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      LXR/RXR pathway signaling associated with triple-negative breast cancer in African American women

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          Abstract

          Background

          Triple-negative breast cancer (TNBC) is more prevalent in African and African American (AA) women compared to European American (EA) women. African and AA women diagnosed with TNBC experience high frequencies of metastases and less favorable outcomes. Emerging evidence indicates that this disparity may in fact be the result of the uniquely aggressive biology of African and AA disease.

          Purpose

          To understand the reasons for TNBC in AA aggressive biology, we designed the present study to examine the proteomic profiles of TNBC and luminal A (LA) breast cancer within and across patients’ racial demographic groups in order to identify proteins or molecular pathways altered in TNBC that offer some explanation for its aggressiveness and potential targets for treatment.

          Materials and methods

          Proteomic profiles of TNBC, LA tumors, and their adjacent normal tissues from AA and EA women were obtained using 2-dimensional gel electrophoresis and bioinformatics, and differentially expressed proteins were validated by Western blot and immunohistochemistry. Our data showed that a number of proteins have significantly altered in expression in LA tumors compared to TNBC, both within and across patients’ racial demographic groups. The differentially overexpressed proteins in TNBC (compared to LA) of AA samples were distinct from those in TNBC (compared to LA) of EA women samples. Among the signaling pathways altered in AA TNBC compared to EA TNBC are innate immune signaling, calpain protease, and pyrimidine de novo synthesis pathways. Furthermore, liver LXR/RXR signaling pathway was altered between LA and TNBC in AA women and may be due to the deficiency of the CYP7B1 enzyme responsible for cholesterol degradation.

          Conclusion

          These findings suggest that TNBC in AA women enriched in signaling pathways that are different from TNBC in EA women. Our study draws a link between LXR/RXR expression, cholesterol, obesity, and the TNBC in AA women.

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          Most cited references17

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          Biological subtypes of breast cancer: Prognostic and therapeutic implications.

          Özlem Yersal, Sabri Barutca (2014)
          Breast cancer is a heterogeneous complex of diseases, a spectrum of many subtypes with distinct biological features that lead to differences in response patterns to various treatment modalities and clinical outcomes. Traditional classification systems regarding biological characteristics may have limitations for patient-tailored treatment strategies. Tumors with similar clinical and pathological presentations may have different behaviors. Analyses of breast cancer with new molecular techniques now hold promise for the development of more accurate tests for the prediction of recurrence. Gene signatures have been developed as predictors of response to therapy and protein gene products that have direct roles in driving the biology and clinical behavior of cancer cells are potential targets for the development of novel therapeutics. The present review summarizes current knowledge in breast cancer molecular biology, focusing on novel prognostic and predictive factors.
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            Race disparities in the contribution of miRNA isoforms and tRNA-derived fragments to triple-negative breast cancer.

            Aristeidis G. Telonis, Isidore Rigoutsos (2018)
            Triple-Negative Breast Cancer (TNBC) is a breast cancer subtype characterized by marked differences between White and Black/African-American women. We performed a systems-level analysis on datasets from The Cancer Genome Atlas (TCGA) to elucidate how the expression patterns of messenger RNAs (mRNAs) are shaped by regulatory non-coding RNAs (ncRNAs). Specifically, we studied isomiRs, i.e. isoforms of microRNAs (miRNAs), and tRNA-derived fragments (tRFs). In normal breast tissue, we observed a marked cohesiveness in both the ncRNA and mRNA layers and the associations between them. This cohesiveness was widely disrupted in TNBC: many mRNAs become either differentially expressed or differentially wired between normal breast and TNBC in tandem with isomiR or tRF dysregulation. The affected pathways included energy metabolism, cell signaling and immune responses. Within TNBC, the wiring of the affected pathways with isomiRs and tRFs differed in each race. Multiple isomiRs and tRFs arising from specific miRNA loci (e.g., miR-200c, miR-21, the miR-17/92 cluster, the miR-183/96/182 cluster) and from specific tRNA loci (e.g. the nuclear tRNAGly and tRNALeu, the mitochondrial tRNAVal and tRNAPro) were strongly associated with the observed race disparities in TNBC. We highlight the race-specific aspects of transcriptome wiring by discussing in detail the metastasis-related MAPK and the Wnt/β-catenin signaling pathways, two of the many key pathways that were found differentially wired. In conclusion, by employing a data- and knowledge-driven approach we comprehensively analyzed the normal and cancer transcriptomes to uncover novel key contributors to the race-based disparities of TNBC.
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              The influence of socioeconomic disparities on breast cancer tumor biology and prognosis: a review.

