Department Of Human Genetics And Molecular Medicine
Permanent URI for this communityhttps://kr.cup.edu.in/handle/32116/103
Browse
12 results
Search Results
Item Brain metastasis in breast cancer: focus on genes and signaling pathways involved, blood�brain barrier and treatment strategies(Springer Science and Business Media Deutschland GmbH, 2023-03-10T00:00:00) Chhichholiya, Yogita; Ruthuparna, Malayil; Velagaleti, Harini; Munshi, AnjanaBreast cancer�(BC) is one of the most prevalent types of cancer in women. Despite advancement in early detection and efficient treatment, recurrence and metastasis continue to pose a significant risk to the life of BC patients. Brain metastasis�(BM) reported in 17�20 percent of BC patients is considered as a major cause of mortality and morbidity in these patients. BM includes various steps from primary breast tumor to secondary tumor formation. Various steps involved are primary tumor formation, angiogenesis, invasion, extravasation, and brain colonization. Genes involved in different pathways have been reported to be associated with BC cells metastasizing to the brain. ADAM8 gene, EN1 transcription factor, WNT, and VEGF signaling pathway have been associated with primary breast tumor; MMP1, COX2, XCR4, PI3k/Akt, ERK and MAPK pathways in angiogenesis; Noth, CD44, Zo-1, CEMIP, S0X2 and OLIG2 are involved in invasion, extravasation and colonization, respectively. In addition, the blood�brain barrier is also a key factor in BM. Dysregulation of cell junctions, tumor microenvironment and loss of function of microglia leads to BBB disruption ultimately resulting in BM. Various therapeutic strategies are currently used to control the BM in BC. Oncolytic virus therapy, immune checkpoint inhibitors, mTOR-PI3k inhibitors and immunotherapy have been developed to target various genes involved in BM in BC. In addition, RNA interference (RNAi) and CRISPR/Cas9 are novel interventions in the field of BCBM where research to validate these and clinical trials are being carried out. Gaining a better knowledge of metastasis biology is critical for establishing better treatment methods and attaining long-term therapeutic efficacies against BC. The current review has been compiled with an aim to evaluate the role of various genes and signaling pathways involved in multiple steps of BM in BC. The therapeutic strategies being used currently and the novel ones being explored to control BM in BC have also been discussed at length. � 2023, The Author(s), under exclusive licence to Federaci�n de Sociedades Espa�olas de Oncolog�a (FESEO).Item High levels of unfolded protein response component CHAC1 associates with cancer progression signatures in malignant breast cancer tissues(Springer Science and Business Media Deutschland GmbH, 2022-08-05T00:00:00) Mehta, Vikrant; Suman, Prabhat; Chander, HarishPurpose: The aberrant mRNA expression of a UPR component Cation transport regulator homolog 1 (CHAC1) has been reported to be associated with poor survival in breast and ovarian cancer patients, however, the expression of CHAC1 at protein levels in malignant breast tissues is underreported. The following study aimed at analyzing CHAC1 protein expression in malignant breast cancer tissues. Methods: Evaluation of CHAC1 expression in invasive ductal carcinomas (IDCs) with known ER, PR, and HER2 status was carried out using immunohistochemistry (IHC) with CHAC1 specific antibody. The Human breast cancer tissue microarray (TMA, cat# BR1503f, US Biomax, Inc., Rockville, MD) was used to determine CHAC1 expression. The analysis of CHAC1 IHC was done to determine its expression in terms of molecular subtypes of breast cancer, lymph node status, and proliferation index using Qu-Path software. Survival analysis was studied with a Kaplan�Meier plotter. Results: Immunohistochemical analysis of CHAC1 in breast cancer tissues showed significant up-regulation of CHAC1 as compared to the adjacent normal and benign tissues. Interestingly, CHAC1 immunostaining revealed high expression in tumor tissues with high proliferation and positive lymph node metastasis suggesting that CHAC1 might have an important role to play in breast cancer progression. Furthermore, high CHAC1 expression is associated with poor overall survival (OS) in large breast cancer patient cohorts. Conclusion: As a higher expression of CHAC1 was observed in tissue cores with high Ki67 index and positive lymph node metastasis it may be concluded that enhanced CHAC1 