scholarly journals Abnormal Hypermethylation of CpG Dinucleotides in Promoter Regions of Matrix Metalloproteinases Genes in Breast Cancer and its Relation to Epigenomic Subtypes and HER2 Overexpression

Biomedicines ◽  
2020 ◽  
Vol 8 (5) ◽  
pp. 116
Author(s):  
Olga A. Simonova ◽  
Ekaterina B. Kuznetsova ◽  
Alexander S. Tanas ◽  
Viktoria V. Rudenko ◽  
Elena V. Poddubskaya ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Matrix Metalloproteinases ◽  
Cpg Island ◽  
Breast Cancer Subtype ◽  
Ectopic Expression ◽  
Her2 Overexpression ◽  
Restriction Enzyme Digestion ◽  
Promoter Regions ◽  
Cpg Dinucleotides ◽  
Mmp Genes

Matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) substantially contribute to the regulation of intercellular interactions and thereby play a role in maintaining the tissue structure and function. We examined methylation of a subset of 5’-cytosine-phosphate-guanine-3’ (CpG) dinucleotides in promoter regions of the MMP2, MMP11, MMP14, MMP15, MMP16, MMP17, MMP21, MMP23B, MMP24, MMP25, MMP28, TIMP1, TIMP2, TIMP3, and TIMP4 genes by methylation-sensitive restriction enzyme digestion PCR. In our collection of 183 breast cancer samples, abnormal hypermethylation was observed for CpGs in MMP2, MMP23B, MMP24, MMP25, and MMP28 promoter regions. The non-methylated status of the examined CpGs in promoter regions of MMP2, MMP23B, MMP24, MMP25, and MMP28 in tumors was associated with low HER2 expression, while the group of samples with abnormal hypermethylation of at least two of these MMP genes was significantly enriched with HER2-positive tumors. Abnormal methylation of MMP24 and MMP25 was significantly associated with a CpG island hypermethylated breast cancer subtype discovered by genome-wide DNA bisulfite sequencing. Our results indicate that abnormal hypermethylation of at least several MMP genes promoters is a secondary event not directly functional in breast cancer (BC) pathogenesis. We suggest that it is elevated and/or ectopic expression, rather than methylation-driven silencing, that might link MMPs to tumorigenesis.

Polymorphisms of the promoter regions of matrix metalloproteinases genes MMP-1 and MMP-9 in breast cancer

2005 ◽  
Vol 95 (1) ◽  
pp. 65-72 ◽  
Author(s):  
Karolina Przybylowska ◽  
Anita Kluczna ◽  
Marek Zadrozny ◽  
Tadeusz Krawczyk ◽  
Andrzej Kulig ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Matrix Metalloproteinases ◽  
Promoter Regions

scholarly journals Targeting PML in triple negative breast cancer elicits growth suppression and senescence

2019 ◽  
Vol 27 (4) ◽  
pp. 1186-1199 ◽  
Author(s):  
Leire Arreal ◽  
Marco Piva ◽  
Sonia Fernández ◽  
Ajinkya Revandkar ◽  
Ariane Schaub- Clerigué ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Cells ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Cell Function ◽  
Breast Cancer Subtype ◽  
Growth Arrest ◽  
Promoter Regions

Abstract Oncogene addiction postulates that the survival and growth of certain tumor cells is dependent upon the activity of one oncogene, despite their multiple genetic and epigenetic abnormalities. This phenomenon provides a foundation for molecular targeted therapy and a rationale for oncogene-based stratification. We have previously reported that the Promyelocytic Leukemia protein (PML) is upregulated in triple negative breast cancer (TNBC) and it regulates cancer-initiating cell function, thus suggesting that this protein can be therapeutically targeted in combination with PML-based stratification. However, the effects of PML perturbation on the bulk of tumor cells remained poorly understood. Here we demonstrate that TNBC cells are addicted to the expression of this nuclear protein. PML inhibition led to a remarkable growth arrest combined with features of senescence in vitro and in vivo. Mechanistically, the growth arrest and senescence were associated to a decrease in MYC and PIM1 kinase levels, with the subsequent accumulation of CDKN1B (p27), a trigger of senescence. In line with this notion, we found that PML is associated to the promoter regions of MYC and PIM1, consistent with their direct correlation in breast cancer specimens. Altogether, our results provide a feasible explanation for the functional similarities of MYC, PIM1, and PML in TNBC and encourage further study of PML targeting strategies for the treatment of this breast cancer subtype.

