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PTK6 domain mutants modulates action in Triple-negative breast cancer

ABSTRACT: PTK6 domain mutants modulates action in Triple-negative breast cancer

PROVIDER: PRJNA658686 | ENA |

REPOSITORIES: ENA

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PTK6 domain mutants modulates action in Triple-negative breast cancer

Project description:Protein tyrosine kinase 6 (PTK6; also called Brk) is overexpressed in 86% of breast cancer patients; high PTK6 expression predicts poor outcome. We reported PTK6 induction by HIF/GR complexes in response to either cellular or host stress. However, PTK6-driven signaling events in the context of TNBC remain undefined. In a mouse model of TNBC, manipulation of PTK6 levels (i.e. via knock-out or add-back) had little effect on primary tumor volume but altered lung metastasis. To delineate the mechanisms of PTK6 downstream signaling, we created kinase-dead (KM) and kinase-intact domain structure mutants of PTK6 via in frame deletions of the N-terminal SH3 or SH2 domains. While the PTK6 kinase domain contributed to soft-agar colony formation, PTK6 kinase activity was entirely dispensable for cell migration. Specifically, TNBC models expressing a PTK6 variant lacking the SH2 domain (SH2-del PTK6) were unresponsive to growth factor-stimulated cell motility relative to SH3-del, KM or wild-type PTK6 controls. Reverse phase protein array (RPPA) revealed that while intact PTK6 mediates spheroid formation via p38 MAPK signaling, the SH2 domain of PTK6 limits this biology, and instead mediates TNBC cell motility via activation of the RhoA and/or AhR signaling pathways. Inhibition of RhoA and/or AhR blocked TNBC cell migration as well as the branching/invasive morphology of PTK6+/AhR+ primary breast tumor tissue organoids. Inhibition of RhoA also enhanced paclitaxel cytotoxicity in TNBC cells, including in a taxane-refractory TNBC model. Together, these studies reveal that the SH2-domain of PTK6 is a potent effector of advanced cancer phenotypes in TNBC and identify RhoA and AhR as novel therapeutic targets in PTK6+ breast tumors.

2020-08-31 | GSE156676 | GEO

Quantitative proteomic profiling reveals key pathways in the anti-cancer action of methoxychalcone derivatives in triple negative breast cancer

Project description:Synthetic analogues of chalcones were investigated as potential therapeutics for triple negative breast cancer. These analogues were used in quantitative proteomic experiments to determine the mechanism of action.

2018-09-13 | PXD009553 | Pride

DAPK3 modulates migration and invasion of triple negative breast cancers

Project description:A mass spectrometry (MS)-based kinase inhibitor pulldown assay (KIPA) was applied to analyze 16 patient-derived xenografts (PDXs) leading to the discovery that Death-Associated Protein Kinase 3 (DAPK3) is significantly and specifically overexpressed in triple negative breast cancer (TNBC). Validation studies confirmed the enrichment of DAPK3 at the protein level, independent of RNA expression, in both TNBC cell lines and tumors. Genomic knockout of DAPK3 in TNBC cell lines inhibited in vitro migration and invasion, along with downregulation of an epithelial-mesenchymal transition (EMT) signature. The kinase and leucine-zipper domains within DAPK3 were shown by mutational analysis to be essential for functionality. Notably, DAPK3 was found to inhibit the levels of desmoplakin (DSP), a crucial component of the desmosome complex, thereby explaining TNBC migration and invasion effects. Further exploration with immunoprecipitation-mass spectrometry (IP-MS) identified Leucine-zipper protein 1 (LUZP1) as a strong binding partner of DAPK3, engaging in a leucine-zipper-domain-mediated interaction that protects DAPK3 from degradation. Thus, DAPK3 emerges as a novel regulator of EMT components in TNBC.

2025-05-06 | PXD049187 | Pride

H3K14ac binding by its Triple Tudor Domain globally directs SETDB1 activity

Project description:H3K14ac binding by its Triple Tudor Domain globally directs SETDB1 activity

| PRJNA1102324 | ENA

Triple therapy reduced metastasis in triple-negative breast cancer.

Project description:Triple therapy reduced metastasis in triple-negative breast cancer.

| PRJNA832953 | ENA

Triple therapy reduced metastasis in triple-negative breast cancer

Project description:Triple therapy reduced metastasis in triple-negative breast cancer

| PRJNA857888 | ENA

In silico analyses guides selection of BET inhibitors for triple negative breast cancer treatment

Project description:Triple negative breast cancer (TNBC) is an incurable disease with poor prognosis. At this moment, therapeutic options are limited to chemotherapy and no targeted agent has reached the clinical setting. Bromodomain and extraterminal (BET) inhibitors are a new family of compounds that inhibit bromodomain containing proteins affecting the expression of transcription factors (TFs), therefore modifying the expression of relevant oncogenic genes. We decided to performed gene-set enrichment analyses to get insights into the mechanism of action of these compounds. We treated cells with JQ1 and extracted RNA at 12 and 24 hours.

2016-03-23 | E-GEOD-79476 | biostudies-arrayexpress

Triple Negative Breast Cancer RNA Sequencing

Project description:We propose to definitively characterise the somatic genetics of triple negative breast cancer through generation of comprehensive catalogues of somatic mutations in breast cancer cases by high coverage genome sequencing coupled with integrated transcriptomic and methylation analyses.

2015-04-16 | E-ERAD-113 | biostudies-arrayexpress

Triple Negative Breast tumors: SPARC Positive Tumors vs SPARC Negative Tumors

Project description:The aim of this study was evaluate the transcriptome changes in the comparison between triple negative tumors with increased SPARC expression and triple negative tumors with decreased SPARC expression according to Nagai et al., 2011 (Breast Cancer Res Treat (2011) 126:1–14) The results generated could be of particular interest to better define the prognostic impact of SPARC expression in triple negative breast tumors

2018-07-01 | GSE98931 | GEO

H3K14ac binding by its Triple Tudor Domain globally directs SETDB1 activity

Project description:SETDB1 is a major H3K9 methyltransferase. It contains a unique Triple Tudor Domain (3TD) which specifically bind the dual modification of H3K14ac in the presence of H3K9me1/2/3. In this study, we explored the role of the 3TD H3K14ac interaction in the methylation of H3K9 methylation activity of SETDB1. We performed genome wide DNA methylation profiling using Infinium MethylationEPIC BeadChip (EPIC, Illumina Inc., San Diego, CA, USA) in HCT116 and SETDB1 KO cells and anlyse the role of H3K14ac in SETDB1 dependent DNA methylation.

2024-12-27 | GSE264388 | GEO

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