Dataset Information

NOWAC blood-based breast cancer case-control study

ABSTRACT: Tumor-host interactions extend beyond the local microenvironment and cancer development largely depends on the ability of malignant cells to hijack and exploit the normal physiological processes of the host. Although abnormalities in a hostâ€™s systemic immunity are associated with increased cancer susceptibility, the functional interplay between tumor cells and circulating immune cells in regulating tumorigenic responses is unclear. We employed the Norwegian Women and Cancer study, a large prospective population-based cohort study, to identify gene expression changes in blood cells that provide a robust and reproducible diagnostic signal specific to breast cancer patients. We further show that circulating blood cells in breast cancer patients are enriched in genes involved in systemic immunosuppression and the motility, metabolism, growth, and proliferation of immune cells. By mining of the cancer-associated blood transcriptome, we identified immune mediators or biomarkers that could permit early detection of breast cancer and open avenues to novel targeted immunotherapies.

PROVIDER: EGAS00000000134 | EGA |

REPOSITORIES: EGA

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Peripheral blood cells inform on the presence of breast cancer: a population-based case-control study.

Dumeaux Vanessa V Ursini-Siegel Josie J Flatberg Arnar A Fjosne Hans E HE Frantzen Jan-Ole JO Holmen Marit Muri MM Rodegerdts Enno E Schlichting Ellen E Lund Eiliv E

International journal of cancer 20140625 3

Tumor-host interactions extend beyond the local microenvironment and cancer development largely depends on the ability of malignant cells to hijack and exploit the normal physiological processes of the host. Here, we established that many genes within peripheral blood cells show differential expression when an untreated breast cancer (BC) is present, and harnessed this fact to construct a 50-gene signature that distinguish BC patients from population-based controls. Our results were derived from ...[more]

PMID: 24931809

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Project description:Aberrant production and/or function of multiple host systemic factors (e.g., metabolic and immune-inflammatory mediators) act in concert to promote a âtumorigenicâ host milieu that directly promotes an aggressive malignant phenotype as well as drug resistance. Hence, strategies with the capacity to simultaneously act across multiple host systemic pathways may be required to optimize therapeutic outcomes in solid tumors. We hypothesized that chronic aerobic training, a pleiotropic whole-body intervention, modulates multiple systemic host pathways that, in turn, effectively alters cancer cell phenotype in vitro. Plasma samples from patients with solid tumors exposed to chronic aerobic training or sedentary control were comprehensively characterized for changes in immune, inflammatory, and metabolic pathways. Compared with sedentary control, aerobic training caused significant reductions in interleukin (IL)-4, macrophage inflammatory protein-1 beta (MIP1-Î²), vascular endothelial growth factor (VEGF), tumor necrosis factor-alpha (TNF-Î±), and hepatocyte growth factor (HGF). There were no significant changes in leukocyte phenotype or any plasma metabolite signatures. Exposure of estrogen receptor (ER) distinct human breast cancer cell lines (MCF-7 and MDA-MB-231) to post-intervention serum from breast cancer patients exposed to aerobic training caused marked increases in proliferation, migration, and apoptosis, compared to control patient serum. Only the combination of cytokines significantly reduced in plasma following aerobic training recapitulated the phenotype observed with patient serum in MCF-7 cells whereas only the single addition of MIP-1Î² or HGF significantly increased apoptosis in MDA-MB-231 cells. Co-culturing of MDA-MB-231 cells with patient exercise serum and a HGF neutralizing antibody increased proliferation and completely abrogated exercise serum-induced apoptosis. Finally, whole-genome microarray of MDA-MB-231 cells exposed to exercise or control patient serum revealed differential modulation of 310 genes including PTEN, CDK3, and IGFBP1. Our findings indicate the widespread potential of chronic aerobic training to modulate host immune-inflammatory systemic factors in patients with solid tumors. Modulation of such pathways directly alters breast cancer phenotypes providing novel insight into the molecular pathways by which exercise may inhibit malignant progression. MDA-MB-231 cells were plated at 250,000 cells/well in triplicate with 10% FBS in 6-well plates and left overnight to adhere. Media was suctioned off and replaced with serum free media. Patient serum was then added to the wells at a 10% final concentration and RNA was harvested using Qiagen RNeasy kit after 4 days.

Project description:Disruptions of systemic homeostasis have emerged as critical regulators of cancer. Recent studies indicate that chronic or acute host stressors (e.g., obesity1, surgery2) alter cancer pathogenesis. Many cancer patients, particularly those with breast cancer, are at increased risk for cardiovascular disease due to treatment toxicity and resulting changes in lifestyle behaviors3-5. While elevated risk and incidence of cardiovascular events in breast cancer is well-established, whether such events impact cancer pathogenesis is not known. Herein, we show that an incident myocardial infarction (MI or heart attack) accelerates breast cancer outgrowth and cancer-specific mortality in mice and humans. In mouse models of breast cancer, MI epigenetically reprogrammed Ly6Chigh monocytes in the bone marrow reservoir to an immunosuppressive phenotype that was maintained at the transcriptional level in monocytes in the circulation and tumor. In parallel, MI increased circulating Ly6Chigh monocyte levels and recruitment to tumors, and depletion of these cells abrogated MI-induced tumor growth. Furthermore, evaluation of the relationship between a new onset post-diagnosis cardiovascular event and cancer outcomes in early-stage breast cancer patients revealed increased risk of recurrence and cancer-specific death, highlighting the clinical relevance of our findings. Collectively, our results demonstrate that MI induces alterations to systemic homeostasis, triggering cross-disease communication Disruptions of systemic homeostasis have emerged as critical regulators of cancer. Recent studies indicate that chronic or acute host stressors (e.g., obesity1, surgery2) alter cancer pathogenesis. Many cancer patients, particularly those with breast cancer, are at increased risk for cardiovascular disease due to treatment toxicity and resulting changes in lifestyle behaviors3-5. While elevated risk and incidence of cardiovascular events in breast cancer is well-established, whether such events impact cancer pathogenesis is not known. Herein, we show that an incident myocardial infarction (MI or heart attack) accelerates breast cancer outgrowth and cancer-specific mortality in mice and humans. In mouse models of breast cancer, MI epigenetically reprogrammed Ly6Chigh monocytes in the bone marrow reservoir to an immunosuppressive phenotype that was maintained at the transcriptional level in monocytes in the circulation and tumor. In parallel, MI increased circulating Ly6Chigh monocyte levels and recruitment to tumors, and depletion of these cells abrogated MI-induced tumor growth. Furthermore, evaluation of the relationship between a new onset post-diagnosis cardiovascular event and cancer outcomes in early-stage breast cancer patients revealed increased risk of recurrence and cancer-specific death, highlighting the clinical relevance of our findings. Collectively, our results demonstrate that MI induces alterations to systemic homeostasis, triggering cross-disease communication that accelerates breast cancer.

Dataset Information

NOWAC blood-based breast cancer case-control study

Publications

Peripheral blood cells inform on the presence of breast cancer: a population-based case-control study.

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