scholarly journals Luminal A Breast Cancer Co-expression Network: Structural and Functional Alterations

2021 ◽  
Vol 12 ◽  
Author(s):  
Diana García-Cortés ◽  
Enrique Hernández-Lemus ◽  
Jesús Espinal-Enríquez
Keyword(s):  
Breast Cancer ◽  
Network Topology ◽  
Binding Sites ◽  
Target Genes ◽  
Molecular Subtype ◽  
Differential Expression Analysis ◽  
Ctcf Binding ◽  
Luminal A ◽  
Long Distance ◽  
Transcriptomic Level

Luminal A is the most common breast cancer molecular subtype in women worldwide. These tumors have characteristic yet heterogeneous alterations at the genomic and transcriptomic level. Gene co-expression networks (GCNs) have contributed to better characterize the cancerous phenotype. We have previously shown an imbalance in the proportion of intra-chromosomal (cis-) over inter-chromosomal (trans-) interactions when comparing cancer and healthy tissue GCNs. In particular, for breast cancer molecular subtypes (Luminal A included), the majority of high co-expression interactions connect gene-pairs in the same chromosome, a phenomenon that we have called loss of trans- co-expression. Despite this phenomenon has been described, the functional implication of this specific network topology has not been studied yet. To understand the biological role that communities of co-expressed genes may have, we constructed GCNs for healthy and Luminal A phenotypes. Network modules were obtained based on their connectivity patterns and they were classified according to their chromosomal homophily (proportion of cis-/trans- interactions). A functional overrepresentation analysis was performed on communities in both networks to observe the significantly enriched processes for each community. We also investigated possible mechanisms for which the loss of trans- co-expression emerges in cancer GCN. To this end we evaluated transcription factor binding sites, CTCF binding sites, differential gene expression and copy number alterations (CNAs) in the cancer GCN. We found that trans- communities in Luminal A present more significantly enriched categories than cis- ones. Processes, such as angiogenesis, cell proliferation, or cell adhesion were found in trans- modules. The differential expression analysis showed that FOXM1, CENPA, and CIITA transcription factors, exert a major regulatory role on their communities by regulating expression of their target genes in other chromosomes. Finally, identification of CNAs, displayed a high enrichment of deletion peaks in cis- communities. With this approach, we demonstrate that network topology determine, to at certain extent, the function in Luminal A breast cancer network. Furthermore, several mechanisms seem to be acting together to avoid trans- co-expression. Since this phenomenon has been observed in other cancer tissues, a remaining question is whether the loss of long distance co-expression is a novel hallmark of cancer.

scholarly journals An H3K4me3 reader, BAP18 as an adaptor of COMPASS-like core subunits co-activates ERα action and associates with the sensitivity of antiestrogen in breast cancer

2020 ◽  
Vol 48 (19) ◽  
pp. 10768-10784
Author(s):  
Ge Sun ◽  
Chunyu Wang ◽  
Shengli Wang ◽  
Hongmiao Sun ◽  
Kai Zeng ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Progression ◽  
Binding Sites ◽  
Estrogen Receptor Alpha ◽  
Target Genes ◽  
Regulatory Element ◽  
Therapy Resistance ◽  
Ctcf Binding ◽  
Promoter Regions ◽  
Positive Breast Cancer

Abstract Estrogen receptor alpha (ERα) signaling pathway is essential for ERα-positive breast cancer progression and endocrine therapy resistance. Bromodomain PHD Finger Transcription Factor (BPTF) associated protein of 18kDa (BAP18) has been recognized as a crucial H3K4me3 reader. However, the whole genomic occupation of BAP18 and its biological function in breast cancer is still elusive. Here, we found that higher expression of BAP18 in ERα-positive breast cancer is positively correlated with poor prognosis. ChIP-seq analysis further demonstrated that the half estrogen response elements (EREs) and the CCCTC binding factor (CTCF) binding sites are the significant enrichment sites found in estrogen-induced BAP18 binding sites. Also, we provide the evidence to demonstrate that BAP18 as a novel co-activator of ERα is required for the recruitment of COMPASS-like core subunits to the cis-regulatory element of ERα target genes in breast cancer cells. BAP18 is recruited to the promoter regions of estrogen-induced genes, accompanied with the enrichment of the lysine 4-trimethylated histone H3 tail (H3K4me3) in the presence of E2. Furthermore, BAP18 promotes cell growth and associates the sensitivity of antiestrogen in ERα-positive breast cancer. Our data suggest that BAP18 facilitates the association between ERα and COMPASS-like core subunits, which might be an essential epigenetic therapeutic target for breast cancer.

