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      Multidrug-resistant breast cancer: current perspectives

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          Abstract

          Breast cancer is the most common cancer in women worldwide, and resistance to the current therapeutics, often concurrently, is an increasing clinical challenge. By understanding the molecular mechanisms behind multidrug-resistant breast cancer, new treatments may be developed. Here we review the recent advances in this understanding, emphasizing the common mechanisms underlying resistance to both targeted therapies, notably tamoxifen and trastuzumab, and traditional chemotherapies. We focus primarily on three molecular mechanisms, the phosphatidylinositide 3-kinase/Akt pathway, the role of microRNAs in gene silencing, and epigenetic alterations affecting gene expression, and discuss how these mechanisms can interact in multidrug resistance. The development of therapeutics targeting these mechanisms is also addressed.

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          Biological determinants of endocrine resistance in breast cancer.

          Elizabeth Musgrove, Robert Sutherland (2009)
          Endocrine therapies targeting oestrogen action (anti-oestrogens, such as tamoxifen, and aromatase inhibitors) decrease mortality from breast cancer, but their efficacy is limited by intrinsic and acquired therapeutic resistance. Candidate molecular biomarkers and gene expression signatures of tamoxifen response emphasize the importance of deregulation of proliferation and survival signalling in endocrine resistance. However, definition of the specific genetic lesions and molecular processes that determine clinical endocrine resistance is incomplete. The development of large-scale computational and genetic approaches offers the promise of identifying the mediators of endocrine resistance that may be exploited as potential therapeutic targets and biomarkers of response in the clinic.
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            Mechanisms of estrogen receptor signaling: convergence of genomic and nongenomic actions on target genes.

            Linda Björnström, Maria Sjöberg (2005)
            Estrogen receptors (ERs) act by regulating transcriptional processes. The classical mechanism of ER action involves estrogen binding to receptors in the nucleus, after which the receptors dimerize and bind to specific response elements known as estrogen response elements (EREs) located in the promoters of target genes. However, ERs can also regulate gene expression without directly binding to DNA. This occurs through protein-protein interactions with other DNA-binding transcription factors in the nucleus. In addition, membrane-associated ERs mediate nongenomic actions of estrogens, which can lead both to altered functions of proteins in the cytoplasm and to regulation of gene expression. The latter two mechanisms of ER action enable a broader range of genes to be regulated than the range that can be regulated by the classical mechanism of ER action alone. This review surveys our knowledge about the molecular mechanism by which ERs regulate the expression of genes that do not contain EREs, and it gives examples of the ways in which the genomic and nongenomic actions of ERs on target genes converge. Genomic and nongenomic actions of ERs that do not depend on EREs influence the physiology of many target tissues, and thus, increasing our understanding of the molecular mechanisms behind these actions is highly relevant for the development of novel drugs that target specific receptor actions.
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              MicroRNAs in human cancer.

              Thalia A Farazi, Jessica I Hoell, Pavel Morozov … (2013)
              Mature microRNAs (miRNAs) are single-stranded RNA molecules of 20-23-nucleotide (nt) length that control gene expression in many cellular processes. These molecules typically reduce the translation and stability of mRNAs, including those of genes that mediate processes in tumorigenesis, such as inflammation, cell cycle regulation, stress response, differentiation, apoptosis, and invasion. miRNA targeting is initiated through specific base-pairing interactions between the 5' end ("seed" region) of the miRNA and sites within coding and untranslated regions (UTRs) of mRNAs; target sites in the 3' UTR lead to more effective mRNA destabilization. Since miRNAs frequently target hundreds of mRNAs, miRNA regulatory pathways are complex. To provide a critical overview of miRNA dysregulation in cancer, we first discuss the methods currently available for studying the role of miRNAs in cancer and then review miRNA genomic organization, biogenesis, and mechanism of target recognition, examining how these processes are altered in tumorigenesis. Given the critical role miRNAs play in tumorigenesis processes and their disease specific expression, they hold potential as therapeutic targets and novel biomarkers.
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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: 2014
                Publication date (Electronic): 10 January 2014
                Volume: 6
                Pages: 1-13
                Affiliations
                [1 ]BioScreening Technology Group, Leeds Institutes of Molecular Medicine, University of Leeds, Leeds, UK
                [2 ]Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, UK
                Author notes
                Correspondence: Darren C Tomlinson, BioScreening Technology Group, Leeds Institutes of Molecular Medicine, Wellcome Trust Brenner Building, St James’s University Hospital, Beckett Street, Leeds LS9 7TF, UK, Tel +44 113 343 9077, Email d.c.tomlinson@ 123456leeds.ac.uk
                Article
                Publisher ID: bctt-6-001
                DOI: 10.2147/BCTT.S37638
                PMC ID: 3929252
                PubMed ID: 24648765
                SO-VID: 1ef1d52d-b03d-452b-8c4b-b69d5dbea642
                Copyright © © 2014 Martin et al. This work is published by Dove Medical Press Limited, and licensed under Creative Commons Attribution – Non Commercial (unported, v3.0) License
                License:

                The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

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                Subject: Review

                Keywords: pi3k/akt,epigenetics,mirna,er,her2,triple negative
                Data availability:
                Keywords: pi3k/akt, epigenetics, mirna, er, her2, triple negative

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