SIX2 Mediates Late-Stage Metastasis via Direct Regulation of <i>SOX2</i> and Induction of a Cancer Stem Cell Program.

Abstract

The capacity for tumor cells to metastasize efficiently is directly linked to their ability to colonize secondary sites. Here we identify Six2, a developmental transcription factor, as a critical regulator of a breast cancer stem cell program that enables metastatic colonization. In several triple-negative breast cancer (TNBC) models, Six2 enhanced the expression of genes associated with embryonic stem cell programs. Six2 directly bound the <i>Sox2</i> Srr2 enhancer, promoting <i>Sox2</i> expression and downstream expression of <i>Nanog</i>, which are both key pluripotency factors. Regulation of <i>Sox2</i> by Six2 enhanced cancer stem cell properties and increased metastatic colonization. <i>Six2</i> and <i>Sox2</i> expression correlated highly in breast cancers including TNBC, where a Six2 expression signature was predictive of metastatic burden and poor clinical outcome. Our findings demonstrate that a SIX2/SOX2 axis is required for efficient metastatic colonization, underscoring a key role for stemness factors in outgrowth at secondary sites. SIGNIFICANCE: These findings provide novel mechanistic insight into stemness and the metastatic outgrowth of triple-negative breast cancer cells.<b>Graphical Abstract:</b> http://cancerres.aacrjournals.org/content/canres/79/4/720/F1.large.jpg.