scholarly journals Prediction of clusters of miRNA binding sites in mRNA candidate genes of breast cancer subtypes

PeerJ ◽  
2019 ◽  
Vol 7 ◽  
pp. e8049 ◽  
Author(s):  
Dana Aisina ◽  
Raigul Niyazova ◽  
Shara Atambayeva ◽  
Anatoliy Ivashchenko
Keyword(s):  
Breast Cancer ◽  
Candidate Genes ◽  
Binding Sites ◽  
Target Genes ◽  
Breast Cancer Subtype ◽  
Luminal A ◽  
Cancer Subtypes ◽  
Nucleotide Binding Sites ◽  
Cancer Subtype ◽  
Gene Mrna

The development of breast cancer (BC) subtypes is controlled by distinct sets of candidate genes, and the expression of these genes is regulated by the binding of their mRNAs with miRNAs. Predicting miRNA associations and target genes is thus essential when studying breast cancer. The MirTarget program identifies the initiation of miRNA binding to mRNA, the localization of miRNA binding sites in mRNA regions, and the free energy from the binding of all miRNA nucleotides with mRNA. Candidate gene mRNAs have clusters (miRNA binding sites with overlapping nucleotide sequences). mRNAs of EPOR, MAZ and NISCH candidate genes of the HER2 subtype have clusters, and there are four clusters in mRNAs of MAZ, BRCA2 and CDK6 genes. Candidate genes of the triple-negative subtype are targets for multiple miRNAs. There are 11 sites in CBL mRNA, five sites in MMP2 mRNA, and RAB5A mRNA contains two clusters in each of the three sites. In SFN mRNA, there are two clusters in three sites, and one cluster in 21 sites. Candidate genes of luminal A and B subtypes are targets for miRNAs: there are 21 sites in FOXA1 mRNA and 15 sites in HMGA2 mRNA. There are clusters of five sites in mRNAs of ITGB1 and SOX4 genes. Clusters of eight sites and 10 sites are identified in mRNAs of SMAD3 and TGFB1 genes, respectively. Organizing miRNA binding sites into clusters reduces the proportion of nucleotide binding sites in mRNAs. This overlapping of miRNA binding sites creates a competition among miRNAs for a binding site. From 6,272 miRNAs studied, only 29 miRNAs from miRBase and 88 novel miRNAs had binding sites in clusters of target gene mRNA in breast cancer. We propose using associations of miRNAs and their target genes as markers in breast cancer subtype diagnosis.

scholarly journals Prediction of clusters of miRNA binding sites in mRNA candidate genes of breast cancer

2019 ◽  
Author(s):  
Dana Aisina ◽  
Raigul Niyazova ◽  
Shara Atambayeva ◽  
Anatoliy Ivashchenko
Keyword(s):  
Breast Cancer ◽  
Candidate Genes ◽  
Binding Sites ◽  
Target Genes ◽  
Untranslated Regions ◽  
Luminal A ◽  
Cancer Subtypes ◽  
Nucleotide Binding Sites ◽  
Free Energy Of Binding ◽  
Triple Negative Subtype

