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      miR‐126 reduces trastuzumab resistance by targeting PIK3R2 and regulating AKT/mTOR pathway in breast cancer cells

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          Abstract

          MicroRNAs (miRNAs) have been found to play a key role in drug resistance. In the current study, we aimed to explore the potential role of miR‐126 in trastuzumab resistance in breast cancer cells. We found that the trastuzumab‐resistant cell lines SKBR3/TR and BT474/TR had low expression of miR‐126 and increased ability to migrate and invade. The resistance, invasion and mobilization abilities of the cells resistant to trastuzumab were reduced by ectopic expression of miR‐126 mimics. In comparison, inhibition of miR‐126 in SKBR3 parental cells had the opposite effect of an increased resistance to trastuzumab as well as invasion and migration. It was also found that miR‐126 directly targets PIK3R2 in breast cancer cells. PIK3R2‐knockdown cells showed decreased resistance to trastuzumab, while overexpression of PIK3R2 increased trastuzumab resistance. In addition, our finding showed that overexpression of miR‐126 reduced resistance to trastuzumab in the trastuzumab‐resistant cells and that inhibition of the PIK3R2/PI3K/AKT/mTOR signalling pathway was involved in this effect. SKBR3/TR cells also showed increased sensitivity to trastuzumab mediated by miR‐126 in vivo. In conclusion, the above findings demonstrated that overexpression of miR‐126 or down‐regulation of its target gene may be a potential approach to overcome trastuzumab resistance in breast cancer cells.

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          A Brief Review on the Mechanisms of miRNA Regulation

          MicroRNAs (miRNAs) are a class of short, endogenously-initiated non-coding RNAs that post-transcriptionally control gene expression via either translational repression or mRNA degradation. It is becoming evident that miRNAs are playing significant roles in regulatory mechanisms operating in various organisms, including developmental timing and host-pathogen interactions as well as cell differentiation, proliferation, apoptosis and tumorigenesis. Likewise, as a regulatory element, miRNA itself is coordinatively modulated by multifarious effectors when carrying out basic functions, such as SNP, miRNA editing, methylation and circadian clock. This mini-review summarized the current understanding of interactions between miRNAs and their targets, including recent advancements in deciphering the regulatory mechanisms that control the biogenesis and functionality of miRNAs in various cellular processes.
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            Molecular mechanisms for tumour resistance to chemotherapy.

            Chemotherapy is one of the prevailing methods used to treat malignant tumours, but the outcome and prognosis of tumour patients are not optimistic. Cancer cells gradually generate resistance to almost all chemotherapeutic drugs via a variety of distinct mechanisms and pathways. Chemotherapeutic resistance, either intrinsic or acquired, is caused and sustained by reduced drug accumulation and increased drug export, alterations in drug targets and signalling transduction molecules, increased repair of drug-induced DNA damage, and evasion of apoptosis. In order to better understand the mechanisms of chemoresistance, this review highlights our current knowledge of the role of altered drug metabolism and transport and deregulation of apoptosis and autophagy in the development of tumour chemoresistance. Reduced intracellular activation of prodrugs (e.g. thiotepa and tegafur) or enhanced drug inactivation by Phase I and II enzymes contributes to the development of chemoresistance. Both primary and acquired resistance can be caused by alterations in the transport of anticancer drugs which is mediated by a variety of drug transporters such as P-glycoprotein (P-gp), multidrug resistance associated proteins, and breast cancer resistance protein. Presently there is a line of evidence indicating that deregulation of programmed cell death including apoptosis and autophagy is also an important mechanism for tumour resistance to anticancer drugs. Reversal of chemoresistance is likely via pharmacological and biological approaches. Further studies are warranted to grasp the full picture of how each type of cancer cells develop resistance to anticancer drugs and to identify novel strategies to overcome it.
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              A review of clinical aspects of breast cancer.

              Breast cancer is the most frequently diagnosed cancer in women and ranks second among causes for cancer related death in women. The ability to identify and diagnose breast cancer has improved markedly. Treatment decisions which were based in the past predominantly on the anatomic extent of the disease are shifting to the underlying biological mechanisms. Gene array technology has led to the recognition that breast cancer is a heterogeneous disease composed of different biological subtypes, and genetic profiling enables response to chemotherapy to be predicted. Breast conservation became an established standard of care and the oncoplastic approach enables wide excisions without compromising the natural shape of the breast. Sentinel lymph node biopsy has replaced axillary dissection as the standard procedure to stage the axilla and spared many patients the excess morbidity of axillary dissection. Targeted therapy to the oestrogen receptor plays a major role in systemic therapy; pathways responsible for endocrine resistance have been targeted as well. Biological therapy has been developed to target HER2 receptor and combination of antibody drug conjugates linked cytotoxic therapy to HER2 antibodies. Meaningful improvements in survival resulted from the new effective systemic agents and patients with metastasis are likely to have a longer survival.
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                Author and article information

                Contributors
                tongjingshan@gmail.com
                Journal
                J Cell Mol Med
                J. Cell. Mol. Med
                10.1111/(ISSN)1582-4934
                JCMM
                Journal of Cellular and Molecular Medicine
                John Wiley and Sons Inc. (Hoboken )
                1582-1838
                1582-4934
                15 May 2020
                July 2020
                : 24
                : 13 ( doiID: 10.1111/jcmm.v24.13 )
                : 7600-7608
                Affiliations
                [ 1 ] College of Chemical Engineering Northeast Electric Power University Jilin city China
                [ 2 ] Department of Pharmacology and Chemical Biology University of Pittsburgh School of Medicine Pittsburgh PA USA
                Author notes
                [*] [* ] Correspondence

                Jing‐Shan Tong, UPMC Hillman Cancer Center, 5117 Centre Avenue, Pittsburgh, PA 15213, USA.

                Email: tongjingshan@ 123456gmail.com

                Author information
                https://orcid.org/0000-0001-8244-9597
                Article
                JCMM15396
                10.1111/jcmm.15396
                7339158
                32410348
                06df385b-f2c0-48a6-8a46-538790f27cba
                © 2020 Northeast Electric Power University. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.

                This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                : 27 February 2020
                : 18 April 2020
                : 27 April 2020
                Page count
                Figures: 6, Tables: 0, Pages: 9, Words: 5201
                Categories
                Original Article
                Original Articles
                Custom metadata
                2.0
                July 2020
                Converter:WILEY_ML3GV2_TO_JATSPMC version:5.8.5 mode:remove_FC converted:07.07.2020

                Molecular medicine
                breast cancer,mir‐126,pik3r2,pik3r2/pi3k/akt/mtor,trastuzumab resistance
                Molecular medicine
                breast cancer, mir‐126, pik3r2, pik3r2/pi3k/akt/mtor, trastuzumab resistance

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