SATB1 reprogrammes gene expression to promote breast tumour growth and metastasis

Mechanisms underlying global changes in gene expression during tumour progression are poorly understood. SATB1 is a genome organizer that tethers multiple genomic loci and recruits chromatin- remodelling enzymes to regulate chromatin structure and gene expression. Here we show that SATB1 is expressed by aggressive breast cancer cells and its expression level has high prognostic significance ( P < 0.0001), independent of lymph- node status. RNA- interference- mediated knockdown of SATB1 in highly aggressive ( MDA- MB- 231) cancer cells altered the expression of >1,000 genes, reversing tumorigenesis by restoring breast- like acinar polarity and inhibiting tumour growth and metastasis in vivo. Conversely, ectopic SATB1 expression in non- aggressive ( SKBR3) cells led to gene expression patterns consistent with aggressive- tumour phenotypes, acquiring metastatic activity in vivo. SATB1 delineates specific epigenetic modifications at target gene loci, directly upregulating metastasis- associated genes while downregulating tumour- suppressor genes. SATB1 reprogrammes chromatin organization and the transcription profiles of breast tumours to promote growth and metastasis; this is a new mechanism of tumour progression.