Distinct sets of candidate genes control the development of breast cancer subtypes. The expression of many genes is regulated by the binding of their mRNAs with miRNAs. The prediction of miRNA associations and target genes is essential in studying of breast cancer. The MirTarget program defines the following features of binding miRNA to mRNA: the start of the initiation of miRNA binding to mRNA; the localization of miRNA binding sites in 5'-untranslated regions (5'UTR), coding domain sequences (CDS) and 3'-untranslated regions (3'UTR); the free energy of binding of all miRNA nucleotides with mRNA; the schemes of interactions of all miRNAs nucleotides with mRNAs. The mRNAs of many genes have clusters (miRNA binding sites with overlapping nucleotide sequences) located in 5'UTR, CDS, or 3'UTR. There are clusters in 5'UTR of mRNA EPOR, MAZ and NISCH candidate genes of HER2 subtype. There are four clusters in CDS of mRNA MAZ gene, and in 3'UTR of mRNA BRCA2 and CDK6 genes. Candidate genes of triple-negative subtype are targets for multiple miRNAs. In 5'UTR of mRNA СBL gene, there are 11 sites; the mRNA for MMP2 gene contains five sites; the mRNA of RAB5A gene contains two clusters each of three sites. In 3'UTR of mRNA SFN gene, there are two clusters, each of three sites, and one cluster of 21 sites. Candidate genes of luminal A and B subtypes are targets for miRNAs: there are 21 sites in 5'UTR of mRNA FOXA1 gene and mRNA HMGA2 gene contains 15 sites. There are clusters of five sites in CDS of mRNA ITGB1 gene and five sites in 3'UTR of mRNA SOX4 genes. Clusters of eight sites and ten sites are identified in 3'UTR of mRNA SMAD3 and TGFB1 genes, respectively. The organization of miRNA binding sites into clusters reduces the proportion of nucleotide binding sites in 5'UTR, CDS and 3'UTRs. This overlapping of miRNA binding sites creates a competition among miRNAs for the binding site. From 6,272 studied miRNAs only 29 miRNAs from miRBase and 88 novel miRNAs have binding sites in clusters of mRNA target genes of breast cancer.

scholarly journals Prediction of clusters of miRNA binding sites in mRNA candidate genes of breast cancer

2019 ◽  
Author(s):  
Dana Aisina ◽  
Raigul Niyazova ◽  
Shara Atambayeva ◽  
Anatoliy Ivashchenko
Keyword(s):  
Breast Cancer ◽  
Candidate Genes ◽  
Binding Sites ◽  
Target Genes ◽  
Untranslated Regions ◽  
Luminal A ◽  
Cancer Subtypes ◽  
Nucleotide Binding Sites ◽  
Free Energy Of Binding ◽  
Triple Negative Subtype

Distinct sets of candidate genes control the development of breast cancer subtypes. The expression of many genes is regulated by the binding of their mRNAs with miRNAs. The prediction of miRNA associations and target genes is essential in studying of breast cancer. The MirTarget program defines the following features of binding miRNA to mRNA: the start of the initiation of miRNA binding to mRNA; the localization of miRNA binding sites in 5'-untranslated regions (5'UTR), coding domain sequences (CDS) and 3'-untranslated regions (3'UTR); the free energy of binding of all miRNA nucleotides with mRNA; the schemes of interactions of all miRNAs nucleotides with mRNAs. The mRNAs of many genes have clusters (miRNA binding sites with overlapping nucleotide sequences) located in 5'UTR, CDS, or 3'UTR. There are clusters in 5'UTR of mRNA EPOR, MAZ and NISCH candidate genes of HER2 subtype. There are four clusters in CDS of mRNA MAZ gene, and in 3'UTR of mRNA BRCA2 and CDK6 genes. Candidate genes of triple-negative subtype are targets for multiple miRNAs. In 5'UTR of mRNA СBL gene, there are 11 sites; the mRNA for MMP2 gene contains five sites; the mRNA of RAB5A gene contains two clusters each of three sites. In 3'UTR of mRNA SFN gene, there are two clusters, each of three sites, and one cluster of 21 sites. Candidate genes of luminal A and B subtypes are targets for miRNAs: there are 21 sites in 5'UTR of mRNA FOXA1 gene and mRNA HMGA2 gene contains 15 sites. There are clusters of five sites in CDS of mRNA ITGB1 gene and five sites in 3'UTR of mRNA SOX4 genes. Clusters of eight sites and ten sites are identified in 3'UTR of mRNA SMAD3 and TGFB1 genes, respectively. The organization of miRNA binding sites into clusters reduces the proportion of nucleotide binding sites in 5'UTR, CDS and 3'UTRs. This overlapping of miRNA binding sites creates a competition among miRNAs for the binding site. From 6,272 studied miRNAs only 29 miRNAs from miRBase and 88 novel miRNAs have binding sites in clusters of mRNA target genes of breast cancer.

scholarly journals Profiling the expression of pro-metastatic genes in association with the clinicopathological features of primary breast cancer

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Seyed-Mohammad Mazloomi ◽  
Mitra Foroutan-Ghaznavi ◽  
Vahid Montazeri ◽  
Gholamreza Tavoosidana ◽  
Ashraf Fakhrjou ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Target Genes ◽  
Case Series ◽  
Clinicopathological Features ◽  
Cell Junctions ◽  
Homologous Gene ◽  
Axillary Lymph ◽  
Luminal A ◽  
Transcriptional Profiles ◽  
First Time