              Linda Vona-Davis, D Rose (2009)
              Socioeconomic deprivation is associated with an increased risk of breast cancer mortality. This article summarizes the relationships between socioeconomic status (SES) and breast cancer in white European women compared with racial and ethnic groups in the United States. Furthermore, we examine the association between obesity and breast cancer within socioeconomic disparities. Mortality rates were published by the American Cancer Society and the National Cancer Institute Surveillance, Epidemiology, and End Results Program. Obesity data were derived from the National Center for Health Statistics Behavioral Risk Factor Surveillance System. MEDLINE searches were performed using keywords, such as socioeconomic status, poverty, African American, Hispanic, race, and combined with related articles. Socioeconomic deprivation may be responsible for the increased risk of breast cancer mortality in African American and Hispanic patients, as they are more likely than white American patients to be diagnosed with advanced disease. Among white women, social deprivation is related to poor breast cancer prognosis, with increased prevalence rates of high-grade, estrogen receptor (ER)-negative tumors, similar to that of triple-negative breast cancers observed in African American and Hispanic women. Obesity is associated with advanced breast cancer at diagnosis, high tumor proliferation rates, and more triple-negative phenotypes, indicating that it may adversely contribute to prognosis. Most studies show an effect of SES on breast cancer incidence and prognosis. Research should focus on the influence of social deprivation on breast cancer characteristics, such as absence of ER expression, that occurs in African Americans and Hispanics and in white European women with a different genetic background.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Breast Cancer (Dove Med Press)
                Journal ID (iso-abbrev): Breast Cancer (Dove Med Press)
                Journal ID (publisher-id): Breast Cancer – Targets and Therapy
                Title: Breast Cancer : Targets and Therapy
                Publisher: Dove Medical Press
                ISSN (Electronic): 1179-1314
                Publication date Collection: 2019
                Publication date (Electronic): 20 December 2018
                Volume: 11
                Pages: 1-12
                Affiliations
                [1 ]Department of Comparative Pathobiology, Purdue University, West Lafayette, IN, USA, mohammes@ 123456purdue.edu
                [2 ]Purdue University Center for Cancer Research, Purdue University, West Lafayette, IN, USA, mohammes@ 123456purdue.edu
                [3 ]Department of Learning Sciences, University of Illinois at Chicago, Chicago, IL, USA
                [4 ]Department of Surgery, Indiana University Health, Lafayette, IN, USA
                [5 ]Center for Clinical Cancer Genetics and Global Health, Department of Medicine, University of Chicago, Chicago, IL, USA
                [6 ]Department of Radiation Oncology, Brigham and Women’s Hospital, Boston, MA, USA
                [7 ]Department of Radiation Oncology, Harvard Medical School, Boston, MA, USA
                [8 ]Department of Oncology, National Cancer Institute, University of Gezira, Gezira, Sudan
                [9 ]Division of Biochemical Toxicology, National Center for Toxicological Research, Jefferson, AR, USA
                Author notes
                Correspondence: Sulma I Mohammed, Department of Comparative Pathobiology, Purdue University, 724 Harrison Street, West Lafayette, IN 47907, USA, Tel +1 765 494 9948, Fax +1 765 494 9830, Email mohammes@ 123456purdue.edu
                Article
                Publisher ID: bctt-11-001
                DOI: 10.2147/BCTT.S185960
                PMC ID: 6304259
                PubMed ID: 30588086
                SO-VID: c9f48ca0-3806-44ee-b27d-44676be4dde6
                Copyright © © 2019 Torres-Luquis et al. This work is published and licensed by Dove Medical Press Limited
                License:

                The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

                History
                Categories
                Subject: Original Research

                Keywords: breast,triple-negative breast cancer,african american,european american,luminal breast cancer,luminal
                Data availability:
                Keywords: breast, triple-negative breast cancer, african american, european american, luminal breast cancer, luminal

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