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

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.

ORGANISM(S): Mus musculus

PROVIDER: GSE20921 | GEO | 2010/09/15

SECONDARY ACCESSION(S): PRJNA124471

REPOSITORIES: GEO

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

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)

2011-01-01 | E-GEOD-22150 | biostudies-arrayexpress

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

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

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

2011-01-01 | GSE22150 | 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

Expression data transgenic mouse mammary tumors

Project description:Immunosurveillance constitutes the first step of cancer immunoediting in which developing malignant lesions are eliminated by anti-tumorigenic immune cells. However, the mechanisms by which neoplastic cells induce an immunosuppressive state to evade the immune response are still unclear. The transcription factor Stat3 has been implicated in breast carcinogenesis and tumor immunosuppression in advanced disease, but its involvement in early disease development has not been established. Here, we genetically ablated Stat3 in the tumor epithelia of the inducible PyVmT mammary tumor model and found that Stat3-deficient mice recapitulated the three phases of immunoediting: elimination, equilibrium, and escape. Pathological analyses revealed that Stat3-deficient mice initially formed hyperplastic and early adenoma-like lesions that later completely regressed, thereby preventing the emergence of mammary tumors in the majority of animals. Furthermore, tumor regression was correlated with massive immune infiltration into the Stat3-deficient lesions, leading to their elimination. In a minority of animals, focal, non-metastatic Stat3-deficient mammary tumors escaped immunosurveillance after a long latency or equilibrium period. Taken together, our findings suggest that tumor epithelial expression of Stat3 plays a critical role in promoting an immunosuppressive tumor microenvironment during breast tumor initiation and progression, and prompt further investigation of Stat3 inhibitory strategies that may reactivate the immunosurveillance program. We used microarrays to detail determine the transcriptional difference between PyVmT-driven mouse mammary tumors that progressed in the presence or absense of epithelial Stat3. Mammary tumors from transgenic mice were excise and flash frozen. Tumors were analyzed from 8 Stat3-proficient tumors and 6 Stat3-deficient tumors. RNA was extracted and hybridization on Affymetrix microarrays.

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Expression data transgenic mouse mammary tumors

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Multipotent mammary cancer stem cells integrate stem cell and clonal expansion theories of tumor progression

Project description:The diversity of human breast cancer subtypes has led to the hypothesis that breast cancer is a number of different diseases arising from cells at various stages of differentiation. We have derived clonal multipotent metastatic mammary cancer stem cells from the polyomavirus middle T mouse model of breast cancer, that can differentiate into luminal, myoepithelial and alveolar cells. When injected orthotopically at low-density, the resulting tumors express estrogen and progesterone receptors. With continued passage in vivo, the tumor cells undergo additional epigenetic and/or genetic changes that result in upregulation of Her2 expression or clonal expansion of cells that give rise to basal-like or claudin-low tumors. As in human tumors, the more aggressive tumor subtypes express nuclear p53. The temporal sequence of events suggests that contrary to current dogma, multiple tumor subtypes can originate from a single multipotent cancer stem cell that undergoes evolution during tumor progression. Furthermore, these data raise the possibility that a human polyomavirus may be a causative agent in spontaneous forms of human breast cancer. Three spontaneous PyVmT tumors and forty cell line derived tumors were analyzed. To generate cell line derived tumors, 10^6 tumor cells were injected orthotopically into four abdominal mammary fat pads in syngeneic C57Bl/6 female mice. After 6-8 weeks the mice were euthanized and the tumors excised and frozen at -80Â°C. One tumor per mouse 8-10mm in diameter was used for array analysis. RNA was extracted using the RNeasy kit (Qiagen) with on column DNA removal.

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