Identification of 41 Novel Promoter-Associated CpG Islands Methylated in Leukemias.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1126-1126 ◽  
Author(s):  
Jaroslav Jelinek ◽  
Rajan Mannari ◽  
Jean-Pierre Issa
Keyword(s):  
Gene Silencing ◽  
Cpg Island ◽  
Methylation Status ◽  
Cpg Islands ◽  
Response To Treatment ◽  
Published Data ◽  
Promoter Regions ◽  
Cpg Dinucleotides ◽  
A Genome ◽  
Methylation Profiling

Abstract DNA methylation within promoter-associated CpG islands is a well-recognized mechanism of gene silencing and plays an important role in the development of malignancies. CpG dinucleotides in human DNA are methylated at 5′-cytosine with the exception of areas with dense concentration of CpGs (CpG islands) located in gene promoter regions. In cancer cells, methylation of CpG islands in promoter regions of tumor suppressor genes is a frequent epigenetic change with a gene-silencing effect analogous to inactivating mutations. Methylation profiling can identify biologically and clinically distinct tumor subgroups by mapping the methylation status of multiple genes, and reports in AML and ALL suggest associations between methylation and poor prognosis. Identification of methylated CpG islands can shed new light on the biology of leukemia. We used Methylated CpG Island Amplification coupled with Representative Difference Analysis (MCA-RDA) as a genome-wide screen for promoter-associated CpG islands methylated in leukemic and/or myeloproliferative cell lines and primary malignant cells, but unmethylated in blood cells from normal controls. We identified 51 unique promoter-associated CpG islands in 321 sequenced clones recovered by MCA-RDA. Forty-one CpG islands belonged to known genes, and 10 to annotated mRNAs. Of the genes with known function, 8 are involved in signaling, 7 in transcription, 3 in dephosphorylation, 2 in oxido-reductive processes, 2 in NO synthesis, 2 in adhesion, 2 in solute transport, and 2 in DNA replication. Seven out of the 51 genes were previously reported as methylated in cancer or leukemia (CDH13, HLA-B, HLA-C, PGR, SCGB3A1, SLC26A4, TERT), thus validating the MCA-RDA approach. Of the 41 new hypermethylated CpG islands recovered, 20 corresponded to genes of known function. Published data infer an association with cancer for 10 of these genes (CTDSPL, ECGF1, EDG4, FOXD2, NOR1, NOS3, OLIG2, SLC16A1, TLE1, WNT5B), and no reports were found for the other 10 genes (CNR1, FADS, FBXW3, FGD1, NPM2, P518, PDE4DIP, SNCB, TCEA3, VENTX2). To further validate our findings we are assessing the methylation status of these genes by bisulfite pyrosequencing. Analyses of the bone marrow samples from AML, ALL, CML and MDS patients are ongoing. Our preliminary data confirm methylation of H-cadherin precursor (CDH13), progesterone receptor (PGR) in AML and ALL and cannabinoid receptor 1 (CNR1) in ALL (Table). In conclusion, MCA-RDA identified methylation of 41 new and 10 previously reported promoter-associated CpG islands in leukemia. Functional studies of these may shed new light on the biology of leukemias, and these genes may be useful for methylation profiling of leukemias for prognosis and response to treatment. Promoter CpG Island Methylation Gene AML ALL Methylation levels over 10% for CDH13 and PGR and over 25% for CNR1 were scored as positive. CDH13 5/23 22% 12/19 63% PGR A Isoform 11/22 50% 12/18 67% PGR B Isoform 17/24 71% 5/13 38% CNR1 0/24 0% 3/18 17%

scholarly journals Detection of Genetic Polymorphism of HER2 Gene in HER2 Positive Breast Cancer Women in Iraq

2021 ◽  
pp. 3507-3520
Author(s):  
Sahar M. Hussein ◽  
Fatimah A. Abdul Jabbar ◽  
Hadeel Mohamed Khalaf
Keyword(s):  
Breast Cancer ◽  
Breast Cancer Subtype ◽  
Critical Role ◽  
Protein A ◽  
Control Group ◽  
Her2 Overexpression ◽  
Her2 Gene ◽  
Her2 Positive ◽  
Her2 Protein ◽  
Iraqi Women