expression correlates with proliferation and metastasis. The further analysis of breast cancer patients� survival data through KM plot indicated that high CHAC1 expression is associated with a bad prognosis hinting that CHAC1 may have a possible prognostic significance in breast cancer. � 2022, The Author(s), under exclusive licence to Federaci�n de Sociedades Espa�olas de Oncolog�a (FESEO).Item Prognostic significance of CHAC1 expression in breast cancer(Springer Science and Business Media B.V., 2022-06-21T00:00:00) Mehta, Vikrant; Meena, Jaipal; Kasana, Harit; Munshi, Anjana; Chander, HarishBackground: An emerging component of Unfolded Protein Response (UPR) pathway, cation transport regulator homolog 1 (CHAC1) has been conferred with the ability to degrade intracellular glutathione and induce apoptosis, however, many reports have suggested a role of CHAC1 in cancer progression. Our study aimed to investigate CHAC1 mRNA levels in large breast cancer datasets using online tools and both mRNA and protein levels in different breast cancer cell lines. Methods and results: Analysis of clinical information from various online tools (UALCAN, GEPIA2, TIMER2, GENT2, UCSCXena, bcGenExMiner 4.8, Km Plotter, and Enrichr) was done to elucidate the CHAC1 mRNA expression in large breast cancer patient dataset and its correlation with disease progression. Later, in vitro techniques were employed to explore the mRNA and protein expression of CHAC1 in breast cancer cell lines. Evidence from bioinformatics analysis as well as in vitro studies indicated a high overall expression of CHAC1 in breast tumor samples and had a significant impact on the prognosis and survival of patients. Enhanced CHAC1 levels in the aggressive breast tumor subtypes such as Human Epidermal growth factor receptor 2 (HER2) and Triple Negative Breast Cancer (TNBC) were evident. Our findings hint toward the possible role of CHAC1 in facilitating the aggressiveness of breast cancer and the disease outcome. Conclusion: In summary, CHAC1 is constantly up-regulated in breast cancer leading to a poor prognosis. CHAC1, therefore, could be a promising candidate in the analysis of breast cancer diagnosis and prognosis. � 2022, The Author(s), under exclusive licence to Springer Nature B.V.Item Structural assembly of Polycomb group protein and Insight of EZH2 in cancer progression: A review(Wolters Kluwer Medknow Publications, 2020-10-13T00:00:00) Gautam, Nisha; Kaur, Mandeep; Kaur, SatbirPolycomb group proteins (PcG) are multi-subunit structure, consisting of polycomb repressive complex 1 (PRC1), PRC2/3, and pleiohomeotic repressive complex. PRC1 is made up of PHC, BMI-1, CBX, and Ring 1A/B. PRC2 protein complex included embryonic ectoderm development, PCL, SUZ12, SET domain, enhancer of zeste homolog-2 protein (EZH2), and Nurf55. The third subunit PhoRC consists of Pho and DSFMBT subunits. One of the important subunits of PcG group of protein is EZH2 (a histone methyltransferase), which catalyzes tri-methylation of histone H3 at Lys 27 (H3K27me3) to regulate gene expression through epigenetic machinery and induces silencing of specific gene transcription. In case of breast cancer and prostate cancer, EZH2 is very well studied. Evidence shows that EZH2 is overexpressed and mutated in a variety of human cancers, rendering EZH2 an attractive target for the design of new chemotherapeutic drugs in cancer. EZH2 also functions both as a transcriptional suppressor and a transcriptional co-activator, depending on H3K27me3 or its absence. In this review, we summarized various studies reported till date, elucidating the structure of PRC2 complex, various mechanisms involved with this, and highlighting the role of EZH2 in breast cancer and prostate cancer progression. An increased understanding of the mechanisms that underlie the pathogenesis of wide spectrum of cancers is therefore needed to develop novel therapeutic approaches for this disease and to improve the quality of life in patients. � 2021 Journal of Cancer Research and Therapeutics | Published by Wolters Kluwer-Medknow.Item Pharmacogenetics of Cyclophosphamide and Doxorubicin in Breast Cancer & Synthesis and Biological Evaluation of New Imidazole Based Putative Anticancer Agents(Central University of Punjab, 2019) Kalra, Sourav; Munshi, Anjana & Kumar, RajBreast cancer is the second most prevalent cancer in women worldwide. It is treated by various strategies, including surgery, radiation therapy, hormonal therapy, targeted