Chronic Inflammation and Breast Cancer Recurrence
Division of Hematology-Oncology, Department of MedicineJournal of Clinical Oncology (Impact Factor: 18.43). 06/2009; 27(21):3418-9. DOI: 10.1200/JCO.2009.21.9782
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- "The consistent expressions of pro-inflammatory cytokines and chemokines are known to induce chronic inflammation in tumor microenvironment    . Chronic inflammatory response mainly carried out by immune cells (such as monocytes, macrophages, neutrophils, eosinophils, dendritic cells, mast cells and lymphocytes) in breast carcinogenesis. "
ABSTRACT: Inflammation has multifaceted role in cancer progression including initiation, promotion and invasion by affecting the immune surveillance and associated signaling pathways. Inflammation facilitates the over-expression of cytokines, chemokines and growth factors involved in progression of different cancers including breast cancer progression. Deregulation of biological processes such as oxidative stress, angiogenesis, and autophagy elicit favorable immune response towards chronic inflammation. Apart from the role in carcinogenesis, chronic inflammation also favors the emergence of drug resistance clones by inducing the growth of breast cancer stem-like cells. Immunomodulation mediated by cytokines, chemokines and several other growth factors present in the tumor microenvironment regulate chronic inflammatory response and alter crosstalk among various signaling pathways such as NF-κB, Nrf-2, JAK-STAT, Akt and MAPKs involved in the progression of breast cancer. In this review, we focused on cellular and molecular processes involved in chronic inflammation, crosstalk among different signaling pathways and their association in breast cancer pathogenesis.
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- "Previous evidence has indicated that inflammation within the tumor microenvironment may play an important role in breast cancer progression . Most previous studies have reported an association of high levels of circulating proinflammatory cytokines with poor prognosis in breast cancer [1,3]. "
ABSTRACT: Inflammation within the tumor microenvironment has been reported to show an association with poor prognosis in breast cancer. However, the associations may differ according to breast cancer subtype. In this study, we investigated the association between inflammation-related markers and breast cancer recurrence according to patients' tumor subtypes. This prospective study included 240 patients who underwent surgery for management of newly diagnosed breast cancer. Levels of inflammation-related markers (interleukin [IL]-1β, IL-6, IL-8, monocyte chemoattractant protein-1 [MCP-1], leptin, and adiponectin) were measured at diagnosis, and the associations between these markers and breast cancer recurrence during a six-year follow-up period were examined using the Kaplan-Meier statistical method. Overall, inflammation-related markers showed no association with breast cancer recurrence. However, when data were stratified by tumor subtype, higher levels of some mediators showed an association with poor prognosis among patients with particular subtypes. Compared to patients without recurrence, patients with recurrence had higher levels of circulating IL-6 (p=0.024) and IL-8 (p=0.016) only among those with HER2(-) tumors and had higher levels of leptin (p=0.034) only among those with estrogen receptor (ER)(+)/progesterone receptor (PR)(+) tumors. Results of survival analyses revealed an association of high levels of IL-6 (p=0.016) and IL-8 (p=0.022) with poor recurrence-free survival in patients with HER2(-) tumors. In addition, higher leptin levels indicated shorter recurrence-free survival time only among patients with ER(+)/PR(+) tumors (p=0.022). We found that certain cytokines could have a differential prognostic impact on breast cancer recurrence according to breast cancer subtype. Conduct of additional large studies will be required in order to elucidate the precise roles of these cytokines in breast cancer progression.
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- "An inflammatory tumor microenvironment consists of infiltrating immune cells and activated fibroblasts, both of which can secrete cytokines, chemokines, and growth factors, as well as DNA-damaging agents 11. Some studies show evidence that chronic inflammation is linked to breast cancer recurrence and that elevated biomarkers of inflammation are associated with reduced survival among breast cancer patients 12, 13. In addition, experimental studies clearly indicate that inflammatory mediators promote tumor development in cancer prone animal strains 14. "
ABSTRACT: Tumor necrosis factor-alpha (TNF-α) is a proinflammatory cytokine that has been linked to breast cancer development. Estrogen metabolic pathway is also involved in breast carcinogenesis and DNA adducts formation. In this study we investigated the effect of TNF-α on the estrogen metabolic pathway in MCF-7, a breast cancer cell line. Capillary liquid chromatography/mass spectrometry (LC/MS) and High performance liquid chromatography (HPLC) were used for analysis of estrogen metabolites and estrogen-DNA adducts levels respectively. Reporter gene assay, Real time reverse transcription polymerase chain reaction (real time RT-PCR) and Western blot were used to assess the expression of estrogen metabolizing genes and enzymes. TNF-α significantly increased the total EM and decreased the estrone (E1) / 17-β estradiol (E2) ratio. Moreover, it altered the expression of genes and enzymes involved in E2 activation and deactivation pathways e.g. Cytochrome P-450 1A1 (CYP1A1), Cytochrome P-450 1B1 (CYP1B1), Catechol-O-methyl transferase (COMT) and Nicotinamide adenine dinucleotide phosphate-quinone oxidoreductase 1 (NQO1). In addition, there were increased levels of some catechol estrogens e.g. 4-hydroxy-estrone (4-OHE1) and 2-hydroxyestradiol (2-OHE2) with decreased levels of methylated catechols e.g. 2-methoxy estradiol (2-MeOE2). DNA adducts especially 4-OHE1--1-N3 Adenine was significantly increased. TNF-α directs the estrogen metabolism into more hormonally active and carcinogenic products in MCF-7. This may implicate a new possible explanation for inflammation associated breast cancer.
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