Department Of Human Genetics And Molecular Medicine

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Author: search.filters.author.Chander, HarishHas files: Yes

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    KIBRA Team Up with Partners to Promote Breast Cancer Metastasis
    (Springer, 2019) Singh G; Mishra, S; Chander, Harish
    Among women, breast cancer is the most frequently diagnosed cancer. Most of the breast cancers represent metastasis to distant organs at the time of diagnosis and accounts for the majority of deaths. Metastasis is characterized by many genetic aberrations including mutations, overexpression of oncogenes etc. KIBRA (KIdney/BRAin protein), a scaffolding protein is recently described as an important player in the process of invasion and metastasis. The Kidney/BRAin protein through its different domains interacts with various proteins to couple cytoskeleton arrangement, cell polarity and migration. N terminal and C terminal of the protein contains the WW, Internal C 2 & putative class III PDZ domain that interacts with DDR1, DLC1 & PKCζ. These protein-protein interactions equip the breast cancer cells to invade and metastasize. Here, we discuss a comprehensive knowledge about the KIBRA protein, its domains and the interacting partners involved in metastasis of breast cancer. © 2019, Arányi Lajos Foundation.
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    Awakening the "guardian of genome": reactivation of mutant p53.
    (Springer, 2019) Binayke, Akshay; Mishra, Sarthak; Suman, Prabhat; Das, Suman; Chander, Harish
    The role of tumor suppressor protein p53 is undeniable in the suppression of cancer upon oncogenic stress. It induces diverse conditions such as cell-cycle arrest, cell death, and senescence to protect the cell from carcinogenesis. The rate of mutations in p53 gene nearly accounts for 50% of the human cancers. Upon mutations, the conformation gets altered and becomes non-native. Mutant p53 displays long half-life and accumulates in the nucleus and interacts with oncoproteins to promote carcinogenesis and these interactions present a formidable challenge for clinicians in therapy of the disease. Variety of approaches have been developed, through which native-like function of p53 can be restored, such as restoration of the native-like structure of p53, activating the p53 family members, etc. Modern scientific techniques have led to the discovery of a variety of molecules to reactivate mutant p53 and restore its transcriptional activity. These compounds include small molecules, various peptides, and phytochemicals. In this review article, we comprehensively discuss these molecules to reactivate mutant p53 to restore the normal function with a particular focus on molecular mechanisms.
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    Recent advances in HER2 positive breast cancer epigenetics: Susceptibility and therapeutic strategies
    (Elsevier Masson SAS, 2017) Singla, Heena; Ludhiadch, Abhilash; Kaur, Raman Preet; Chander, Harish; Kumar, Vinod; Munshi, Anjana
    HER2 amplification/overexpression accounts for aggressive clinical features of HER2 positive breast cancer. Epigenetic changes including DNA methylation, histone modifications and ncRNAs/miRNAs are associated with regulation of DNA chromatin and specifically, gene transcription. Hence, these produce eminent effects upon proto-oncogenes, tumor-suppressors and key cancer-regulatory signaling pathways. Understanding of epigenomic regulation of HER2 overexpression and signaling may help uncover the unmatchable physiology of HER2 gene/protein. Moreover, this may also aid in resolving the major issue of resistance-development towards HER2 targeted agents (trastuzumab and lapatinib), since epigenetic alterations are important therapeutic markers and modulate the response towards HER2 targeted therapy. Therefore, in this review the information regarding various epigenetic markers implicated in HER2 positive breast cancer susceptibility and therapeutic-strategies has been compiled. ? 2017 Elsevier Masson SAS
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    Toca-1 is suppressed by p53 to limit breast cancer cell invasion and tumor metastasis
    (BioMed Central Ltd., 2014) Chander, Harish; Brien, Colin D; Truesdell, Peter; Kathleen, Watt; Meens, Jalna; Schick, Colleen; Germain, Doris; Craig, Andrew WB
    Introduction: Transducer of Cdc42-dependent actin assembly-1 (Toca-1) recruits actin regulatory proteins to invadopodia, and promotes breast tumor metastasis. Since metastatic breast tumors frequently harbor mutations in the tumor suppressor p53, we tested whether p53 regulates Toca-1 expression. Methods: Normal mammary epithelial cells (HBL-100, MCF10A) and breast cancer cell lines expressing wild-type (WT) p53 (DU4475, MTLn3) were treated with camptothecin or Nutlin-3 to stabilize p53 to test effects on Toca-1 mRNA and protein levels. Chromatin immunoprecipitation (ChIP) assays were performed to identify p53 binding site in Toca-1 gene. Stable silencing of p53 and Toca-1 were performed in MTLn3 cells to test effects on invadopodia and cell invasion in vitro, and tumor metastasis in vivo. Results: We observed that breast cancer cell lines with mutant p53 have high levels of Toca-1 compared to those with WT p53. Stabilization of WT p53 led to further reduction in Toca-1 mRNA and protein levels in normal breast epithelial cells and breast cancer cells. ChIP assays revealed p53 binding within intron 2 of toca1, and reduced histone acetylation within its promoter region upon p53 upregulation or activation. Stable silencing of WT p53 in MTLn3 cells led to increased extracellular matrix degradation and cell invasion compared to control cells. Interestingly, the combined silencing of p53 and Toca-1 led to a partial rescue of these effects of p53 silencing in vitro and reduced lung metastases in mice. In human breast tumors, Toca-1 levels were high in subtypes with frequent p53 mutations, and high Toca-1 transcript levels correlated with increased risk of relapse. Conclusions: Based on these findings, we conclude that loss of p53 tumor suppressor function in breast cancers leads to upregulation of Toca-1, and results in enhanced risk of developing metastatic disease. ? Chander et al.
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    High expression of FBP17 in invasive breast cancer cells promotes invadopodia formation
    (Humana Press Inc., 2018) Suman, Prabhat; Mishra, Sarthak; Chander, Harish; Suman, P.; Mishra, S.; Chander, H.
    Metastatic spread of the cancer is usually the consequence of the activation of signaling pathways that generate cell motility and tissue invasion. Metastasis involves the reorganization of cytoskeleton and cell shape for the swift movement of the cells through extracellular matrix. Previously, we have described the invasive and metastatic role played by one of the members (Toca-1) of CIP4 subfamily of F-BAR proteins. In the present study, we address the role of another member (FBP17) of same family in the invasion breast cancer cells. Here, we report that the formin-binding protein 17 (FBP17) is highly expressed at both mRNA and protein levels in breast cancer cells. The study showed the association of FBP17 with cytoskeletal actin regulatory proteins like dynamin and cortactin. To determine its role in extracellular matrix (ECM) degradation, we achieved stable knockdown of FBP17 in MDA-MB-231 cells. FBP17 knockdown cells showed a defect and were found to be compromised in the degradation of ECM indicating the role of FBP17 in the invasion of breast cancer cells. Our results suggest that FBP17 is highly expressed in breast cancer cells and facilitates the invasion of breast cancer cells. ? 2018, Springer Science+Business Media, LLC, part of Springer Nature.