therapy and chemotherapy. Chemotherapeutic drugs like cyclophosphamide, doxorubicin, paclitaxel and docetaxal are used to treat the cancer either alone or in combination with other therapies, such as surgery, radiation, or hormone therapy depending upon the stage and the location of cancer cells. Cyclophosphamide and doxorubicin are also given in combination known as adjuvant chemotherapy (AC therapy). However, all the patients do not get benefited by this treatment. Inter-individual response in patients on AC therapy might be on account of variation in genes involved in pharmacokinetics and pharmacodynamics of cyclophosphamide and doxorubicin. Therefore, a detailed pharmacogenomic study was performed using global screening array microchip that contains more than 700,000 upto-date markers, optimized for human genome-wide backbone for unparalleled genomic coverage, including clinically relevant content and all pharma GKB markers. Two gene variants CYP2C19*2 and ALDH1A1*2 involved in the metabolism of cyclophosphamide were found to influence the clinical outcome in breast cancer patients on AC therapy in Malwa region of Punjab. However, none of the gene variants involved in pharmacokinetics vi and pharmacodynamics of doxorubicin were found to be involved in the interindividual response. Therefore, patients should be screened for CYP2C19*2 and ALDH1A1*2 gene variants before prescribing the AC therapy. Due to several problems with the chemotherapeutic drugs the new therapeutic strategies have been introduced in the recent past that have led to the target based drug design. In an attempt to develop new drugs for targeting breast cancer, imidazole based anti-cancer agents were computationally designed and synthesized (Series 1 and Series 2). All the compounds were first assessed for their anti-proliferative activity in T47D, MDA-MB-231, and MCF7 breast cancer cell lines. Lead compounds with IC50 values less than 10 µM in at least two cell lines such as A12, SA1, SA3, SA8, SA11 from series 1 and SRA1, SRA8, SRA12, SRA14 from series 2 were selected for further evaluation of their cytotoxicity (if any) against normal HBL100 and HPBMC cell lines. Two compounds SRA12 and SRA14 were found to be non toxic and upon lead optimisation through in silico approach at CDK4/6 protein afforded ANP12 that emerged out to be potent anticancer compound and exhibited good anti- breast cancer profile. Compounds ANP12 and SRA14 (from series 2) elevated ROS levels, altered mitochondrial membrane potential and induced cell cycle arrest at G0 phase indicating their anticancer mechanism possibly via CDK4/6 inhibiton.Item Epidemiological factors, genetic and inflammatory markers in the development of Breast Cancer in Malwa region of Punjab(Central University of Punjab, 2019) Kaur, Raman Preet; Munshi, AnjanaBreast cancer is one of the most common malignancy among women and also the leading cause of death worldwide. Malwa region of Punjab is reported to have the highest number of cancer cases in comparison with the other two regions (Doaba and Majha). The cancer prevalence in this region was reported to be 1089 per million/year in 2013 (with around 35.7% breast cancer cases), as per the Department of Health and Family Welfare. The aim of present study was to carry out a systematic epidemiological study, explore the contribution of mutations in breast cancer susceptibility genes, and gene-gene interactions in the development of breast cancer in Malwa region of Punjab. In addition, exome sequencing of the male breast cancer patients was carried out to identify the specific genetic alterations associated with the disease in this region. Inflammatory markers (cytokines and C-reactive protein levels) and albumin levels were also estimated to evaluate their association with the development of the disease and outcome including death, recurrence, and metastasis. Three hundred breast cancer patients (Female:Male = 296:4) were recruited from Guru Gobind Singh Medical College & Hospital, Faridkot and Max Hospital, Bathinda. Equal number of age and sex matched controls were also recruited from the same demographic area with the help of Rural Medical Officers. The study was approved by the ethics committee of the Central University of Punjab. The information regarding the demographic profile was collected in a structured questionnaire. The blood samples were collected with the written informed consent of the patients. DNA isolation was carried out by