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Diet and lifestyle factors modify immune/inflammation response genes to alter breast cancer risk and prognosis: the Breast Cancer Health Disparities Study.

ABSTRACT: Tumor necrosis factor-? (TNF) and toll-like receptors (TLR) are important mediators of inflammation. We examined 10 of these genes with respect to breast cancer risk and mortality in a genetically admixed population of Hispanic/Native American (NA) (2111 cases, 2597 controls) and non-Hispanic white (NHW) (1481 cases, 1585 controls) women. Additionally, we explored if diet and lifestyle factors modified associations with these genes. Overall, these genes (collectively) were associated with breast cancer risk among women with >70% NA ancestry (P(ARTP) = 0.0008), with TLR1 rs7696175 being the primary risk contributor (OR 1.77, 95% CI 1.25, 2.51). Overall, TLR1 rs7696175 (HR 1.40, 95% CI 1.03, 1.91; P(adj) = 0.032), TLR4 rs5030728 (HR 1.96, 95% CI 1.30, 2.95; P(adj) = 0.014), and TNFRSF1A rs4149578 (HR 2.71, 95% CI 1.28, 5.76; P(adj) = 0.029) were associated with increased breast cancer mortality. We observed several statistically significant interactions after adjustment for multiple comparisons, including interactions between our dietary oxidative balance score and CD40LG and TNFSF1A; between cigarette smoking and TLR1, TLR4, and TNF; between body mass index (BMI) among pre-menopausal women and TRAF2; and between regular use of aspirin/non-steroidal anti-inflammatory drugs and TLR3 and TRA2. In conclusion, our findings support a contributing role of certain TNF-? and TLR genes in both breast cancer risk and survival, particularly among women with higher NA ancestry. Diet and lifestyle factors appear to be important mediators of the breast cancer risk associated with these genes.

SUBMITTER: Slattery ML

PROVIDER: S-EPMC4201121 | biostudies-literature | 2014 Dec

REPOSITORIES: biostudies-literature

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Diet and lifestyle factors modify immune/inflammation response genes to alter breast cancer risk and prognosis: the Breast Cancer Health Disparities Study.

Slattery Martha L ML Lundgreen Abbie A Torres-Mejia Gabriela G Wolff Roger K RK Hines Lisa L Baumgartner Kathy K John Esther M EM

Mutation research 20141201

Tumor necrosis factor-α (TNF) and toll-like receptors (TLR) are important mediators of inflammation. We examined 10 of these genes with respect to breast cancer risk and mortality in a genetically admixed population of Hispanic/Native American (NA) (2111 cases, 2597 controls) and non-Hispanic white (NHW) (1481 cases, 1585 controls) women. Additionally, we explored if diet and lifestyle factors modified associations with these genes. Overall, these genes (collectively) were associated with breast ...[more]

PMID: 25332681

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Project description:BackgroundBreast cancer has become the malignancy with the highest mortality rate in female patients worldwide. The limited efficacy of immunotherapy as a breast cancer treatment has fueled the development of research on the tumor immune microenvironment.MethodsIn this study, data on breast cancer patients were collected from The Cancer Genome Atlas Breast Invasive Carcinoma (TCGA-BRCA) and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) cohorts. Differential gene expression analysis, univariate Cox regression analysis, and least absolute shrinkage and selection operator (LASSO) Cox regression analysis were performed to select overall survival (OS)-related, tumor tissue highly expressed, and immune- and inflammation-related genes. A tumor immune-inflammation signature (TIIS) consisting of 18 genes was finally screened out in the LASSO Cox regression model. Model performance was assessed by time-dependent receiver operating characteristic (ROC) curves. In addition, the CIBERSORT algorithm and abundant expression of immune checkpoints were utilized to clarify the correlation between the risk signature and immune landscape in breast cancer. Furthermore, the association of IL27 with the immune signature was analyzed in pan-cancer and the effect of IL27 on the migration of breast cancer cells was investigated since the regression coefficient of IL27 was the highest.ResultsA TIIS based on 18 genes was constructed via LASSO Cox regression analysis. In the TCGA-BRCA training cohort, 10-year AUC reached 0.89, and prediction performance of this signature was also validated in the METABRIC set. The high-risk group was significantly correlated with less infiltration of tumor-killing immune cells and the lower expression level of the immune checkpoint. Furthermore, we recommended some small-molecule drugs as novel targeted drugs for new breast cancer types. Finally, the relationship between IL27, a significant prognostic immune and inflammation cytokine, and immune status was analyzed in pan-cancer. Expression of IL27 was significantly correlated with immune regulatory gene expression and immune cell infiltration in pan-cancer. Furthermore, IL27 treatment improved breast cancer cell migration.ConclusionThe TIIS represents a promising prognostic tool for estimating OS in patients with breast cancer and is correlated with immune status.

Project description:BACKGROUND:Racial disparities in breast cancer survival between Black and White women persist across all stages of breast cancer. The metabolic syndrome (MetS) of insulin resistance disproportionately affects more Black than White women. It has not been discerned if insulin resistance mediates the link between race and poor prognosis in breast cancer. We aimed to determine whether insulin resistance mediates in part the association between race and breast cancer prognosis, and if insulin receptor (IR) and insulin-like growth factor receptor (IGF-1R) expression differs between tumors from Black and White women. METHODS:We conducted a cross-sectional, multi-center study across ten hospitals. Self-identified Black women and White women with newly diagnosed invasive breast cancer were recruited. The primary outcome was to determine if insulin resistance, which was calculated using the homeostatic model assessment of insulin resistance (HOMA-IR), mediated the effect of race on prognosis using the multivariate linear mediation model. Demographic data, anthropometric measurements, and fasting blood were collected. Poor prognosis was defined as a Nottingham Prognostic Index (NPI) >?4.4. Breast cancer pathology specimens were evaluated for IR and IGF-1R expression by immunohistochemistry (IHC). RESULTS:Five hundred fifteen women were recruited (83% White, 17% Black). The MetS was more prevalent in Black women than in White women (40% vs 20%, p?<?0.0001). HOMA-IR was higher in Black women than in White women (1.9?±?1.2 vs 1.3?±?1.4, p?=?0.0005). Poor breast cancer prognosis was more prevalent in Black women than in White women (28% vs 15%. p?=?0.004). HOMA-IR was positively associated with NPI score (r?=?0.1, p?=?0.02). The mediation model, adjusted for age, revealed that HOMA-IR significantly mediated the association between Black race and poor prognosis (??=?0.04, 95% CI 0.005-0.009, p?=?0.002). IR expression was higher in tumors from Black women than in those from White women (79% vs 52%, p?=?0.004), and greater IR/IGF-1R ratio was also associated with higher NPI score (IR/IGF-1R?>? 1: 4.2?±?0.8 vs IR/IGF-1R?=?1: 3.9?±?0.8 vs IR/IGF-1R?<?1: 3.5?±?1.0, p?<?0.0001). CONCLUSIONS:In this multi-center, cross-sectional study of US women with newly diagnosed invasive breast cancer, insulin resistance is one factor mediating part of the association between race and poor prognosis in breast cancer.

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Diet and lifestyle factors modify immune/inflammation response genes to alter breast cancer risk and prognosis: the Breast Cancer Health Disparities Study.

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Diet and lifestyle factors modify immune/inflammation response genes to alter breast cancer risk and prognosis: the Breast Cancer Health Disparities Study.

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