Chemotherapeutic Stress Influences Epithelial–Mesenchymal Transition and Stemness in Cancer Stem Cells of Triple-Negative Breast Cancer

Abstract

Triple-negative breast cancer (TNBC) is a subtype of breast cancer characterized by the absence of estrogen and progesterone receptors (ER, PR) and lacking an overexpression of human epidermal growth factor receptor 2 (HER2). Apart from this lack of therapeutic targets, TNBC also shows an increased capacity for early metastasis and therapy resistance. Currently, many TNBC patients receive neoadjuvant chemotherapy (NACT) upon detection of the disease. With TNBC likely being driven at least in part by a cancer stem-like cell type, we wanted to evaluate the response of primary cancer stem cells (CSCs) to standard chemotherapeutics. Therefore, we set up a survival model using primary CSCs to mimic tumor cells in patients under chemotherapy. Breast cancer stem cells (BCSCs) were exposed to chemotherapeutics with a sublethal dose for six days. Surviving cells were allowed to recover in culture medium without chemotherapeutics. Surviving and recovered cells were examined in regard to proliferation, migratory capacity, sphere forming capacity, epithelial–mesenchymal transition (EMT) factor expression at the mRNA level, and cancer-related microRNA (miRNA) profile. Our results indicate that chemotherapeutic stress enhanced sphere forming capacity of BCSCs, and changed cell morphology and EMT-related gene expression at the mRNA level, whereas the migratory capacity was unaffected. Six miRNAs were identified as potential regulators in this process.

A computational systems biology approach identifies SLUG as a mediator of partial Epithelial-Mesenchymal Transition (EMT)

“…Thus, while the proposed role of SLUG in stabilizing hybrid E/M phenotype(s) is largely robust to parametric variations, including other links and/or nodes at can alter the landscape of EMP dynamics. A better understanding of similarities and differences in terms of networks activated by SNAIL vs. SLUG to influence the different states of EMT and associated traits such as drug resistance [Kurrey et al, 2009;Li et al, 2020], immune evasion [Tripathi et al, 2016], anoikis resistance [Huang et al, 2013] and autophagy [Xu et al, 2019] across different cancer types is therefore required.…”

Plecstatin-1 induces an immunogenic cell death signature in colorectal tumour spheroids

“…These structural proteins are important players in invasiveness and metastatic processes. [46][47][48][49][50][51] Further studies are required to understand and fully characterize the intriguing mechanisms that shape and influence the cytoskeletal homeostasis of cancer cells induced by plecstatin-1. Finally, our work highlights another ruthenium compound that is able to induce an ICD signature in vitro with potential to be used in future in vivo experiments.…”

“…EMT is a process in which epithelial cells acquire a mesenchymal phenotype. [49][50][51] Moreover, epithelial cells form layers where they are in close contact with each other, while mesenchymal cells are loosely organized in a three-dimensional extracellular matrix. Tumour cells undergoing EMT are characterized by increased motility and invasiveness, which favours their dissemination to other sites and the formation of metastasis.…”

MicroRNAs Modulate Drug Resistance-Related Mechanisms in Hepatocellular Carcinoma

“…By undergoing EMT, cancer cells can acquire resistance to chemotherapies ( 15 ). The relationship between EMT and drug resistance was first discovered in 2008 and was further verified by the findings that blocking or reversing EMT could convert the resistant cells into sensitive cells ( 64 ).…”