Abstract Background Metastasis accounts for ninety percent of breast cancer (BrCa) mortality. Cortactin, Ras homologous gene family member A (RhoA), and Rho-associated kinase (ROCK) raise cellular motility in favor of metastasis. Claudins (CLDN) belong to tight junction integrity and are dysregulated in BrCa. Thus far, epidemiologic evidence regarding the association of different pro-metastatic genes with pathological phenotypes of BrCa is largely inconsistent. This study aimed to determine the possible transcriptional models of pro-metastatic genes incorporate in holding the integrity of epithelial cell–cell junctions (CTTN, RhoA, ROCK, CLDN-1, CLDN-2, and CLDN-4), for the first time, in association with clinicopathological features of primary BrCa. Methods In a consecutive case-series design, 206 newly diagnosed non-metastatic eligible BrCa patients with histopathological confirmation (30–65 years) were recruited in Tabriz, Iran (2015–2017). Real-time RT-PCR was used. Then fold changes in the expression of target genes were measured. Results ROCK amplification was associated with the involvement of axillary lymph node metastasis (ALNM; ORadj. = 3.05, 95%CI 1.01–9.18). Consistently, inter-correlations of CTTN-ROCK (β = 0.226, P < 0.05) and RhoA-ROCK (β = 0.311, P < 0.01) were determined among patients diagnosed with ALNM+ BrCa. In addition, the overexpression of CLDN-4 was frequently observed in tumors identified by ALNM+ or grade III (P < 0.05). The overexpression of CTTN, CLDN-1, and CLDN-4 genes was correlated positively with the extent of tumor size. CTTN overexpression was associated with the increased chance of luminal-A positivity vs. non-luminal-A (ORadj. = 1.96, 95%CI 1.02–3.77). ROCK was also expressed in luminal-B BrCa tumors (P < 0.05). The estrogen receptor-dependent transcriptions were extended to the inter-correlations of RhoA-ROCK (β = 0.280, P < 0.01), ROCK-CLDN-2 (β = 0.267, P < 0.05), and CLDN-1-CLDN-4 (β = 0.451, P < 0.001). Conclusions For the first time, our findings suggested that the inter-correlations of CTTN-ROCK and RhoA-ROCK were significant transcriptional profiles determined in association with ALNM involvement; therefore the overexpression of ROCK may serve as a potential molecular marker for lymphatic metastasis. The provided binary transcriptional profiles need more approvals in different clinical features of BrCa metastasis.

scholarly journals Differential expression of mab-21 like 1 in cancers of the breast.

2021 ◽  
Author(s):  
Shahan Mamoor
Keyword(s):  
Breast Cancer ◽  
Differential Expression ◽  
Survival Data ◽  
Molecular Subtype ◽  
Differentially Expressed Gene ◽  
Normal Breast ◽  
Differentially Expressed ◽  
Luminal A ◽  
Significant Differential Expression ◽  
Primary Tumors

Breast cancer affects women at relatively high frequency (1). We mined published microarray datasets (2, 3) to determine in an unbiased fashion and at the systems level genes most differentially expressed in the primary tumors of patients with breast cancer. We report here significant differential expression of the gene encoding mab-21 like 1, MAB21L1, when comparing primary tumors of the breast to the tissue of origin, the normal breast. MAB21L1 was also differentially expressed in the tumor cells of patients with triple negative breast cancer. MAB21L1 mRNA was present at significantly lower quantities in tumors of the breast as compared to normal breast tissue. Analysis of human survival data revealed that expression of MAB21L1 in primary tumors of the breast was correlated with overall survival in patients with luminal A subtype cancer, demonstrating a relationship between primary tumor expression of a differentially expressed gene and patient survival outcomes influenced by molecular subtype. MAB21L1 may be of relevance to initiation, maintenance or progression of cancers of the female breast.

scholarly journals Differential expression of defective in cullin neddylation 1 domain-containing 3 in cancers of the breast.

