SNAI1 is required for tumor growth and lymph node metastasis of human breast carcinoma MDA-MB-231 cells.
The transcription factor, SNAI1 (Snail), has recently been proposed as an important mediator of tumor invasion because of its role in E-cadherin down-regulation and induction of epithelial-mesenchymal transition. In human breast cancer, the expression of SNAI1 and/or the homologous SNAI2 (Slug) has been associated with E-cadherin repression, local or distant metastasis, tumor recurrence, or poor prognosis in different tumor series. However, the specific contribution of either factor to breast tumor progression is still unclear. We have analyzed the role of SNAI1 in human breast cancer by loss of function studies and provide evidence of a major role for SNAI1 in both primary tumor growth and metastasis of human breast carcinoma MDA-MB-231 cells. Specific silencing of SNAI1 by short hairpin RNA induces a decrease in mesenchymal and proinvasive markers (MMP9, ID1, SPARC) in MDA-MB-231 cells, concomitant with reduced in vitro invasive behavior. More importantly, stable SNAI1 silencing in MDA-MB-231 cells leads to a dramatic reduction of in vivo tumor incidence and growth rate. Tumors induced by MDA-MB-231-SNAI1-silenced cells show extensive necrotic regions and a significant decrease in invasive and angiogenic markers. Moreover, SNAI1 silencing increases the sensitivity of MDA-MB-231 cells to chemotherapeutics relevant in breast cancer treatments, gemcitabine and docetaxel. Remarkably, analysis of cell lines derived from lymph node metastasis indicates that SNAI1 expression is required for metastatic dissemination.
Olmeda
David
D
Departamento de Bioquímica, Facultad de Medicina, Instituto de Investigaciones Biomédicas Alberto Sols, Consejo Superior de Investigaciones Cientificas-Universidad Autónoma de Madrid, Madrid, Spain.
Moreno-Bueno
Gema
G
Flores
Juana M
JM
Fabra
Angels
A
Portillo
Francisco
F
Cano
Amparo
A
D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D002455:Cell Division / Q000502:physiology*; D045744:Cell Line, Tumor; D005260:Female; D005822:Genetic Vectors; D006801:Humans; D008207:Lymphatic Metastasis / Q000473:pathology*; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D017354:Point Mutation; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D014162:Transfection; D016335:Zinc Fingers
C000604407:SNAI1 protein, human; C000604408:SNAI2 protein, human; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors