Transforming growth factor-β regulates the sphere-initiating stem cell-like feature in breast cancer through miRNA-181 and ATM

Abstract

Recent studies indicate that a subset of cancer cells possessing stem cell properties, referred to as cancer-initiating or cancer stem cells (CSCs), play crucial roles in tumor initiation, metastasis and resistance to anticancer therapies. Transforming growth factor (TGF)-βs and their family members have been implicated in both normal (embryonic and somatic) stem cells and CSCs. In this study, we observed that exposure to TGF-β increased the population of breast cancer (BC) cells that can form mammospheres in suspension, a feature endowed by stem cells. This was mediated by the micro(mi)RNA family miR-181, which was upregulated by TGF-β at the post-transcriptional level. Levels of the miR-181 family members were elevated in mammospheres grown in undifferentiating conditions, compared to cells grown in two dimensional (2D) conditions. Ataxia telangiectasia mutated (ATM), a target gene of miR-181, exhibited reduced expression in mammospheres and upon TGF-β treatment. Overexpression of miR-181a/b, or depletion of ATM or its substrate CHK2, was sufficient to induce sphere formation in BC cells. Finally, knockdown of ATM enhanced in vivo tumorigenesis of the MDA361 BC cells. Our results elucidate a novel mechanism through which the TGF-β pathway regulates the CSC property by interfering with the tumor suppressor ATM, providing insights into the cellular and environmental factors regulating CSCs, which may guide future studies on therapeutic strategies targeting these cells.

Evaluation of MiR-181a as a potential therapeutic target in osteoarthritis

“…Luciferase reporter assays further confirmed the potential binding of miR-181a to the 3'UTR of BCL2 in chondrocytes. This is in agreement with previous studies wherein miR181a binding to the 3'UTR of BCL2 was demonstrated in hepatocytes [14].…”

“…Additionally, TGF-β primarily acts via activation of Smad, a signal transducer protein which translocates to the nucleus and binds to Smad responsive promoter regions, thereby resulting in transcriptional modulation of target miRNAs and mRNAs [25]. Importantly, TGF-β has also been shown to cause up regulation of miR-181a in hepatocytes [16] and breast cancer cells [14]. Furthermore, TGF-β levels are reported to be elevated in the synovial fluid of OA patients [23].…”

“…However, the aforementioned members share target seed sequence similarity within the main 5-p precursor arm, which binds to target mRNAs. miR-181 family members are reported to be differentially expressed in various cancers namely breast [14], ovarian [15] and hepatic [16]. miR-181 has also been shown to target the antiapoptotic regulator, BCL2, in hepatocytes [16].…”

Histone Deacetylase Inhibitor Entinostat Inhibits Tumor-Initiating Cells in Triple-Negative Breast Cancer Cells

“…In colorectal cancer, miR-181a has been associated with poor prognosis (13). In addition, miR-181 family members have been implicated with acquisition of the CSC phenotype in hepatic cancer (14) and in breast cancer (15). As such, miR-181a serves as a marker for increased "stemness" and invasive ability.…”

Breast Cancer Stem Cells

“…Other evidence also showed miR-181 was elevated in breast cancer stem cells. Overexpression of miR-181a/b, or depletion of its target ataxia telangiectasia mutated(ATM), was sufficient to induce sphere formation in breast cancer cells and promote tumorgenesis 108 .…”