Cadherins Associate with Distinct Stem Cell-Related Transcription Factors to Coordinate the Maintenance of Stemness in Triple-Negative Breast Cancer.

Abstract

Triple-negative breast cancer (TNBC) is an aggressive type of breast cancer with poor prognosis and is enriched in cancer stem cells (CSCs). However, it is not completely understood how the CSCs were maintained in TNBC. In this study, by analyzing The Cancer Genome Atlas (TCGA) provisional datasets and several small-size breast datasets, we found that cadherins (CDHs) 2, 4, 6, and 17 were frequently amplified/overexpressed in 47% of TNBC while E-cadherin (CDH1) was downregulated/mutated at 10%. The alterations of CDH2/4/6/17 were strongly associated with the elevated levels of several stem cell-related transcription factors (SC-TFs) including FOXM1, MCM2, WWTR1, SNAI1, and SOX9. CDH2/4/6/17-enriched genes including FOXM1 and MCM2 were also clustered and regulated by NFY (nuclear transcription factor Y) and/or EVI1/MECOM. Meanwhile, these SC-TFs including NFYA were upregulated in TNBC cells, but they were downregulated in luminal type of cells. Furthermore, small compounds might be predicted via the Connectivity Map analysis to target TNBC with the alterations of CDH2/4/6/17 and SC-TFs. Together with the important role of these SC-TFs in the stem cell regulation, our data provide novel insights into the maintenance of CSCs in TNBC and the discovery of these SC-TFs associated with the alterations of CDH2/4/6/17 has an implication in targeted therapy of TNBC.