GATA3 suppresses metastasis and modulates the tumour microenvironment by regulating microRNA-29b expression.
Despite advances in our understanding of breast cancer, patients with metastatic disease have poor prognoses. GATA3 is a transcription factor that specifies and maintains mammary luminal epithelial cell fate, and its expression is lost in breast cancer, correlating with a worse prognosis in human patients. Here, we show that GATA3 promotes differentiation, suppresses metastasis and alters the tumour microenvironment in breast cancer by inducing microRNA-29b (miR-29b) expression. Accordingly, miR-29b is enriched in luminal breast cancers and loss of miR-29b, even in GATA3-expressing cells, increases metastasis and promotes a mesenchymal phenotype. Mechanistically, miR-29b inhibits metastasis by targeting a network of pro-metastatic regulators involved in angiogenesis, collagen remodelling and proteolysis, including VEGFA, ANGPTL4, PDGF, LOX and MMP9, and targeting ITGA6, ITGB1 and TGFB, thereby indirectly affecting differentiation and epithelial plasticity. The discovery that a GATA3-miR-29b axis regulates the tumour microenvironment and inhibits metastasis opens up possibilities for therapeutic intervention in breast cancer.
Department of Anatomy, University of California, San Francisco, 94143-0452, USA.
Jonathan
J
Chou
Jeffrey H
JH
Lin
Audrey
A
Brenot
Jung-whan
JW
Kim
Sylvain
S
Provot
Zena
Z
Werb
D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000556:secondary; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D002465:Cell Movement; D005260:Female; D050990:GATA3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D053263:Gene Regulatory Networks; D005838:Genotype; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism / Q000517:prevention & control / Q000556:secondary; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D035683:MicroRNAs / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D010641:Phenotype; D014162:Transfection; D059016:Tumor Microenvironment; D015854:Up-Regulation
D050990:GATA3 Transcription Factor; C494749:GATA3 protein, human; C494748:Gata3 protein, mouse; C547014:MIRN29 microRNA, mouse; C532045:MIRN29a microRNA, human; D035683:MicroRNAs