     The human epidermal growth factor receptor-2 (HER2) gene plays a critical role in breast cancer development and progression. HER2 overexpression characterizes a biologically and clinically aggressive breast cancer subtype. In this study, 60 samples from Iraqi women with breast cancer were collected and investigated for HER2 protein in the tissue by immunohistochemistry. Also, 20 samples from healthy Iraqi women were used as a control. The results showed that 18 (30 %) patients expressed the HER2 protein. A molecular study for single nucleotide polymorphism (SNP) was conducted on samples metastasizing to lymph nodes. DNA was extracted and polymerase chain reaction (PCR) was performed to amplify exon 17 and intron 17 of HER2 gene. Sequencing of PCR product was achieved and  two SNPs of HER2 gene, one in exon 17 (Ile655Val) and another  close to it in intron 17 (rs903506) were studied.  In exon 17, SNP Ile655Val was found in 41% of patients, while in intron 17, the non-coding SNP rs903506 was found in 27% of patients. However, no polymorphism was found in the control group. The results may suggest that HER2 gene can be used as a molecular marker for breast cancer.

Therapeutic inhibition of USP9x-mediated Notch signaling in triple-negative breast cancer

2021 ◽  
Vol 118 (38) ◽  
pp. e2101592118
Author(s):  
Arushi Jaiswal ◽  
Kiichi Murakami ◽  
Andrew Elia ◽  
Yukiko Shibahara ◽  
Susan J. Done ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Microenvironment ◽  
Tumor Growth ◽  
Triple Negative Breast Cancer ◽  
Proinflammatory Cytokines ◽  
Triple Negative ◽  
Breast Cancer Subtype ◽  
Interleukin 1 ◽  
Ectopic Expression ◽  
Notch Pathway

Triple-negative breast cancer (TNBC) is a breast cancer subtype that lacks targeted treatment options. The activation of the Notch developmental signaling pathway, which is a feature of TNBC, results in the secretion of proinflammatory cytokines and the recruitment of protumoral macrophages to the tumor microenvironment. While the Notch pathway is an obvious therapeutic target, its activity is ubiquitous, and predictably, anti-Notch therapies are burdened with significant on-target side effects. Previously, we discovered that, under conditions of cellular stress commonly found in the tumor microenvironment, the deubiquitinase USP9x forms a multiprotein complex with the pseudokinase tribbles homolog 3 (TRB3) that together activate the Notch pathway. Herein, we provide preclinical studies that support the potential of therapeutic USP9x inhibition to deactivate Notch. Using a murine TNBC model, we show that USP9x knockdown abrogates Notch activation, reducing the production of the proinflammatory cytokines, C-C motif chemokine ligand 2 (CCL2) and interleukin-1 beta (IL-1β). Concomitant with these molecular changes, a reduction in tumor inflammation, the augmentation of antitumor immune response, and the suppression of tumor growth were observed. The pharmacological inhibition of USP9x using G9, a partially selective, small-molecule USP9x inhibitor, reduced Notch activity, remodeled the tumor immune landscape, and reduced tumor growth without associated toxicity. Proving the role of Notch, the ectopic expression of the activated Notch1 intracellular domain rescued G9-induced effects. This work supports the potential of USP9x inhibition to target Notch in metabolically vulnerable tissues like TNBC, while sparing normal Notch-dependent tissues.

scholarly journals Survival of breast cancer patients treated with cyclophosphamide depending on the expression of the LTB4R leukotriene receptor gene in tumor tissue

2020 ◽  
pp. 18-19
Author(s):  
А.И. Калинкин ◽  
В.О. Сигин ◽  
В.В. Стрельников ◽  
А.С. Танас
Keyword(s):  
Breast Cancer ◽  
Tumor Tissue ◽  
Triple Negative ◽  
Cpg Island ◽  
Receptor Gene ◽  
Ectopic Expression ◽  
Differential Methylation ◽  
Breast Cancer Patients ◽  
Genome Wide ◽  
Leukotriene Receptor

По результатам широкогеномного скрининга дифференциального метилирования в образцах рака молочной железы (РМЖ) нами было обнаружено аномальное деметилирование CpG-островка гена лейкотриенового рецептора LTB4R, которое может приводить к его эктопической экспрессии. В настоящей работе мы использовали данные, полученные при анализе 1083 образцов РМЖ в рамках проекта TCGA-BRCA, для определения влияния экспрессии LTB4R на эффективность лечения циклофосфамидом. Анализ кривых выживаемости пациенток с трижды-негативным (ТН) РМЖ с высокой экспрессией LTB4R в опухолях показал увеличение общей выживаемости при лечении циклофосфамидом (p<0,05). Для LumB подтипа РМЖ эффект циклофосфамида не зависел от экспрессии LTB4R. Полученные результаты расширяют возможности персонализации терапии РМЖ. Based on the results of genome-wide screening of differential methylation in breast cancer samples (BC), we have identified abnormal demethylation of the LTB4R leukotriene receptor gene CpG island, which can lead to its ectopic expression. In this paper, we used the data obtained for 1083 BC samples under the TCGA-BRCA project to determine impact of LTB4R expression on the effectiveness of treatment with cyclophosphamide. Analysis of survival curves for patients with triple-negative (TN) breast cancer and high expression of LTB4R showed an increase in overall survival of patients treated with cyclophosphamide (p <0.05). For LumB BC subtype, the effect of cyclophosphamide was not dependent on LTB4R expression. The results obtained expand the possibilities of personalizing BC therapy.

