERIN expression and a parallel reduction in their invasive capacity. The growth of subcutaneous xenografts produced with MCF-7 cells was boosted after N1ICD induction, in a cell autonomous manner. In vivo Notch1 activation in the mammary gland using the MMTV-Cre driver caused the formation of papillary tumors that showed increased Hes1 and Hey1 expression and delocalized E-cadherin staining.

Conclusions

These results confirm NOTCH1 as a signal triggering epithelial-mesenchymal transition in epithelial cancer cells, which may have implications in tumor dissemination, metastasis and proliferation in vivo. The identification of specific factors interacting with NOTCH signaling could thus be relevant to fully understanding the role of NOTCH in breast neoplasia.

Keywords:
Mammary tumor; MCF-7; HT-29; MDA-MB-231; NOTCH; E-CADHERIN; EMT; migration; growth