2021 ◽  
Author(s):  
Shahan Mamoor
Keyword(s):  
Breast Cancer ◽  
Differential Expression ◽  
Survival Data ◽  
Molecular Subtype ◽  
Differentially Expressed Gene ◽  
Normal Breast ◽  
Differentially Expressed ◽  
Luminal A ◽  
Significant Differential Expression ◽  
Primary Tumors

Breast cancer affects women at relatively high frequency (1). We mined published microarray datasets (2, 3) to determine in an unbiased fashion and at the systems level genes most differentially expressed in the primary tumors of patients with breast cancer. We report here significant differential expression of the gene encoding defective in cullin neddylation 1 domain-containing 3, DCUN1D3, when comparing primary tumors of the breast to the tissue of origin, the normal breast. DCUN1D3 mRNA was present at significantly lower quantities in tumors of the breast as compared to normal breast tissue. Analysis of human survival data revealed that expression of DCUN1D3 in primary tumors of the breast was correlated with recurrence-free survival in patients with basal, luminal A and luminal B subtype cancers, demonstrating a relationship between primary tumor expression of a differentially expressed gene and patient survival outcomes influenced by PAM50 molecular subtype. DCUN1D3 may be of relevance to initiation, maintenance or progression of cancers of the female breast.

scholarly journals Differential expression of dystrophin in cancers of the breast.

2021 ◽  
Author(s):  
Shahan Mamoor
Keyword(s):  
Breast Cancer ◽  
Differential Expression ◽  
Survival Data ◽  
Molecular Subtype ◽  
Differentially Expressed Gene ◽  
Normal Breast ◽  
Differentially Expressed ◽  
Luminal A ◽  
Significant Differential Expression ◽  
Primary Tumors

Breast cancer affects women at relatively high frequency (1). We mined published microarray datasets (2, 3) to determine in an unbiased fashion and at the systems level genes most differentially expressed in the primary tumors of patients with breast cancer. We report here significant differential expression of the gene encoding dystrophin, DMD, when comparing primary tumors of the breast to the tissue of origin, the normal breast. DMD was also differentially expressed in the tumor cells of patients with triple negative breast cancer. DMD mRNA was present at significantly lower quantities in tumors of the breast as compared to normal breast tissue. Analysis of human survival data revealed that expression of DMD in primary tumors of the breast was correlated with overall survival in patients with basal and luminal A subtype cancer, demonstrating a relationship between primary tumor expression of a differentially expressed gene and patient survival outcomes influenced by molecular subtype. DMD may be of relevance to initiation, maintenance or progression of cancers of the female breast.

Breast Cancer Prognosis: A Genetic Code for Personalized Therapy

2021 ◽  
Author(s):  
Antonio Rulli ◽  
Laura Fortuna ◽  
Svitlana Zayik ◽  
Piero Covarelli ◽  
Fabrizio Stracci ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Molecular Subtype ◽  
Rna Extraction ◽  
Diagnostic Category ◽  
Good Prognosis ◽  
Personalized Therapy ◽  
Cancer Prognosis ◽  
Luminal A ◽  
Biological Behaviour ◽  
Disease Recovery

Abstract Background: Breast cancer is distinguished in three different subtypes, based on clinical and molecular parameters: Luminal - HER2 - Basal type. Luminal carcinomas (which represent about 65% of the total) are distinguished by a particular heterogeneity of biological behaviour with disease recovery in about 40-50% and death in about two-thirds of these patients at 5 years from diagnosis, despite initial anatomopathological pictures of apparent low aggressiveness. Precisely, more biomolecular parameters are desirable for this diagnostic category which starting from an estimated disease recovery can guide therapeutic choices in a more articulated way that is modelled on the actual needs.Method: The aim of this work is to build a panel of genes that can be used to personalize therapy and consequently reduce mortality. Our kit is patented and includes 33 genes that best characterize neoplastic heterogeneity and sensitivity to drugs. The study involved the total transcriptome (RNA) sequencing of 40 patient samples carried out in the two-year period 1994/1995 with the aim of identifying a group of genes expressed differentially among patients with good prognosis and those with poor prognosis. Results: Total RNA extraction from formalin-fixed, paraffin-embedded samples and then Library preparation for RNA-Seq was achieved. The study highlighted some genes: CXCL13 life gene, IFITM10 death gene always present regardless of molecular subtype, and DSCAM-AS1 gene, specific for Luminal A subtype, that if present, let the patient avoid standard PBI and neoadjuvant therapy. Conclusion: The goal is to implement a different surgical and adjuvant personalized therapy for every single patient.

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