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      Molecular and Cellular Factors Associated with Racial Disparity in Breast Cancer

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          Abstract

          Recent studies have demonstrated that racial differences can influence breast cancer incidence and survival rate. African American (AA) women are at two to three fold higher risk for breast cancer than other ethnic groups. AA women with aggressive breast cancers show worse prognoses and higher mortality rates relative to Caucasian (CA) women. Over the last few years, effective treatment strategies have reduced mortality from breast cancer. Unfortunately, the breast cancer mortality rate among AA women remains higher compared to their CA counterparts. The focus of this review is to underscore the racial differences and differential regulation/expression of genetic signatures in CA and AA women with breast cancer. Moreover, immune cell infiltration significantly affects the clinical outcome of breast cancer. Here, we have reviewed recent findings on immune cell recruitment in the tumor microenvironment (TME) and documented its association with breast cancer racial disparity. In addition, we have extensively discussed the role of cytokines, chemokines, and other cell signaling molecules among AA and CA breast cancer patients. Furthermore, we have also reviewed the distinct genetic and epigenetic changes in AA and CA patients. Overall, this review article encompasses various molecular and cellular factors associated with breast cancer disparity that affects mortality and clinical outcome.

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          Most cited references98

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          RB and cell cycle progression.

          The Rb protein is a tumor suppressor, which plays a pivotal role in the negative control of the cell cycle and in tumor progression. It has been shown that Rb protein (pRb) is responsible for a major G1 checkpoint, blocking S-phase entry and cell growth. The retinoblastoma family includes three members, Rb/p105, p107 and Rb2/p130, collectively referred to as 'pocket proteins'. The pRb protein represses gene transcription, required for transition from G1 to S phase, by directly binding to the transactivation domain of E2F and by binding to the promoter of these genes as a complex with E2F. pRb represses transcription also by remodeling chromatin structure through interaction with proteins such as hBRM, BRG1, HDAC1 and SUV39H1, which are involved in nucleosome remodeling, histone acetylation/deacetylation and methylation, respectively. Loss of pRb functions may induce cell cycle deregulation and so lead to a malignant phenotype. Gene inactivation of pRB through chromosomal mutations is one of the principal reasons for retinoblastoma tumor development. Functional inactivation of pRb by viral oncoprotein binding is also shown in many neoplasias such as cervical cancer, mesothelioma and AIDS-related Burkitt's lymphoma.
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            Association between CD8+ T-cell infiltration and breast cancer survival in 12,439 patients.

            T-cell infiltration in estrogen receptor (ER)-negative breast tumours has been associated with longer survival. To investigate this association and the potential of tumour T-cell infiltration as a prognostic and predictive marker, we have conducted the largest study of T cells in breast cancer to date.
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              LXR/ApoE Activation Restricts Innate Immune Suppression in Cancer

              Therapeutic harnessing of adaptive immunity via checkpoint inhibition has transformed treatment of many cancers. Despite unprecedented long-term responses, most patients do not respond to these therapies. Immunotherapy non-responders often harbor high levels of circulating myeloid-derived suppressor cells (MDSC)—an immunosuppressive innate cell population. Through genetic and pharmacological approaches, we uncovered a pathway governing MDSC abundance in multiple cancer types. Therapeutic liver-X nuclear receptor (LXR) agonism reduced MDSC abundance in murine models and in patients treated in a first-in-human dose escalation phase 1 trial. MDSC depletion was associated with activation of cytotoxic T lymphocyte (CTL) responses in mice and patients. The LXR transcriptional target ApoE mediated these effects in mice, where LXR/ApoE activation therapy elicited robust anti-tumor responses and also enhanced T cell activation during various immune-based therapies. We implicate the LXR/ApoE axis in regulation of innate immune suppression and as a target for enhancing efficacy of cancer immunotherapy in patients. Therapeutic agonism of the LXR/ApoE axis improves response to immunotherapy by targeting immunosuppresive innate immune cells
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                Author and article information

                Journal
                Int J Mol Sci
                Int J Mol Sci
                ijms
                International Journal of Molecular Sciences
                MDPI
                1422-0067
                18 August 2020
                August 2020
                : 21
                : 16
                : 5936
                Affiliations
                [1 ]Department of Pathology, Ohio State University, Columbus, OH 43210, USA; charan.2@ 123456osu.edu (M.C.); Verma.201@ 123456osu.edu (A.K.V.); Shahid.sofi@ 123456osumc.edu (S.H.); Swati.misri@ 123456osumc.edu (S.M.); Sanjay.mishra@ 123456osumc.edu (S.M.)
                [2 ]Comprehensive Cancer Center, Ohio State University, Columbus, OH 43210, USA; sarmila.majumder@ 123456osumc.edu (S.M.); Bhuvaneswari.ramaswamy@ 123456osumc.edu (B.R.)
                Author notes
                [†]

                These authors contribute equally to this work.

                Author information
                https://orcid.org/0000-0003-4648-8112
                https://orcid.org/0000-0002-5874-6732
                Article
                ijms-21-05936
                10.3390/ijms21165936
                7460595
                32824813
                1214cca8-4d5c-410d-b1ae-9df585de3a23
                © 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
                : 17 July 2020
                : 13 August 2020
                Categories
                Review

                Molecular biology
                breast cancer,racial disparity,tumor microenvironment,immune cells
                Molecular biology
                breast cancer, racial disparity, tumor microenvironment, immune cells

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