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Constitutively activated PI3K accelerates tumor initiation and modifies histopathology of breast cancer.

ABSTRACT: The gene encoding phosphatidylinositol 3-kinase catalytic subunit ?-isoform (PIK3CA, p110?) is frequently activated by mutation in human cancers. Based on detection in some breast cancer precursors, PIK3CA mutations have been proposed to have a role in tumor initiation. To investigate this hypothesis, we generated a novel mouse model with a Cre-recombinase regulated allele of p110? (myristoylated-p110?, myr-p110?) along with p53^fl/fl deletion and Kras^G12D also regulated by Cre-recombinase. After instillation of adenovirus-expressing Cre-recombinase into mammary ducts, we found that myr-p110? accelerated breast tumor initiation in a copy number-dependent manner. Breast tumors induced by p53^fl/fl;Kras^G12D with no or one copy of myr-p110? had predominantly sarcomatoid features, whereas two copies of myr-p110? resulted in tumors with a carcinoma phenotype. This novel model provides experimental support for importance of active p110? in breast tumor initiation, and shows that the amount of PI3K activity can affect the rate of tumor initiation and modify the histological phenotype of breast cancer.

SUBMITTER: Sheen MR

PROVIDER: S-EPMC5141269 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature

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Constitutively activated PI3K accelerates tumor initiation and modifies histopathology of breast cancer.

Sheen M R MR Marotti J D JD Allegrezza M J MJ Rutkowski M M Conejo-Garcia J R JR Fiering S S

Oncogenesis 20161031 10

The gene encoding phosphatidylinositol 3-kinase catalytic subunit α-isoform (PIK3CA, p110α) is frequently activated by mutation in human cancers. Based on detection in some breast cancer precursors, PIK3CA mutations have been proposed to have a role in tumor initiation. To investigate this hypothesis, we generated a novel mouse model with a Cre-recombinase regulated allele of p110α (myristoylated-p110α, myr-p110α) along with p53<sup>fl/fl</sup> deletion and Kras<sup>G12D</sup> also regulated by ...[more]

PMID: 27797363

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Project description:IntroductionAdrenomedullin (AM) is secreted by breast cancer cells and increased by hypoxia. It is a multifunctional peptide that stimulates angiogenesis and proliferation. The peptide is also a potent paracrine stimulator of osteoblasts and bone formation, suggesting a role in skeletal metastases-a major site of treatment-refractory tumor growth in patients with advanced disease.MethodsThe role of adrenomedullin in bone metastases was tested by stable overexpression in MDA-MB-231 breast cancer cells, which cause osteolytic bone metastases in a standard animal model. Cells with fivefold increased expression of AM were characterized in vitro, inoculated into immunodeficient mice and compared for their ability to form bone metastases versus control subclones. Bone destruction was monitored by X-ray, and tumor burden and osteoclast numbers were determined by quantitative histomorphometry. The effects of AM overexpression on tumor growth and angiogenesis in the mammary fat pad were determined. The effects of AM peptide on osteoclast-like multinucleated cell formation were tested in vitro. A small-molecule AM antagonist was tested for its effects on AM-stimulated ex vivo bone cell cultures and co-cultures with tumor cells, where responses of tumor and bone were distinguished by species-specific real-time PCR.ResultsOverexpression of AM mRNA did not alter cell proliferation in vitro, expression of tumor-secreted factors or cell cycle progression. AM-overexpressing cells caused osteolytic bone metastases to develop more rapidly, which was accompanied by decreased survival. In the mammary fat pad, tumors grew more rapidly with unchanged blood vessel formation. Tumor growth in the bone was also more rapid, and osteoclasts were increased. AM peptide potently stimulated bone cultures ex vivo; responses that were blocked by small-molecule adrenomedullin antagonists in the absence of cellular toxicity. Antagonist treatment dramatically suppressed tumor growth in bone and decreased markers of osteoclast activity.ConclusionsThe results identify AM as a target for therapeutic intervention against bone metastases. Adrenomedullin potentiates osteolytic responses in bone to metastatic breast cancer cells. Small-molecule antagonists can effectively block bone-mediated responses to tumor-secreted adrenomedullin, and such agents warrant development for testing in vivo.

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Constitutively activated PI3K accelerates tumor initiation and modifies histopathology of breast cancer.

Publications

Constitutively activated PI3K accelerates tumor initiation and modifies histopathology of breast cancer.

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