Role of ZEB1 Knockout in MDA-MB-231 Triple-Negative Breast Cancer

Abstract

Epithelial-mesenchymal transition (EMT) is a cellular mechanism that involves the conversion of epithelial cells into mesenchymal. Epithelial cells express high levels of cell-cell adhesion molecules. They are polarized and not motile. Through the EMT process, these cells become mesenchymal and lose their polarity, cell adhesion to the extracellular matrix (ECM), and acquire migratory capacity (Heerboth et al., 2015). It is important to study EMT mechanisms for cancer development and metastasis. Triple-negative breast cancer is a type of breast cancer that lacks the expression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor-2 (HER2) (Cleator et al., 2007). Breast cancer treatment typically works by blocking ER, PR, and HER2 therefore the absence of these biomarkers makes it difficult to find an effective treatment option without the risk of metastasis and disease recurrence (Maqbool et al., 2022). In vitro and in vivo studies conducted in preclinical and clinical tumor models show that EMT contributes to drug resistance development. This resistance refers to all types of cancer treatment including chemotherapy, radiotherapy, immunotherapies, and targeted therapies. Therefore, it is crucial to identify what specifically to target to avoid therapy resistance, the risk of distant tumor migration, and cancer relapse (Rivas et al., 2021). ZEB1 protein is currently considered a potential biomarker that could be specifically targeted to treat TNBC (Jang et al., 2015). Cells going through the EMT process have reduced levels of epithelial genes including E-cadherin, ZO-1, and occludin whereas the expression levels of mesenchymal genes are increased (N-cadherin, vimentin, and fibronectin) (Du and Shim, 2016). ZEB1 acting as a transcription factor works by repressing epithelial genes (such as E-cadherin). ZEB1 protein normally functions to allow multiple tissue differentiation. Overexpression of ZEB1 has been observed in pancreatic cancer, lung cancer, and most importantly breast cancer. Thus making it an important target for studying its effects on TNBC (Wu et al., 2020). This paper describes the role of Zeb1 in TNBC by knocking out this gene using CRISPR-Cas9.

Keywords: Zinc fnger E-box binding homeobox 1 (ZEB1), Epithelial-mesenchymal transition (EMT), Triple-negative breast cancer (TNBC), Metastasis, Drug resistance