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Differentiation of Mammary Tumors by SKI-606 (bostutinib) (gene expression)

ABSTRACT: While c-Src is infrequently mutated in human cancers, it mediates oncogenic signals of many activated growth factor receptors and thus remains a key potential target of cancer therapy. However, the widespread function of Src in many cell types and processes requires evaluation of Src-targeted therapeutics within a normal developmental and immune competent environment. In an effort to direct clinical use of Src inhibitors, we tested the effectiveness of one of the four Src inhibitors in clinical testing, SKI-606 (bosutinib), in the MMTV-PyVmT transgenic mouse model of breast cancer. Tumor formation in this model is dependent on the presence of Src, but the necessity of Src kinase activity for tumor formation has not been determined. Furthermore, Src inhibitors have not been examined in an autochthonous tumor model. Here we show that oral administration of the Src inhibitor SKI-606 inhibited the phosphorylation of Src in mammary tumors, and caused a rapid decrease in the Ezh2 Polycomb group histone H3K27 methyltransferase and an increase in epithelial organization. SKI-606 prevented the appearance of palpable tumors in more than half of the animals treated from puberty and stopped tumor growth in older animals with preexisting tumors. These antitumor effects were accompanied by decreased cellular proliferation, altered tumor blood vessel organization and dramatically increased differentiation to lactational and epidermal cell fates. SKI-606 controls the development of mammary tumors in this model by inducing differentiation. Differentiation of Mammary Tumors by SKI-606 (bostutinib)

ORGANISM(S): Mus musculus

SUBMITTER: Roy Williams

PROVIDER: E-GEOD-22150 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Differentiation of Mammary Tumors by SKI-606 (bostutinib) (illumina)

Project description:While c-Src is infrequently mutated in human cancers, it mediates oncogenic signals of many activated growth factor receptors and thus remains a key potential target of cancer therapy. However, the widespread function of Src in many cell types and processes requires evaluation of Src-targeted therapeutics within a normal developmental and immune competent environment. In an effort to direct clinical use of Src inhibitors, we tested the effectiveness of one of the four Src inhibitors in clinical testing, SKI-606 (bosutinib), in the MMTV-PyVmT transgenic mouse model of breast cancer. Tumor formation in this model is dependent on the presence of Src, but the necessity of Src kinase activity for tumor formation has not been determined. Furthermore, Src inhibitors have not been examined in an autochthonous tumor model. Here we show that oral administration of the Src inhibitor SKI-606 inhibited the phosphorylation of Src in mammary tumors, and caused a rapid decrease in the Ezh2 Polycomb group histone H3K27 methyltransferase and an increase in epithelial organization. SKI-606 prevented the appearance of palpable tumors in more than half of the animals treated from puberty and stopped tumor growth in older animals with preexisting tumors. These antitumor effects were accompanied by decreased cellular proliferation, altered tumor blood vessel organization and dramatically increased differentiation to lactational and epidermal cell fates. SKI-606 controls the development of mammary tumors in this model by inducing differentiation. Differentiation of Mammary Tumors by SKI-606 (bostutinib)

2010-09-15 | E-GEOD-20921 | biostudies-arrayexpress

Differentiation of Mammary Tumors by SKI-606 (bostutinib) (gene expression)

2011-01-01 | GSE22150 | GEO

Differentiation of Mammary Tumors by SKI-606 (bostutinib) (illumina)

2010-09-15 | GSE20921 | GEO

Mus musculus

Project description:Differentiation of Mammary Tumors by SKI-606 (bostutinib) (illumina)

| PRJNA124471 | ENA

Mus musculus

Project description:Differentiation of Mammary Tumors by SKI-606 (bostutinib) (gene expression)

| PRJNA127709 | ENA

The translational repair pathway is a frequent synthetic lethal target in cancer

Project description:Synthetic lethality exploits the genetic vulnerabilities of cancer cells enabling, a targeted, precision approach to treat cancer. Synthetic lethal discovery approaches have led to clinical successes of PARP inhibitors and the progression of several next-generation therapeutic targets such as WRN, USP1, PKMYT1, POLQ, and PRMT5 into the clinic. To date, however, most discovery efforts in the synthetic lethal space have focused on DNA repair. Here, we show, for the first time in humans, a frequent synthetic lethal interaction between two complexes of the translational repair pathway, PELO/HBS1L and the superkiller (SKI) complex. In distinct genetic contexts, either in 9p21.3 (FOCAD) deleted or MSI-H tumors, we found that phenotypically destabilized SKI complex leads to dependence on the PELO/HBS1L ribosomal rescue complex. We estimate that 20% of all tumors have a destabilized SKI complex. The concomitant loss of PELO in a SKI destabilized tumor drives an unfolded protein stress response, cell cycle arrest, and robust tumor growth inhibition. Furthermore, we demonstrate that the loss of HBS1L phenocopies PELO loss, presenting a second potential therapeutic target within the rescue complex. Our results indicate that PELO/HBS1L represent novel therapeutic targets whose dependence converges upon SKI complex destabilization, a common phenotypic biomarker in diverse genetic contexts and a significant patient population.

