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      Aberrant Promoter Methylation of YAP Gene and its Subsequent Downregulation in Indian Breast Cancer Patients

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          Abstract

          Background

          YAP, a potent oncogene and major downstream effector of the mammalian Hippo tumor suppressor pathway can act as either oncogene or tumor suppressor gene based on the type of tissue involved. Despite various studies, the role and mechanism through which YAP mediates its tumor suppressor or oncogenic effects are not yet fully understood. Therefore in the present study we aimed to investigate YAP at DNA, mRNA and protein level and also attempted to correlate our molecular findings with various clinicopathological variables of the patients.

          Methods

          The study comprised of a total 137 genetically unrelated women with sporadic breast cancer cases and normal adjacent tissues not infiltrated with tumor. Mutation of YAP gene was analyzed by automated DNA sequencing. YAP promoter methylation was studied using MS-PCR. Expression at mRNA and protein level was studied using qPCR and IHC respectively.

          Results

          In our study YAP mRNA expression was found to be 8.65 ± 6.17 fold downregulated in 67.15% cases. The expression of YAP when analyzed at the protein level by IHC was found to be absent in 78.83% cases. Results from MS-PCR analysis showed that YAP promoter methylation plays an important role in declining the expression of YAP protein. The absence of YAP protein coincided with 86.60% methylated cases thereby showing a very strong correlation ( p = 0.001). We also investigated YAP mutation at the major check point sites in the Hippo pathway and observed no mutation. A significant association was observed on correlating mRNA expression with clinical stages ( p = 0.038) and protein expression with ER status ( p = 0.018) among Indian breast cancer patients.

          Conclusion

          The expression of YAP was found to be downregulated in response to aberrant promoter methylation. The downregulation of YAP are consistent with previous studies suggesting it to have a tumor suppressive role in breast cancer. We did not observe any mutation at the major check point sites in the Hippo pathway.

          Electronic supplementary material

          The online version of this article (10.1186/s12885-018-4627-8) contains supplementary material, which is available to authorized users.

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          Most cited references17

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          Molecular biology in breast cancer: intrinsic subtypes and signaling pathways.

          The last decade has brought a breakthrough in the knowledge of the biology of breast cancer. The technological development, and in particular the high throughput technologies, have allowed researchers to inquire more deeply into the nature of the disease through the comparative study of large numbers of samples. The classification of breast cancer by traditional parameters has been joined by rankings based on gene expression. Among the most popular platforms are MammaPrint®, Oncotype DX® the wound-response model, the rate of two genes model, the genomic grade index and the intrinsic subtype model. The latter one provides the amplest biological information and allows for the classification of breast cancer into six intrinsic subtypes: luminal A, luminal B, HER2-enriched, basal-like, normal breast and claudin-low. These new classifications are not yet fully applicable to clinical practice not only because they have not been standardized, but also because they entail a substantial economic outlay. Nevertheless, they have provided valuable information on tumor biology that has led to a better understanding of the signaling pathways governing the processes of formation, maintenance and expansion of the tumors. Researchers now know more about the HER2, estrogen receptor, IGF1R, PI3K/AKT, mTOR, AMPK and angiogenesis pathways which has allowed for the development of new targeted therapeutics now being tested in ongoing clinical trials. In general, one can say that the last decade has changed the way researchers understand, classify and study breast cancer, and it has reshaped the way doctors diagnose and treat this disease. In addition, it has undoubtedly changed the search for alternative therapies by integrating molecular studies and the selection of study populations based on their molecular markers into clinical trials. The present review summarizes the advances that have allowed researchers to both better classify the disease, as well as explore some of the most important signaling pathways. Copyright © 2011 Elsevier Ltd. All rights reserved.
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            Breast cancer: origins and evolution.

            Breast cancer is not a single disease, but rather is composed of distinct subtypes associated with different clinical outcomes. Understanding this heterogeneity is key for the development of targeted cancer-preventative and -therapeutic interventions. Current models explaining inter- and intratumoral diversity are the cancer stem cell and the clonal evolution hypotheses. Although tumor initiation and progression are predominantly driven by acquired genetic alterations, recent data implicate a role for microenvironmental and epigenetic changes as well. Comprehensive unbiased studies of tumors and patient populations have significantly advanced our molecular understanding of breast cancer, but translating these findings into clinical practice remains a challenge.
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              Aberrant patterns of DNA methylation, chromatin formation and gene expression in cancer.

              Gene function in cancer can be disrupted either through genetic alterations, which directly mutate or delete genes, or epigenetic alterations, which alter the heritable state of gene expression. The latter events are mediated by formation of transcriptionally repressive chromatin states around gene transcription start sites and an associated gain of methylation in normally unmethylated CpG islands in these regions. The genes affected include over half of the tumor suppressor genes that cause familial cancers when mutated in the germline; the selective advantage for genetic and epigenetic dysfunction in these genes is very similar. The aberrant methylation can begin very early in tumor progression and mediate most of the important pathway abnormalities in cancer including loss of cell cycle control, altered function of transcription factors, altered receptor function, disruption of normal cell-cell and cell-substratum interaction, inactivation of signal transduction pathways, loss of apoptotic signals and genetic instability. The active role of the aberrant methylation in transcriptional silencing of genes is becoming increasingly understood and involves a synergy between the methylation and histone deacetylase (HDAC) activity. This synergy can be mediated directly by HDAC interaction with DNA methylating enzymes and by recruitment through complexes involving methyl-cytosine binding proteins. In the translational arena, the promoter hypermethylation changes hold great promise as DNA tumor markers and their potentially reversible state creates a target for cancer therapeutic strategies involving gene reactivation.
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                Author and article information

                Contributors
                realsumayya@gmail.com
                farahkhan8383@gmail.com
                b4uasad@gmail.com
                aasifkaleemi@gmail.com
                svsdeo@aiims.ac.in
                nshukla@aiims.ac.in
                91-9818298707 , akhtarhusain2000@yahoo.com
                Journal
                BMC Cancer
                BMC Cancer
                BMC Cancer
                BioMed Central (London )
                1471-2407
                3 July 2018
                3 July 2018
                2018
                : 18
                : 711
                Affiliations
                [1 ]ISNI 0000 0004 0498 8255, GRID grid.411818.5, Department of Biosciences, , Jamia Millia Islamia, ; New Delhi, 110025 India
                [2 ]ISNI 0000 0004 1767 6103, GRID grid.413618.9, Department of Surgical Oncology, , All India Institute of Medical Science, ; New Delhi, 110608 India
                Author information
                http://orcid.org/0000-0001-5569-4941
                Article
                4627
                10.1186/s12885-018-4627-8
                6031145
                29970036
                28c19b81-5a5c-4e9d-8f1a-7dffb20789ec
                © The Author(s). 2018

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 7 December 2017
                : 21 June 2018
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100001501, University Grants Commission;
                Award ID: F1-17.1/2015-16/MANF-2015-17-GUJ-65323
                Award Recipient :
                Categories
                Research Article
                Custom metadata
                © The Author(s) 2018

                Oncology & Radiotherapy
                downregulation,hippo pathway,mrna,tumor suppressor gene,yap
                Oncology & Radiotherapy
                downregulation, hippo pathway, mrna, tumor suppressor gene, yap

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