phenol:chloroform method. The genotyping was performed by global screening array (GSA; Illumina Infinium HD), exome sequencing and PCRRFLP. The levels of inflammatory markers and albumin were estimated by using BD Accuri flow cytometer and ERBA 200 bioautoanlyzer. The association of demographic features with the disease was evaluated by Student’s t-test. Mann-Whitney test was used to evaluate the association of CRP, cytokines and albumin with the outcome. Softwares including R/Bioconductor and OpenEpi were used to evaluate the association of pathogenic alterations with the disease. The influence of novel mutations on protein structure was examined by molecular dynamics simulations. Follow-up of the patients was carried out with the help of clinicians. Infiltrating breast cancer was the most common type of breast cancer in patients. Triple negative breast cancer was observed in 17.5% of patients. All the patients underwent modified radical mastectomy and lumpectomy. The breast cancer patients v carried mono/biallelic alteration in 15 breast cancer susceptibility genes including ATM, BRCA2, STK11, PTEN, BRIP1, CHEK2, RAD51C, NBN, MLH1, MSH2, MSH6, MUTYH, CDK2NA, CYTB and MTHFR as per the results of GSA. Familial cases of breast cancer were found to carry alterations in ATM, BRCA2, STK11, PTEN, BRIP1, CHEK2, RAD51C, NBN, MLH1, MSH2, MSH6, MUTYH, CDK2NA, CYTB and MTHFR genes. Novel pathogenic variants in PALB2, STK11, CHEK2, BRCA2, BARD1, BRIP1, NF2, and FZR1 genes were detected in male breast cancer patients. These were found to alter the specific protein structure. Among the inflammatory markers CRP, IL-6 & IL17A were found to be significantly associated with poor outcome in the patients. High levels of albumin were also found to be associated with increased overall survival. In conclusion, results of this study can guide to develop a panel to test the breast cancer patients for pathogenic mutations from Malwa region of Punjab. The present study suggests that the screening of BRCA2, MSH2, and MLH1 should be carried out in general population since previous studies have reported that these mutations increase the risk of breast cancer by 10-fold and accordingly evidence-based management recommendations can be given to the individuals bearing these mutations. Familial breast cancer patients need to be screened for BRAD1, MSH2, MLH1, BRCA2 and CYTB genes since these alterations were observed in familial breast cancer patients. IL-6, IL-17A, CRP, and albumin can be used as prognostic markers for breast cancer in Malwa region of Punjab.Item Transcriptional Regulation of Pro-metastatic Protein Formin Binding Protein17 (FBP17) in Breast Cancer(Central University of Punjab, 2018) Suman, Prabhat; Chander, HarishBreast cancer is a diverse disease with multiple subtypes. Among the different molecular subtypes, triple negative breast cancers (TNBC) harbor frequent mutation in tumor suppressor p53. Recently it was shown that p53 suppresses Transducer of Cdc42-dependent Actin assembly-1 (Toca-1) that belongs to CIP4 subfamily. Members of the family including FBP17 play a significant role in actin assembly. FBP17 and Toca-1 have been recognized as key scaffolds for recruiting actin regulatory protein to promote invadopodia formation. Metastatic cancer cells form invadopodia and the F-BAR proteins are shown to enhance invadopodia. FBP17 consists of F-BAR domain, Cdc-15 homology, putative Rho-binding domain and SH3 domain. In the present study, we elucidate the correlation between p53 and FBP17 that affects metastatic potential of cancer cells. We observed that cancer cell lines with mutated p53 have high levels of FBP17. Activation of wild type p53 reduces FBP17 both at mRNA and protein level. Further, the ectopic expression of wild type p53 reduces FBP17 whereas mutant p53 failed to do so. Different cell lines and different methods of p53 activation were used to study the p53-FBP17 axis. Chromatin immunoprecipitation studies revealed the binding of p53 in the promoter of FBP17. The metastatic potential of breast cancer cells was observed after double knock down of both p53 and FBP17. Interestingly, we found that combined silencing of these two proteins led to a partial rescue of invasion upon p53 silencing in vitro. In conclusion we suggest that p53 controls FBP17 expression and FBP17 contributes to the invasion of cancer cells upon loss of p53 activity in cancer.Item Dietary Patterns and Breast Cancer Risk: A Multi-Centre Case Control