FZD7 has a critical role in cell proliferation in triple negative breast cancer

Abstract

Breast cancer is genetically and clinically heterogeneous. Triple negative breast cancer (TNBC) is a subtype of breast cancer that is usually associated with poor outcome and lack of benefit from targeted therapy. We used microarray analysis to perform a pathway analysis of TNBC compared with non-triple negative breast cancer (non-TNBC). Overexpression of several Wnt pathway genes, such as frizzled homolog 7 (FZD7), low density lipoprotein receptor-related protein 6 and transcription factor 7 (TCF7) was observed in TNBC, and we directed our focus to the Wnt pathway receptor, FZD7. To validate the function of FZD7, FZD7shRNA was used to knock down FZD7 expression. Notably, reduced cell proliferation and suppressed invasiveness and colony formation were observed in TNBC MDA-MB-231 and BT-20 cells. Study of the possible mechanism indicated that these effects occurred through silencing of the canonical Wnt signaling pathway, as evidenced by loss of nuclear accumulation of b-catenin and decreased transcriptional activity of TCF7. In vivo studies revealed that FZD7shRNA significantly suppressed tumor formation, through reduced cell proliferation, in mice bearing xenografts without FZD7 expression. Our findings suggest that FZD7-involved canonical Wnt signaling pathway is essential for tumorigenesis of TNBC, and thus, FZD7 shows promise as a biomarker and a potential therapeutic target for TNBC.

GPCRs and cancer

“…For instance, the pharmacological inhibition of Fzd7, which is frequently overexpressed in hepatocellular carcinoma (HCC), displayed anti-tumor properties by involving β-catenin and PKCδ signals [63] . Fzd7 was also crucial through the canonical Wnt pathway for cell proliferation and invasiveness in triple negative breast cancer cells as well as for tumor formation in xenograft models [64] . Moreover, the increased expression of Fzd4 through the up-regulation of β-catenin dependent Wnt signaling promoted in invasive glioma cells the acquisition of glioma stem cell-like properties and resistance to apoptosis [65] .…”

Developing and characterization of single chain variable fragment (scFv) antibody against frizzled 7 (Fzd7) receptor

“…35 It has been shown that Fzd7 is upregulated in cancers 24 and inhibition of Fzd7 in cancer cells leads to decrease of cell growth 36 and tumor transformation. 2 Recognition of the importance Wnt signaling pathway mutations in some cancers has provided strong evidence that the pathway plays a major role in the genesis of some types of human cancers. 37 The findings suggested that targeting Fzd7 receptor and related signaling pathway molecules can be considered as a novel pharmacologic tool for caners therapy.…”

“…Upregulation of Wnt pathway genes such as low density lipoprotein receptor-related protein 6, frizzled homolog 7 (Fzd7), and transcription factor 7 (TCF7) is well documented in TNBC. 2 Over the past decade, our understanding and treatment of several types of breast cancers have improved but treatment of TNBC remained as a clinical unmet need Period 3 Frizzled (Fzd) proteins are receptor family of 7-pass transmembrane molecules comprising 10 members in humans. Fdzs consist of the N-terminal extracellular called cysteine-rich domain (CRD) 4,5 and intracellular C-terminal domain, including PDZ domain.…”

Differential Effects of Dishevelled 2 and 3 on TCF/LEF- Mediated Transcriptional Activation in Wnt-3a-Treated Breast Cancer Cell Line MDA-MB-231

“…The canonical Wnt signalling pathway play an important role in cell proliferation and TCF/LEF mediated transcriptional activation on TNBC. 35,36 MDA-MB-231 is a highly invasive, "basal type" fibroblastic breast cancer cell line, 37 undergoes autocrine Wnt signaling which down regulates E-cadherin expression at cell-cell borders.…”