2024-10-14 | GSE261804 | GEO

Consequences of sEH deletion in the polyoma middle T (PyMT) breast cancer tumor proteome

Project description:The aim of this investigation was to study the consequences of interfering with soluble epoxide hydrolase (sEH) expression on tumor growth and metastasis in genetically modified animals that spontaneously generate tumors without the exogenous application of high concentrations of epoxide mediators or inhibitors. Therefore, breast cancer development was studied in mice expressing the polyoma middle T oncogene (PyMT) under the control of the mouse mammary tumor virus promoter, to induce spontaneous mammary tumors. To facilitate the study of endogenous sEH activity in tumor growth, PyMT mice were then crossed with sEH-/- mice to generate sEH-deficient mice that spontaneously generate breast tumors (so called PyMTsEH mice). For these analyses, primary tumors were removed from 20 week old mice.

2021-09-14 | PXD026214 | Pride

Uncovering tumor-stroma inter-relationships using quantitative MALDI-Mass spectrometry imaging

Project description:To facilitate analysis of protein expression changes in in situ tumors and stroma, we took advantage of a mouse model that permits conditional activation of the Ser-Thr kinase ROCK within mammary tumor cells. In this study, we undertook MALDI-MSI analysis of tissue samples derived from our conditional ROCK mammary tumor model, to quantify in an unbiased manner, the proteomic changes occurring during the progression of mammary cancers in their specific spatial contexts.

2020-09-07 | PXD019255 | Pride

Cistrome analysis of SKI and RUNX1 in HL60

Project description:SKI is a transcriptional co-regulator and overexpressed in various human tumors, for example in acute myeloid leukemia (AML). SKI contributes to the origin and maintenance of the leukemic phenotype. Here we use ChIP-seq and RNA-seq to identify the epigenetic alterations induced by SKI overexpression in AML cells. We show that approximately two thirds of differentially expressed genes are up-regulated upon SKI deletion, of which nearly 50% harbour SKI binding sites in their proximity, primarily in enhancer regions. Gene ontology analysis reveals that many of the differentially expressed genes are annotated to hematopoietic cell differentiation and inflammatory response, corroborating our finding that SKI deletion causes a release of the myeloid differentiation block in HL60 cells. We find that SKI peaks are enriched for RUNX1 consensus motifs, particularly in up-regulated SKI targets. RUNX1 ChIP-seq demonstrates that nearly 70% of RUNX1 binding sites overlap with SKI peaks, mainly at enhancer regions. SKI and RUNX1 co-occupy the same genomic sites and cooperate in gene silencing. Our work demonstrates for the first time on a genome-wide scale the predominant co-repressive function of SKI in AML cells and uncovers the transcription factor RUNX1 as an important mediator of SKI-dependent transcriptional repression.

2018-02-07 | GSE107553 | GEO

Analysis of differentiation therapeutic approaches on murine breast cancer organoids

Project description:In this experiment, we have tested the effect of microRNA-203 as a potential differentiation inducer in breast cancer organoids, derived from the PyMT mouse model. MMTV-PyVT transgenic mice express the Polyoma Virus middle T antigen under the direction of the mouse mammary tumor virus promoter/enhancer. Hemizygous MMTV-PyMT females develop palpable mammary tumors which metastasize to the lung. These mice have high penetrance of early onset of mammary cancer compared to other mammary tumor models. PyMT mice were crossed with miR-203 knock-in mice, where miR-203 expression is induced upon DOX treatment. Thus, organoids derived from the mammary gland tumors of such mouse model where evaluated in vitro. miR-203 expression was therefore induced by Doxycycline in vitro, and compared to other well-defined differentiation media for breast cancer tissue, such as the mammary epithelial cell culture media and kit (CC-2551B; Lonza).

2023-08-09 | GSE202831 | GEO

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