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FZD7 Plays a Critical Role in Triple Negative Breast Cancer Proliferation

ABSTRACT: Breast cancer is genetically and clinically heterogeneous. Triple negative cancer (TNBC) is a subtype of breast cancer usually associated with poor outcome and lack of benefit from target therapy. A pathway analysis in a microarray study was performed using 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 (LRP6) and transcription factor 7 (TCF7) has been observed in TNBC. Focus was given to the Wnt pathway receptor, FZD7. To validate its function, inhibition of FZD7 using FZD7shRNA was carried out. Notably decreased cell proliferation, suppressed invasiveness and colony formation in triple negative MDA-MB-231 and BT-20 cells were observed. Mechanism study indicated that these effects occurred through silencing the canonical Wnt signaling pathway, as evidenced by loss of nuclear accumulation of beta-catenin and decreased transcriptional activity of TCF7. In vivo study revealed that FZD7shRNA significantly suppressed the tumor formation in xenotransplation mice due to decrease cell proliferation. Our finding suggests that FZD7 involved canonical Wnt signaling pathway is essential for tumorigenesis of TNBC. Thus, FZD7 may be a biomarker and a potential therapeutic target for triple negative breast cancer.

ORGANISM(S): Homo sapiens

PROVIDER: GSE27447 | GEO | 2011/06/01

SECONDARY ACCESSION(S): PRJNA137075

REPOSITORIES: GEO

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FZD7 Plays a Critical Role in Triple Negative Breast Cancer Proliferation

Project description:Breast cancer is genetically and clinically heterogeneous. Triple negative cancer (TNBC) is a subtype of breast cancer usually associated with poor outcome and lack of benefit from target therapy. A pathway analysis in a microarray study was performed using 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 (LRP6) and transcription factor 7 (TCF7) has been observed in TNBC. Focus was given to the Wnt pathway receptor, FZD7. To validate its function, inhibition of FZD7 using FZD7shRNA was carried out. Notably decreased cell proliferation, suppressed invasiveness and colony formation in triple negative MDA-MB-231 and BT-20 cells were observed. Mechanism study indicated that these effects occurred through silencing the canonical Wnt signaling pathway, as evidenced by loss of nuclear accumulation of ï?¢-catenin and decreased transcriptional activity of TCF7. In vivo study revealed that FZD7shRNA significantly suppressed the tumor formation in xenotransplation mice due to decrease cell proliferation. Our finding suggests that FZD7 involved canonical Wnt signaling pathway is essential for tumorigenesis of TNBC. Thus, FZD7 may be a biomarker and a potential therapeutic target for triple negative breast cancer. 14 pretreatment non-triple negative breast tumors compare with 5 triple negative breast tumor.

2011-06-01 | E-GEOD-27447 | biostudies-arrayexpress

A Novel Role of Wnt/β Catenin Signaling in Regulating the Nucleolus in Triple Negative Breast CancerA Novel Role of Wnt/β Catenin Signaling in Regulating the Nucleolus in Triple Negative Breast Cancer

Project description:Breast cancer is one of the most common types of cancer in women. One key signaling pathway known to regulate tumor growth, metabolic adaptation, and cellular stress response in breast cancer is Wnt signaling. Breast cancer patients, specifically triple negative breast cancer (TNBC), with upregulated Wnt signaling often have a poor clinical prognosis. However, the effects of Wnt/β-catenin signaling on the nucleolus and the resultant impact on cancer development and progression remain unclear. A notable reduction was observed in the number of nucleoli per nucleus in response to Wnt/β-catenin signaling inhibition in multiple TNBC cell lines. Our comparative proteomic analysis revealed several changes in the composition of the nucleolar proteome of TNBC cells upon inhibition of Wnt signaling. Overall, we demonstrate that Wnt/β-catenin signaling will affects nucleolar functionality and thus influences breast cancer progression. Understanding the role of Wnt signaling in the nucleolus and breast cancer is a critical step towards developing novel therapeutic options for the treatment of breast cancer.

2021-03-05 | PXD021181 | Pride

Transcriptome analysis of FMF-04-159-2 treated MDA-MB-231 cells

Project description:Wnt/β-catenin signaling pathway has become a key signaling pathway regulating mammary organogenesis and oncogenesis. However, the therapeutic methods by targeting Wnt pathway against breast cancer has been limited. To address this challenge, we investigated the function of cyclin-dependent kinase 14 (CDK14), a member of Wnt signaling pathway, in mammary development and breast cancer progression. We showed that CDK14 was expressed in the mammary basal layer and elevated in triple negative breast cancer (TNBC). CDK14 knockdown reduces colony formation ability and regeneration capacity of mammary basal cells, and significantly inhibits murine MMTV-Wnt-1 basal-like mammary tumor progression. Excitingly, knockdown of CDK14 or pharmacological inhibition of CDK14 by FMF-04-159-2 significantly inhibited the progression and metastasis of human TNBC. Mechanistically, CDK14 inhibition inhibits mammary regeneration and TNBC progression by attenuating Wnt/β-catenin signaling. Together, we demonstrated that CDK14 regulates mammary regeneration and breast tumorigenesis, and is a promising therapeutic target for TNBC.

