SNAI1-mediated transcriptional regulation of epithelial-to-mesenchymal transition genes in breast cancer stem cells

• Published in: Cellular signalling Vol. 87; p. 110151
• Main Authors: Singh, Digvijay, Deshmukh, Rohit K., Das, Amitava
• Format: Journal Article
• Language: English
• Published: England Elsevier Inc 01.11.2021
• Subjects: Breast cancer stem cells; Cell Line, Tumor; Cell Movement - genetics; EMT-associated differential expressed genes; Epithelial-Mesenchymal Transition - genetics; Epithelial-to-mesenchymal transition; Gene Expression Regulation, Neoplastic; GM6001 (Ilomastat); Humans; Neoplastic Stem Cells - metabolism; SNAI1; Snail Family Transcription Factors - genetics; Snail Family Transcription Factors - metabolism; Triple Negative Breast Neoplasms - genetics; Triple Negative Breast Neoplasms - metabolism; SNAI1; GM6001 (Ilomastat); Breast cancer stem cells; Epithelial-to-mesenchymal transition; EMT-associated differential expressed genes
• ISSN: 0898-6568; 1873-3913
• DOI: 10.1016/j.cellsig.2021.110151

Triple-negative breast cancer (TNBC) tumors are composed of a heterogeneous population containing both cancer cells and cancer stem cells (CSCs). These CSCs are generated through an epithelial-to-mesenchymal transition (EMT), thus making it pertinent to identify the unique EMT-molecular targets that regulate this phenomenon. In the present study, we performed in silico analysis of microarray data from luminal, Her2+, and TNBC cell lines and identified 15 relatively unexplored EMT-related differentially expressed genes (DEGs) along with the markedly high expression of EMT-transcription factor (EMT-TF), SNAI1. Interestingly, stable overexpression of SNAI1 in MCF-7 induced the expression of DEGs along with increased migration, invasion, and in vitro tumorigenesis that was comparable to TNBCs. Next, stable SNAI1 overexpression led to increased expression of DEGs that was reverted with SNAI1 silencing in both breast cancer cells and CSCs sorted from various TNBC cell lines. Higher fold enrichment of SNAI1 on E-boxes in the promoter regions suggested a positive regulation of ALCAM, MMP2, MMP13, MMP14, VCAN, ANKRD1, KRT16, CTGF, TGFRIIβ, PROCR negative regulation of CDH1, DSP and DSC3B by SNAI1 leading to EMT. Furthermore, SNAI1-mediated increased migration, invasion, and tumorigenesis in these sorted cells led to the activation of signaling mediators, ERK1/2, STAT3, Src, and FAK. Finally, the SNAI1-mediated activation of breast CSC phenotypes was perturbed by inhibition of downstream target, MMPs using Ilomastat. Thus, the molecular investigation for the gene regulatory framework in the present study identified MMPs, a downstream effector in the SNAI1-mediated EMT regulation. •SNAI1 regulate DEGs associated with EMT in breast CSCs.•SNAI1 induced migration, invasion, and in vitro tumorigenesis in breast CSCs.•SNAI1 overexpression in breast CSCs activated the signaling mediators, ERK1/2, STAT3, Src, and FAK.•SNAI1-mediated activation of breast CSC phenotypes was perturbed by inhibition of downstream target, MMPs using Ilomastat.