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      Inflammatory Biomarkers and Breast Cancer Risk: A Systematic Review of the Evidence and Future Potential for Intervention Research

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          Abstract

          Measuring systemic chronic inflammatory markers in the blood may be one way of understanding the role of inflammation in breast cancer risk, and might provide an intermediate outcome marker in prevention studies. Here, we present the results of a systematic review of prospective epidemiologic studies that examined associations between systemic inflammatory biomarkers measured in blood and breast cancer risk. From 1 January 2014 to 20 April 2020, we identified 18 unique studies (from 16 publications) that examined the association of systemic inflammatory biomarkers measured in blood with breast cancer risk using prospectively collected epidemiologic data. Only one marker, C-reactive protein, was studied extensively (measured in 13 of the 16 publications), and had some evidence of a positive association with breast cancer risk. Evidence associating other inflammatory biomarkers and more comprehensive panels of markers with the development of breast cancer is limited. Future prospective evidence from expanded panels of systemic blood inflammatory biomarkers is needed to establish strong and independent links with breast cancer risk, along with mechanistic studies to understand inflammatory pathways and demonstrate how breast tissue responds to chronic inflammation. This knowledge could ultimately support the development and evaluation of mechanistically driven interventions to reduce inflammation and prevent breast cancer.

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          Adipose tissue, adipokines, and inflammation.

          White adipose tissue is no longer considered an inert tissue mainly devoted to energy storage but is emerging as an active participant in regulating physiologic and pathologic processes, including immunity and inflammation. Macrophages are components of adipose tissue and actively participate in its activities. Furthermore, cross-talk between lymphocytes and adipocytes can lead to immune regulation. Adipose tissue produces and releases a variety of proinflammatory and anti-inflammatory factors, including the adipokines leptin, adiponectin, resistin, and visfatin, as well as cytokines and chemokines, such as TNF-alpha, IL-6, monocyte chemoattractant protein 1, and others. Proinflammatory molecules produced by adipose tissue have been implicated as active participants in the development of insulin resistance and the increased risk of cardiovascular disease associated with obesity. In contrast, reduced leptin levels might predispose to increased susceptibility to infection caused by reduced T-cell responses in malnourished individuals. Altered adipokine levels have been observed in a variety of inflammatory conditions, although their pathogenic role has not been completely clarified.
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            The complex role of estrogens in inflammation.

            There is still an unresolved paradox with respect to the immunomodulating role of estrogens. On one side, we recognize inhibition of bone resorption and suppression of inflammation in several animal models of chronic inflammatory diseases. On the other hand, we realize the immunosupportive role of estrogens in trauma/sepsis and the proinflammatory effects in some chronic autoimmune diseases in humans. This review examines possible causes for this paradox. This review delineates how the effects of estrogens are dependent on criteria such as: 1) the immune stimulus (foreign antigens or autoantigens) and subsequent antigen-specific immune responses (e.g., T cell inhibited by estrogens vs. activation of B cell); 2) the cell types involved during different phases of the disease; 3) the target organ with its specific microenvironment; 4) timing of 17beta-estradiol administration in relation to the disease course (and the reproductive status of a woman); 5) the concentration of estrogens; 6) the variability in expression of estrogen receptor alpha and beta depending on the microenvironment and the cell type; and 7) intracellular metabolism of estrogens leading to important biologically active metabolites with quite different anti- and proinflammatory function. Also mentioned are systemic supersystems such as the hypothalamic-pituitary-adrenal axis, the sensory nervous system, and the sympathetic nervous system and how they are influenced by estrogens. This review reinforces the concept that estrogens have antiinflammatory but also proinflammatory roles depending on above-mentioned criteria. It also explains that a uniform concept as to the action of estrogens cannot be found for all inflammatory diseases due to the enormous variable responses of immune and repair systems.
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              Obesity, inflammation and the immune system.

              Obesity shares with most chronic diseases the presence of an inflammatory component, which accounts for the development of metabolic disease and other associated health alterations. This inflammatory state is reflected in increased circulating levels of pro-inflammatory proteins, and it occurs not only in adults but also in adolescents and children. The chronic inflammatory response has its origin in the links existing between the adipose tissue and the immune system. Obesity, like other states of malnutrition, is known to impair the immune function, altering leucocyte counts as well as cell-mediated immune responses. In addition, evidence has arisen that an altered immune function contributes to the pathogenesis of obesity. This review attempts to briefly comment on the various plausible explanations that have been proposed for the phenomenon: (1) the obesity-associated increase in the production of leptin (pro-inflammatory) and the reduction in adiponectin (anti-inflammatory) seem to affect the activation of immune cells; (2) NEFA can induce inflammation through various mechanisms (such as modulation of adipokine production or activation of Toll-like receptors); (3) nutrient excess and adipocyte expansion trigger endoplasmic reticulum stress; and (4) hypoxia occurring in hypertrophied adipose tissue stimulates the expression of inflammatory genes and activates immune cells. Interestingly, data suggest a greater impact of visceral adipose tissue and central obesity, rather than total body fat, on the inflammatory process. In summary, there is a positive feedback loop between local inflammation in adipose tissue and altered immune response in obesity, both contributing to the development of related metabolic complications.
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                Author and article information

                Journal
                Int J Environ Res Public Health
                Int J Environ Res Public Health
                ijerph
                International Journal of Environmental Research and Public Health
                MDPI
                1661-7827
                1660-4601
                28 July 2020
                August 2020
                : 17
                : 15
                : 5445
                Affiliations
                [1 ]Department of Epidemiology, Mailman School of Public Health, Columbia University, 722 W 168th St, New York, NY 10032, USA; rk2967@ 123456cumc.columbia.edu (R.D.K.); jam2319@ 123456cumc.columbia.edu (J.A.M.)
                [2 ]Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, 1130 St Nicholas Ave, New York, NY 10032, USA
                [3 ]National Toxicology Program Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, 111 TW Alexander Drive, Durham, NC 27709, USA; suzanne.fenton@ 123456nih.gov
                [4 ]California Breast Cancer Research Program, University of California, 300 Lakeside Drive, Oakland, CA 94612, USA; Marion.Kavanaugh-Lynch@ 123456ucop.edu (M.K.-L.); Katherine.McKenzie@ 123456ucop.edu (K.E.M.)
                [5 ]Sapientiae, 1977 Manzanita Dr, Oakland, CA 94611, USA; gustane@ 123456gmail.com
                [6 ]Department of Oncology, Cancer Prevention and Control Program, Georgetown-Lombardi Comprehensive Cancer Center, Georgetown University, 3800 Reservoir Rd. NW, Washington, DC 20057, USA
                Author notes
                [* ]Correspondence: mandelbj@ 123456georgetown.edu (J.S.M.); mt146@ 123456columbia.edu (M.B.T.)
                [†]

                These two authors are joint senior authors.

                Author information
                https://orcid.org/0000-0002-6089-6799
                https://orcid.org/0000-0002-8270-8074
                https://orcid.org/0000-0002-9568-5684
                https://orcid.org/0000-0002-8146-3570
                https://orcid.org/0000-0002-2490-005X
                Article
                ijerph-17-05445
                10.3390/ijerph17155445
                7432395
                32731638
                3e01e13a-30ac-462b-acad-e7863d0b509f
                © 2020 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 05 June 2020
                : 24 July 2020
                Categories
                Review

                Public health
                breast cancer risk,blood inflammatory biomarkers,c-reactive protein,intervention research,prospective epidemiologic studies,systematic review

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