Expression Profiling of Clinical Specimens Supports the Existence of Neural Progenitor-Like Stem Cells in Basal Breast Cancers

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BackgroundWe previously characterized in salivary adenoid cystic carcinoma (ACC) a novel population of cancer stem cells (CSCs) marked by coexpression of 2 stemness genes, sex-determining region Y (SRY)-related HMG box-containing factor 10 (SOX10) and CD133. We also reported that in ACC and basal-like breast carcinoma (BBC), a triple-negative breast cancer subtype, expression of SOX10 similarly demarcates a highly conserved gene signature enriched with neural stem cell genes. On the basis of these findings, we hypothesized that BBC might be likewise driven by SOX10-positive (SOX10+)/CD133+ cells with neural stem cell properties.Materials and MethodsTo validate our hypothesis on clinical data, we used a novel approach to meta-analysis that merges gene expression data from independent breast cancer studies and ranks genes according to statistical significance of their coexpression with the gene of interest. Genes that showed strong association with CD133/PROM1 as well as SOX10 were validated across different platforms and data sets and analyzed for enrichment with genes involved in neurogenesis.ResultsWe identified in clinical breast cancer data sets a highly conserved SOX10/PROM1 gene signature that contains neural stem cell markers common for Schwann cells, ACC, BBC, and melanoma. Identification of tripartite motif-containing 2 (TRIM2), TRIM29, MPZL2, potassium calcium-activated channel subfamily N member 4 (KCNN4), and V-set domain containing T cell activation inhibitor 1 (VTCN1)/B7 homolog 4 (B7H4) within this signature provides insight into molecular mechanisms of CSC maintenance.ConclusionOur results suggest that BBC is driven by SOX10+/CD133+ cells that express neural stem cell-specific markers and share molecular similarities with CSCs of neural crest origin. Our study provides clinically relevant information on possible drivers of these cells that might facilitate development of CSC-targeting therapies against this cancer distinguished with poor prognosis and resistance to conventional therapies.Micro-AbstractTo facilitate development of cancer stem cell (CSC)-targeting therapies, we analyzed publicly available breast cancer data sets to identify genes coexpressed with sex-determining region Y (SRY)-related high-mobility group (HMG) box-containing factor 10 (SOX10), a neural crest marker, and prominin 1 (PROM1)/CD133, a common CSC marker. The conserved SOX10/PROM1 gene signature that we characterized supports the existence in basal breast cancers of SOX10-positive (SOX10+)/CD133+ cells with neural stem-like features exposing clinically relevant CSC markers and signaling networks.

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