Archives of Gynecology and Obstetrics

, Volume 297, Issue 1, pp 161–183 | Cite as

Identification of differentially expressed genes regulated by molecular signature in breast cancer-associated fibroblasts by bioinformatics analysis

  • Basavaraj Vastrad
  • Chanabasayya Vastrad
  • Anandkumar Tengli
  • Sudhir Iliger
Gynecologic Oncology

Abstract

Objective

Breast cancer is a severe risk to public health and has adequately convoluted pathogenesis. Therefore, the description of key molecular markers and pathways is of much importance for clarifying the molecular mechanism of breast cancer-associated fibroblasts initiation and progression. Breast cancer-associated fibroblasts gene expression dataset was downloaded from Gene Expression Omnibus database.

Methods

A total of nine samples, including three normal fibroblasts, three granulin-stimulated fibroblasts and three cancer-associated fibroblasts samples, were used to identify differentially expressed genes (DEGs) between normal fibroblasts, granulin-stimulated fibroblasts and cancer-associated fibroblasts samples. The gene ontology (GO) and pathway enrichment analysis was performed, and protein-protein interaction (PPI) network of the DEGs was constructed by NetworkAnalyst software.

Results

Totally, 190 DEGs were identified, including 66 up-regulated and 124 down-regulated genes. GO analysis results showed that up-regulated DEGs were significantly enriched in biological processes (BP), including cell-cell signalling and negative regulation of cell proliferation; molecular function (MF), including insulin-like growth factor II binding and insulin-like growth factor I binding; cellular component (CC), including insulin-like growth factor binding protein complex and integral component of plasma membrane; the down-regulated DEGs were significantly enriched in BP, including cell adhesion and extracellular matrix organization; MF, including N-acetylgalactosamine 4-sulfate 6-O-sulfotransferase activity and calcium ion binding; CC, including extracellular space and extracellular matrix. WIKIPATHWAYS analysis showed the up-regulated DEGs were enriched in myometrial relaxation and contraction pathways. WIKIPATHWAYS, REACTOME, PID_NCI and KEGG pathway analysis showed the down-regulated DEGs were enriched endochondral ossification, TGF beta signalling pathway, integrin cell surface interactions, beta1 integrin cell surface interactions, malaria and glycosaminoglycan biosynthesis—chondroitin sulfate/dermatan sulphate. The top 5 up-regulated hub genes, CDKN2A, MME, PBX1, IGFBP3, and TFAP2C and top 5 down-regulated hub genes VCAM1, KRT18, TGM2, ACTA2, and STAMBP were identified from the PPI network, and subnetworks revealed these genes were involved in significant pathways, including myometrial relaxation and contraction pathways, integrin cell surface interactions, beta1 integrin cell surface interaction. Besides, the target hsa-mirs for DEGs were identified. hsa-mir-759, hsa-mir-4446-5p, hsa-mir-219a-1-3p and hsa-mir-26a-5p were important miRNAs in this study.

Conclusions

We pinpoint important key genes and pathways closely related with breast cancer-associated fibroblasts initiation and progression by a series of bioinformatics analysis on DEGs. These screened genes and pathways provided for a more detailed molecular mechanism underlying breast cancer-associated fibroblasts occurrence and progression, holding promise for acting as molecular markers and probable therapeutic targets.

Keywords

Differentially expressed gene Gene ontology Fibroblasts Protein-protein interaction 

Notes

Acknowledgements

We thank Marsh T., very much, the author who deposited their microarray dataset, GSE75333, into the public Gene Expression Omnibus (GEO) database.

Author contributions

BV carried out the design of this study, performed the statistical analysis and drafted the manuscript. CV collected important background information and software. AKT and SI participated in its design and coordination, visualizations and also helped to draft the manuscript. All authors read and approved the final manuscript.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

This article does not contain any studies with human participants or animals performed by any of the authors.

Informed consent

No informed consent because this study does not contain human or animals participants.

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Copyright information

© Springer-Verlag GmbH Germany 2017

Authors and Affiliations

  • Basavaraj Vastrad
    • 1
  • Chanabasayya Vastrad
    • 2
  • Anandkumar Tengli
    • 3
  • Sudhir Iliger
    • 1
  1. 1.Department of PharmaceuticsSET’s College of PharmacyDharwadIndia
  2. 2.Department of Computer ScienceKarnataka UniversityDharwadIndia
  3. 3.Department of Pharmaceutical Chemistry, JSS College of PharmacyJagadguru Sri Shivarathreeshwara University MysuruMysuruIndia

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