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ROR1 Is Expressed In Human Breast Cancer And Associated With Enhanced Tumor-cell Growth

ABSTRACT: Receptor-tyrosine-kinase-like orphan receptor 1 (ROR1) is expressed during embryogenesis and by certain leukemias, but not by tissues of healthy adults. Here we show that the neoplastic cells of many human breast cancers express the ROR1 protein and high-level expression of ROR1 in breast adenocarcinoma was associated with aggressive disease. Total mRNA from Ct-shRNA MDA-MB-231 stable cell line and ROR1-shRNA MDA-MB-231 stable cell line were labeled with Cy5, hybridized to a human Oligo Microarray (Phalanx Human Whole Genome OneArrayTM, Phalanx Biotech) according to the manufacturer’s protocol. Arrays in duplicates were then scanned using GenePix 4000B scanner (Molecular Devices) and the probe intensities were extracted and processed using the GenePix Pro 6.0 software (Molecular Devices). After removing experimental control probes, the intensities of 30968 probes were quantile normalized to have similar distributions across all 4 arrays. The normalized intensity of probes derived from the same gene was collapsed into a single NCBI Entrez gene by the maximal value in each sample (mapping information is obtained from Phalanx’s probe annotation table). In total, 15598 genes were measured at transcription level. Differential expression of genes was quantified using fold enrichment. Gene functional annotation regarding cell proliferation, cell apoptosis, CREB signaling, breast cancer signature was downloaded from MSigDB database. Gene set enrichment analysis was described by Mootha.

ORGANISM(S): Homo sapiens

SUBMITTER: zhang suping

PROVIDER: S-ECPF-GEOD-31631 | biostudies-other |

REPOSITORIES: biostudies-other

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Project description:Background:The histamine receptor 2 antagonist ranitidine is a commonly used, non-prescription, medication. It limits the development, growth, and metastasis of breast cancers in mouse models of disease. In this study, we examined the role of B cells in this response, the impact of ranitidine on the development of antitumor antibodies and subpopulations of natural killer cells using murine breast cancer models. Methods:Peripheral blood granulocyte populations were assessed in both E0771-GFP and 4T1 orthotopic tumor-bearing mice by evaluation of stained blood smears. Antibody responses were assessed both in terms of the levels of anti-GFP antibodies detected by enzyme-linked immunosorbent assay and also by antibody binding to the surface of tumor cells evaluated by flow cytometry. B cell and NK cell populations were examined in the draining lymph nodes and spleens of tumor-bearing animals, by flow cytometry with and without ranitidine treatment. Results:Oral ranitidine treatment was not associated with changes in peripheral blood granulocyte populations in tumor-bearing mice. However, ranitidine treatment was associated with the development of enhanced antitumor antibody responses. This was not limited to the tumor setting since ranitidine-treated mice immunized with ovalbumin also demonstrated increased IgG antibody responses. Analysis of B cell populations indicated that while B1 cell populations remained unchanged there was a significant decrease in B2 cells in the tumor-draining inguinal lymph nodes. Notably, ranitidine did not significantly inhibit primary tumor growth in B cell-deficient animals. Examination of NK cell populations revealed a significant decrease in the proportion of intermediately functionally mature NK cells populations (CD27+CD11b-) in ranitidine-treated tumor-bearing mice compared with untreated tumor-bearing controls. Conclusion:These data demonstrate an important role for B cells in the enhanced antitumor immune response that occurs in response to ranitidine treatment. Our findings are consistent with a model, whereby ranitidine reduces tumor-associated immune suppression allowing for the development of more effective antitumor responses mediated by B cells which may include the participation of NK cells. These data underline the importance of considering widely used histamine receptor antagonists as modulators of antitumor immunity to breast cancer.

Project description:Adrenomedullin (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.The 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.Overexpression 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.The 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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ROR1 Is Expressed In Human Breast Cancer And Associated With Enhanced Tumor-cell Growth

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