2022-02-27 | GSE197213 | GEO

Transcriptome analysis of Scramble control and Cdk14-sh mouse mammary basal cells

2022-04-29 | GSE201526 | GEO

Transcriptome analysis of Scramble control and CDK14-sh MDA-MB-231 cells

2022-02-22 | GSE197000 | GEO

Comprehensive genomic analysis identify novel subtypes and targets of triple-negative breast cancer (198 TNBC tumors)

Project description:Recent meta-analyses suggest triple-negative breast cancer (TNBC) is a heterogenous disease. In this study we sought to define these TNBC subtypes and identify subtype-specific markers and targets. We identified and confirmed four distinct, stable TNBC subtypes: (1) Luminal-AR (LAR); 2) Mesenchymal (MES); 3) Basal-Like Immune-Suppressed (BLIS), and 4) Basal-Like Immune-Activated (BLIA). RNA profiling analysis was conducted on 198 TNBC tumors (ER-negativity defined as Allred Scale value â¤2) with >50% cellularity (discovery set: n=84; validation set: n=114)

2015-12-18 | E-GEOD-76124 | biostudies-arrayexpress

KK-LC-1 as a feasible therapeutic target to eliminate ALDH+ stem cells in triple negative breast cancer

Project description:Failure to achieve complete elimination of triple negative breast cancer (TNBC) stem cells after adjuvant therapy is associated with poor outcomes. Aldehyde dehydrogenase 1 (ALDH1) is a marker of breast cancer stem cells (BCSCs), and its enzymatic activity regulates tumor stemness. Identifying upstream targets to control ALDH+ cells may facilitate TNBC tumor suppression. Here, we show that KK-LC-1 determines the stemness of TNBC ALDH+ cells via binding with FAT1 and subsequently promoting its ubiquitination and degradation. This compromised the Hippo pathway and led to nuclear translocation of YAP1 and ALDH1A1 transcription. These findings identified the KK-LC-1-FAT1-Hippo-ALDH1A1 pathway in TNBC ALDH+ cells as a therapeutic target. To reverse the malignancy due to KK-LC-1 expression, we employed a novel computational approach and discovered Z839878730 (Z8) as an small-molecule inhibitor which may disrupt KK-LC-1 and FAT1 binding. We demonstrate that Z8 suppressed TNBC tumor growth via a mechanism that reactivated the Hippo pathway and decreased TNBC ALDH+ cell stemness and viability.

2023-04-12 | PXD040200 | Pride

Comprehensive genomic analysis identify novel subtypes and targets of triple-negative breast cancer (198 TNBC tumors)

2015-12-18 | GSE76124 | GEO

Comprehensive genomic analysis identify novel subtypes and targets of triple-negative breast cancer (67 not triple-negative tumors)

2015-12-23 | GSE76274 | GEO

CDK7-dependent Transcriptional Addiction in Triple-Negative Breast Cancer (Microarray)

Project description:Triple-negative breast cancer (TNBC) is a highly aggressive form of breast cancer that exhibits extremely high levels of genetic complexity and yet a relatively uniform transcriptional program. We postulate that TNBC might be highly dependent on uninterrupted transcription of a key set of genes within this gene expression program and might therefore be exceptionally sensitive to inhibitors of transcription. Utilizing a novel kinase inhibitor and CRISPR/Cas9-mediated gene editing, we show here that triple-negative but not ER/PR+ breast cancer cells are exceptionally dependent on CDK7, a transcriptional cyclin-dependent kinase. TNBC cells are unique in their dependence on this transcriptional CDK and suffer apoptotic cell death upon CDK7 inhibition. An “Achilles cluster” of TNBC-specific genes are extremely sensitive to CDK7 inhibition and frequently associated with super-enhancers. We conclude that CDK7 mediates transcriptional addiction to a vital cluster of genes in TNBC and CDK7 inhibition may be useful therapy for this challenging cancer. Expression microarrays in H3K27ac in triple-negative breast cancer +/- treatment with covalent CDK7 inhibitor THZ1 treatment

2015-09-24 | E-GEOD-69106 | biostudies-arrayexpress

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