Luminal A Breast Cancer Co-expression Network: Structural and Functional Alterations
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 previou...
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doaj-4cf6e9eb6ead44a0b9fb54d80a9dbe9a2021-04-20T05:59:48ZengFrontiers Media S.A.Frontiers in Genetics1664-80212021-04-011210.3389/fgene.2021.629475629475Luminal A Breast Cancer Co-expression Network: Structural and Functional AlterationsDiana García-Cortés0Diana García-Cortés1Enrique Hernández-Lemus2Enrique Hernández-Lemus3Jesús Espinal-Enríquez4Jesús Espinal-Enríquez5Computational Genomics Division, National Institute of Genomic Medicine, Mexico City, MexicoPrograma de Doctorado en Ciencias Biomédicas, Universidad Nacional Autónoma de México, Mexico City, MexicoComputational Genomics Division, National Institute of Genomic Medicine, Mexico City, MexicoCentro de Ciencias de la Complejidad, Universidad Nacional Autónoma de México, Mexico City, MexicoComputational Genomics Division, National Institute of Genomic Medicine, Mexico City, MexicoCentro de Ciencias de la Complejidad, Universidad Nacional Autónoma de México, Mexico City, MexicoLuminal 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.https://www.frontiersin.org/articles/10.3389/fgene.2021.629475/fullloss of long range co-expressiongene co-expression networksLuminal A breast cancerbreast cancertranscription factor analysisCTCF binding site analysis |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Diana García-Cortés Diana García-Cortés Enrique Hernández-Lemus Enrique Hernández-Lemus Jesús Espinal-Enríquez Jesús Espinal-Enríquez |
spellingShingle |
Diana García-Cortés Diana García-Cortés Enrique Hernández-Lemus Enrique Hernández-Lemus Jesús Espinal-Enríquez Jesús Espinal-Enríquez Luminal A Breast Cancer Co-expression Network: Structural and Functional Alterations Frontiers in Genetics loss of long range co-expression gene co-expression networks Luminal A breast cancer breast cancer transcription factor analysis CTCF binding site analysis |
author_facet |
Diana García-Cortés Diana García-Cortés Enrique Hernández-Lemus Enrique Hernández-Lemus Jesús Espinal-Enríquez Jesús Espinal-Enríquez |
author_sort |
Diana García-Cortés |
title |
Luminal A Breast Cancer Co-expression Network: Structural and Functional Alterations |
title_short |
Luminal A Breast Cancer Co-expression Network: Structural and Functional Alterations |
title_full |
Luminal A Breast Cancer Co-expression Network: Structural and Functional Alterations |
title_fullStr |
Luminal A Breast Cancer Co-expression Network: Structural and Functional Alterations |
title_full_unstemmed |
Luminal A Breast Cancer Co-expression Network: Structural and Functional Alterations |
title_sort |
luminal a breast cancer co-expression network: structural and functional alterations |
publisher |
Frontiers Media S.A. |
series |
Frontiers in Genetics |
issn |
1664-8021 |
publishDate |
2021-04-01 |
description |
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. |
topic |
loss of long range co-expression gene co-expression networks Luminal A breast cancer breast cancer transcription factor analysis CTCF binding site analysis |
url |
https://www.frontiersin.org/articles/10.3389/fgene.2021.629475/full |
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