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      Gender Differences in Cancer Susceptibility: An Inadequately Addressed Issue

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          Abstract

          The gender difference in cancer susceptibility is one of the most consistent findings in cancer epidemiology. Hematologic malignancies are generally more common in males and this can be generalized to most other cancers. Similar gender differences in non-malignant diseases including autoimmunity, are attributed to hormonal or behavioral differences. Even in early childhood, however, where these differences would not apply, there are differences in cancer incidence between males and females. In childhood, few cancers are more common in females, but overall, males have higher susceptibility. In Hodgkin lymphoma, the gender ratio reverses toward adolescence. The pattern that autoimmune disorders are more common in females, but cancer and infections in males suggests that the known differences in immunity may be responsible for this dichotomy. Besides immune surveillance, genome surveillance mechanisms also differ in efficiency between males and females. Other obvious differences include hormonal ones and the number of X chromosomes. Some of the differences may even originate from exposures during prenatal development. This review will summarize well-documented examples of gender effect in cancer susceptibility, discuss methodological issues in exploration of gender differences, and present documented or speculated mechanisms. The gender differential in susceptibility can give important clues for the etiology of cancers and should be examined in all genetic and non-genetic association studies.

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          Estrogen receptors: how do they signal and what are their targets.

          During the past decade there has been a substantial advance in our understanding of estrogen signaling both from a clinical as well as a preclinical perspective. Estrogen signaling is a balance between two opposing forces in the form of two distinct receptors (ER alpha and ER beta) and their splice variants. The prospect that these two pathways can be selectively stimulated or inhibited with subtype-selective drugs constitutes new and promising therapeutic opportunities in clinical areas as diverse as hormone replacement, autoimmune diseases, prostate and breast cancer, and depression. Molecular biological, biochemical, and structural studies have generated information which is invaluable for the development of more selective and effective ER ligands. We have also become aware that ERs do not function by themselves but require a number of coregulatory proteins whose cell-specific expression explains some of the distinct cellular actions of estrogen. Estrogen is an important morphogen, and many of its proliferative effects on the epithelial compartment of glands are mediated by growth factors secreted from the stromal compartment. Thus understanding the cross-talk between growth factor and estrogen signaling is essential for understanding both normal and malignant growth. In this review we focus on several of the interesting recent discoveries concerning estrogen receptors, on estrogen as a morphogen, and on the molecular mechanisms of anti-estrogen signaling.
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            The X-files in immunity: sex-based differences predispose immune responses

            Sex-based differences in immune responses can influence the susceptibility to autoimmune and infectious diseases and the efficacy of therapeutic drugs. In this Perspective, Eleanor Fish discusses factors, such as X-linked genes, hormones and societal context, that underlie disparate immune responses in men and women.
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              Tumor cells disseminate early, but immunosurveillance limits metastatic outgrowth, in a mouse model of melanoma.

              Although metastasis is the leading cause of cancer-related death, it is not clear why some patients with localized cancer develop metastatic disease after complete resection of their primary tumor. Such relapses have been attributed to tumor cells that disseminate early and remain dormant for prolonged periods of time; however, little is known about the control of these disseminated tumor cells. Here, we have used a spontaneous mouse model of melanoma to investigate tumor cell dissemination and immune control of metastatic outgrowth. Tumor cells were found to disseminate throughout the body early in development of the primary tumor, even before it became clinically detectable. The disseminated tumor cells remained dormant for varying periods of time depending on the tissue, resulting in staggered metastatic outgrowth. Dormancy in the lung was associated with reduced proliferation of the disseminated tumor cells relative to the primary tumor. This was mediated, at least in part, by cytostatic CD8+ T cells, since depletion of these cells resulted in faster outgrowth of visceral metastases. Our findings predict that immune responses favoring dormancy of disseminated tumor cells, which we propose to be the seed of subsequent macroscopic metastases, are essential for prolonging the survival of early stage cancer patients and suggest that therapeutic strategies designed to reinforce such immune responses may produce marked benefits in these patients.
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                Author and article information

                Journal
                Front Genet
                Front Genet
                Front. Gene.
                Frontiers in Genetics
                Frontiers Media S.A.
                1664-8021
                25 August 2012
                28 November 2012
                2012
                : 3
                : 268
                Affiliations
                [1] 1Robert Stempel College of Public Health and Social Work, Florida International University Miami, FL, USA
                [2] 2College of Veterinary Medicine, University of Georgia Athens, GA, USA
                Author notes

                Edited by: M. J. Mosher, Western Washington University, USA

                Reviewed by: Yiran Guo, Children’s Hospital of Philadelphia, USA; Satyanarayana M. R. Rao, Jawaharlal Nehru Center for Advanced Scientific Research, India

                *Correspondence: M. Tevfik Dorak, Department of Environmental and Occupational Health, Robert Stempel College of Public Health and Social Work, Florida International University, 11200 SW 12th Street, AHC2 No. 584, Miami, FL 33199, USA. e-mail: mdorak@ 123456fiu.edu

                This article was submitted to Frontiers in Applied Genetic Epidemiology, a specialty of Frontiers in Genetics.

                Article
                10.3389/fgene.2012.00268
                3508426
                23226157
                9fb3a899-1891-485f-b74c-b6acad196704
                Copyright © 2012 Dorak and Karpuzoglu.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in other forums, provided the original authors and source are credited and subject to any copyright notices concerning any third-party graphics etc.

                History
                : 03 August 2012
                : 06 November 2012
                Page count
                Figures: 0, Tables: 4, Equations: 0, References: 128, Pages: 11, Words: 10984
                Categories
                Genetics
                Review Article

                Genetics
                sex factors,cancer susceptibility,sex chromosomes,genetic predisposition to disease,genetic epidemiology,sex hormones

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