SIX2 Mediates Late-Stage Metastasis via Direct Regulation of SOX2 and Induction of a Cancer Stem Cell Program

• Published in: Cancer research (Chicago, Ill.) Ill.), 2019-02, Vol.79 (4), p.720-734
• Main Authors: Oliphant, Michael U J, Vincent, Melanie Y, Galbraith, Matthew D, Pandey, Ahwan, Zaberezhnyy, Vadym, Rudra, Pratyaydipta, Johnson, Katherine R, Costello, James C, Ghosh, Debashis, DeGregori, James, Espinosa, Joaquin M, Ford, Heide L
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis; Biomarkers, Tumor - genetics; Biomarkers, Tumor - metabolism; Cell Proliferation; Female; Follow-Up Studies; Gene Expression Regulation, Neoplastic; Homeodomain Proteins - genetics; Homeodomain Proteins - metabolism; Humans; Mice; Mice, Inbred BALB C; Mice, Inbred NOD; Mice, SCID; Nanog Homeobox Protein - genetics; Nanog Homeobox Protein - metabolism; Neoplasm Metastasis; Neoplasm Recurrence, Local - genetics; Neoplasm Recurrence, Local - metabolism; Neoplasm Recurrence, Local - pathology; Neoplastic Stem Cells - metabolism; Neoplastic Stem Cells - pathology; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Prognosis; SOXB1 Transcription Factors - genetics; SOXB1 Transcription Factors - metabolism; Survival Rate; Triple Negative Breast Neoplasms - genetics; Triple Negative Breast Neoplasms - metabolism; Triple Negative Breast Neoplasms - secondary; Tumor Cells, Cultured; Xenograft Model Antitumor Assays
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-18-1791

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 Srr2 enhancer, promoting expression and downstream expression of , which are both key pluripotency factors. Regulation of by Six2 enhanced cancer stem cell properties and increased metastatic colonization. and 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. http://cancerres.aacrjournals.org/content/canres/79/4/720/F1.large.jpg.