Matrix metalloproteinases: structure, functions and genetic polymorphism

2017 ◽  
pp. 14-23
Author(s):  
А.С. Шадрина ◽  
И.В. Терешкина ◽  
Я.З. Плиева ◽  
Д.Н. Кушлинский ◽  
Д.О. Уткин ◽  
...  
Keyword(s):  
Genetic Polymorphism ◽  
Matrix Metalloproteinases ◽  
Active Center ◽  
Human Body ◽  
Enzymatic Catalysis ◽  
Structure Functions ◽  
Zinc Ion ◽  
Etiological Factors ◽  
Mmp Genes

Матриксные металлопротеиназы (ММП) - ферменты класса гидролаз, осуществляющие ферментативный катализ с помощью связанного в активном центре иона цинка. Функции ММП разнообразны, и нарушение баланса их активности может быть одним из этиологических факторов различных заболеваний. В данном обзоре рассмотрена классификация ММП человека, особенности их структуры и регуляции, а также роль в физиологических и патологических процессах в организме человека. Приведен перечень наиболее изученных на настоящий момент полиморфных вариантов генов MMП, описаны их функциональные эффекты и представлены результаты ассоциативных исследований. Matrix metalloproteinases (MMPs) are enzymes of the hydrolase class that carry out enzymatic catalysis with the help of a zinc ion bound in the active center. MMP functions are diverse, and a disturbance in the balance of their activity may be one of the etiological factors of various diseases. In this review, the classification of human MMP, the features of their structure and regulation, as well as the role in physiological and pathological processes in the human body are considered. A list of the most studied polymorphic versions of MMP genes has been given, their functional effects have been described, and the results of associative studies have been presented.

scholarly journals A case–control study in France showing that a pro-inflammatory diet is associated with a higher risk of breast cancer

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Mariem Hajji-Louati ◽  
Emilie Cordina-Duverger ◽  
Nasser Laouali ◽  
Francesca-Romana Mancini ◽  
Pascal Guénel
Keyword(s):  
Breast Cancer ◽  
Breast Cancer Risk ◽  
Cancer Risk ◽  
Odds Ratio ◽  
Hormone Receptors ◽  
Case Control Study ◽  
Breast Cancer Subtype ◽  
Case Control ◽  
Tumor Subtype ◽  
Control Study

AbstractDietary regimens promoting inflammatory conditions have been implicated in breast cancer development, but studies on the association between pro-inflammatory diet and breast cancer risk have reported inconsistent results. We investigated the association between the inflammatory potential of diet and breast cancer risk in a case–control study in France including 872 breast cancer cases and 966 population controls. All women completed a food frequency questionnaire that was used to compute a Dietary Inflammatory Index (DII) based on the inflammatory weight of 33 dietary components. The DII ranged from a median of − 3.22 in the lowest quartile (anti-inflammatory) to + 2.96 in the highest quartile (pro-inflammatory). The odds ratio contrasting quartile 4 to quartile 1 was 1.31 (95% CI 1.00, 1.73; p-trend = 0.02). Slightly higher odds ratios were observed in post-menopausal women, particularly those with body mass index > 25 kg/m2 (odds ratio 1.62; 95% CI 0.92, 2.83; p-trend = 0.02), and among ever smokers (odds ratio 1.71; 95% CI 1.11, 2.65; p-trend 0.01). The analyses by breast cancer subtype showed that the DII was associated with breast tumors that expressed either the estrogen (ER) or progesterone (PR) hormone receptors or the Human Epidermal Growth Factor Receptor-2 (HER2), but no association was seen for the triple negative breast tumor subtype. Our results add further evidence that a pro-inflammatory diet is associated with breast cancer risk with possible effect variation according to tumor subtype.

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