FZD2 promotes TGF-β-induced epithelial-to-mesenchymal transition in breast cancer via activating notch signaling pathway

Abstract

Background Breast cancer (BC) is one of the commonest female cancers, which is characterized with high incidence. Although treatments have been improved, the prognosis of BC patients in advanced stages remains unsatisfactory. Thus, exploration of the molecular mechanisms underneath BC progression is necessary to find novel therapeutic methods. Frizzled class receptor 2 (FZD2) belongs to Frizzled family, which has been proven to promote cell growth and invasion in various human cancers. The purpose of our current study was to detect the functions of FZD2 in BC and explore its underlying molecular mechanism. Methods The level of FZD2 was measured in BC tissues by quantitative real-time polymerase chain reaction (qRT-PCR), western blot, immunohistochemistry (IHC), respectively. Cell Counting Kit-8 (CCK-8), colony formation assay, transwell assays, wound healing assay and flow cytometry analyses were separately conducted to detect cell viability, invasion, migration, apoptosis and cell cycle distribution. The levels of Epithelial-mesenchymal transition (EMT) biomarkers were examined by using Immunofluorescence assay. Xenograft tumorigenicity assay was performed to assess the effect of FZD2 on tumor growth in vivo. Results FZD2 mRNA and protein expression was abundant in BC tissues. Moreover, high level of FZD2 had significant correlation with poor prognosis in BC patients. In vitro functional assays revealed that silencing of FZD2 had suppressive effects on BC cell growth, migration and invasion. Animal study further demonstrated that FZD2 silencing inhibited BC cell growth in vivo. In addition, FZD2 induced EMT process in BC cells in a transforming growth factor (TGF)-β1-dependent manner. Mechanistically, knockdown of FZD2 led to the inactivation of Notch signaling pathway. Conclusion FZD2 facilitates BC progression and promotes TGF-β1-inudced EMT process through activating Notch signaling pathway.

Antitumor Effect of Pseudolaric Acid B Involving Regulation of Notch1/Akt Signaling Response in Human Hepatoma Cell In Vitro

“…Furthermore, our results indicated that Notch1 protein was widely distributed in the cytoplasm of Huh7 cells, which was consistent with previous findings that Notch1 protein was mainly allocated in the cytoplasm rather than the nucleus of HCC cells [ 48 , 49 ]. Moreover, we found that Jagged1, a ligand of Notch signaling, was widely presented in the cytoplasm of Huh7 cells, but it could be inhibited by PAB and DAPT (a Notch signaling inhibitor), resulting in a significant reduction in the expression of Notch1 protein.…”

Comparing gene expression in deep infiltrating endometriosis with adenomyosis uteri: evidence for dysregulation of oncogene pathways

“…If we look at the changes of single genes, it is striking that Frizzled class receptor 2 ( FDZ2 ) is the only gene that is significantly upregulated in adenomyosis compared to DIE. FZD2 is discussed as an important trigger of TGF-ß induced epithelial–mesenchymal transition (EMT) [ 38 ] and cell migration [ 39 ]. Accordingly, the induction of EMT and ultimate fibrosis by TGF-β1 appears to play a critical role in the pathogenesis of adenomyosis [ 40 ].…”

Epithelial–mesenchymal plasticity in cancer: signaling pathways and therapeutic targets

“… 112 Interestingly, recent research indicates that Notch signaling participates in the EMT induction mediated by TGF‐β, and this process is mediated via the TGF‐β‐triggered phosphorylated SMAD3. 113 , 114 …”