Study among North Indian Women(mdpi, 2018) Shridhar, Krithiga; Singh, Gurpreet; Dey, Subhojit; Dhatt, Sarvdeep Singh; Gill, Jatinder Paul Singh; Goodman, Michael; Magsumbol, Melina Samar; Pearce, Neil; Singh, Sandeep; Singh, Archna; Singh, Preeti; Thakur, Jarnail Singh; Dhillon, Preet KaurEvidence from India, a country with unique and distinct food intake patterns often characterized by lifelong adherence, may offer important insight into the role of diet in breast cancer etiology. We evaluated the association between Indian dietary patterns and breast cancer risk in a multi-centre case-control study conducted in the North Indian states of Punjab and Haryana. Eligible cases were women 30–69 years of age, with newly diagnosed, biopsy-confirmed breast cancer recruited from hospitals or population-based cancer registries. Controls (hospital- or population-based) were frequency matched to the cases on age and region (Punjab or Haryana). Information about diet, lifestyle, reproductive and socio-demographic factors was collected using a structured interviewer-administered questionnaire. All participants were characterized as non-vegetarians, lacto-vegetarians (those who consumed no animal products except dairy) or lacto-ovo-vegetarians (persons whose diet also included eggs). The study population included 400 breast cancer cases and 354 controls. Most (62%) were lacto-ovo-vegetarians. Breast cancer risk was lower in lacto-ovo-vegetarians compared to both non-vegetarians and lacto-vegetarians with odds ratios (95% confidence intervals) of 0.6 (0.3–0.9) and 0.4 (0.3–0.7), respectively. The unexpected difference between lacto-ovo-vegetarian and lacto-vegetarian dietary patterns could be due to egg-consumption patterns which requires confirmation and further investigation.Item Role of p53 gene in breast cancer: Focus on mutation spectrum and therapeutic strategies(Bentham Science Publishers B.V., 2018) Kaur, Raman Preet; Vasudeva, Kanika; Kumar, Roshan; Munshi, AnjanaTP53 is a tumor suppressor gene which is commonly mutated in various cancers including breast cancer. Alterations in the gene lead to an altered expression of various genes that are directly or indirectly under the transcriptional control of p53. This results in malfunctioning of DNA damage repair pathways, cell-cycle arrest, chromatin remodeling and apoptosis. Different mutations in TP53 gene have been reported in different ethnic groups and exon 4 and intron 3 are reported to be frequently mutated in breast cancer patients especially triple-negative breast cancer. Increased global burden of TP53 mutated breast tumors has paved the path for various therapies targeting p53/TP53. Numerous molecules including nutilins, MI series, RO5693, PRIMA-1, RITA, etc. have been developed. Majority of these restore p53/TP53 function by targeting negative regulators of p53/TP53, wtp53/TP53 (wild-type) and mtp53/TP53 (mutant). Most of these molecules are in the preclinical phase except for two APR-246 and COTI-2 that have progressed to clinical trials. The current review has been compiled with an aim to give an overview of mutations in p53 across various ethnic groups, the effect of these alterations on TP53 function and the therapeutic strategies developed till date targeting p53/TP53 especially in breast cancer.Item Identification of Novel lncRNA in Breast Cancer Cell Line(Central University of Punjab, 2018) Sharma, Divya; Singh,SandeepLong non-coding RNA(lncRNA) is RNA transcript having size of more 200 nucleotides and low number of exons are present due to which it expressed at lower level in specific tissues. Mainly the lncRNA is involved in gene regulations such as epigenetic regulation, chromatin remodeling and posttranscriptional regulations.The localization of lncrna is mainly in nucleus but there is considerable amount of lncrna present in cytoplasm. Lncrna can also target the mitochondrial genome. Identification of the targets of lncrna on mitochondrial genome helps to find the relationship between lncrna and mitochondrial functions which further helps in diagnosis and in therapy of the mitochondrial related diseases. One such lncRNA is MIR503HG, which act as a tumor suppressor in breast cancer cell line. Expression of lncRNA MIR503HG was analyzed in normoxic and hypoxic conditions upon the treatments of three different types of drugs on breast cancer cell line. The study of expression level of lncRNA MIR503HG in breast cancer cell line suggest a new cancer biomarker.