Formal modeling and analysis of ER-α associated Biological Regulatory Network in breast cancer

Samra Khalid, Rumeza Hanif, Samar H K Tareen, Amnah Siddiqa, Zurah Bibi, Jamil Ahmad

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

BACKGROUND: Breast cancer (BC) is one of the leading cause of death among females worldwide. The increasing incidence of BC is due to various genetic and environmental changes which lead to the disruption of cellular signaling network(s). It is a complex disease in which several interlinking signaling cascades play a crucial role in establishing a complex regulatory network. The logical modeling approach of René Thomas has been applied to analyze the behavior of estrogen receptor-alpha (ER-α) associated Biological Regulatory Network (BRN) for a small part of complex events that leads to BC metastasis.

METHODS: A discrete model was constructed using the kinetic logic formalism and its set of logical parameters were obtained using the model checking technique implemented in the SMBioNet software which is consistent with biological observations. The discrete model was further enriched with continuous dynamics by converting it into an equivalent Petri Net (PN) to analyze the logical parameters of the involved entities.

RESULTS: In-silico based discrete and continuous modeling of ER-α associated signaling network involved in BC provides information about behaviors and gene-gene interaction in detail. The dynamics of discrete model revealed, imperative behaviors represented as cyclic paths and trajectories leading to pathogenic states such as metastasis. Results suggest that the increased expressions of receptors ER-α, IGF-1R and EGFR slow down the activity of tumor suppressor genes (TSGs) such as BRCA1, p53 and Mdm2 which can lead to metastasis. Therefore, IGF-1R and EGFR are considered as important inhibitory targets to control the metastasis in BC.

CONCLUSION: The in-silico approaches allow us to increase our understanding of the functional properties of living organisms. It opens new avenues of investigations of multiple inhibitory targets (ER-α, IGF-1R and EGFR) for wet lab experiments as well as provided valuable insights in the treatment of cancers such as BC.

Original languageEnglish
Article number2542
Pages (from-to)e2542
Number of pages33
JournalPEERJ
Volume4
DOIs
Publication statusPublished - 20 Oct 2016

Keywords

  • Breast cancer
  • Biological Regulatory Network
  • Estrogen receptor-alpha
  • Discrete and continuous modeling
  • GENOTECH
  • Rene Thomas formalism
  • SMBioNet
  • Continuous Hybrid Petri Net
  • ESTROGEN-RECEPTOR-ALPHA
  • FACTOR-I RECEPTOR
  • GROWTH-FACTOR RECEPTOR
  • IGF-I
  • TRANSCRIPTIONAL REGULATION
  • PROGESTERONE-RECEPTOR
  • CELL-DIFFERENTIATION
  • THERAPEUTIC TARGETS
  • DYNAMICAL BEHAVIOR
  • ENDOCRINE THERAPY

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