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Exploration of targets and molecular mechanisms of cinnamaldehyde in overcoming fulvestrant-resistant breast cancer: a bioinformatics study

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Abstract

The efficacy of fulvestrant therapy for estrogen receptor positive (ER+) or luminal breast cancer therapy may decrease on account of chemoresistance, which contributes to tumor relapse and metastasis. Cinnamaldehyde has previously been shown to trigger apoptosis in MCF-7 cells, which are ER+ breast cancer cells. This study aimed to identify the targets and molecular mechanisms of cinnamaldehyde in overcoming fulvestrant-resistant breast cancer using a bioinformatics approach. The microarray data of fulvestrant-resistant and cinnamaldehyde-treated MCF-7 cells were obtained from GSE74391 and GSE85871, respectively, and a total of 310 differentially expressed genes (DEGs) were recovered from these databases. Gene Ontology analysis revealed several DEGs that participated in metabolic processes, responded to a stimulus, were located in the membrane and nucleus, and regulated the molecular functions of the protein and ion binding. Drug association analysis revealed the associations between these DEGs and protein kinase inhibitors. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis showed that the DEGs regulated pathways for cancer, erbB, and MAPK signaling. Genetic alterations for each target gene ranged from 3 to 14% (CDK2, 3%; MDM2, 6%; KRAS, 7%; PIK3R1, 7%; CDH1, 8%; ESR1, 14%). Further investigation was conducted to examine the impact of genetic alterations on the signaling, resulting in BRCA-2012-RTK-RAS-PI(3)K-pathway. This study identified six possible targets of cinnamaldehyde in overcoming fulvestrant-resistant breast cancer, including CDK2, MDM2, KRAS, PIK3R1, CDH1, and ESR1. PI3K/Akt signaling is a possible target of cinnamaldehyde in overcoming fulvestrant-resistant breast cancer. Molecular docking study results showed that cinnamaldehyde could bind to several protein targets with specific properties and could also be considered to inhibit the activity of target proteins because of its protein-binding distance. Further investigations to verify the findings of this study are necessary.

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Abbreviations

GO:

Gene ontology

DEGs:

Differentially expressed genes

WebGestalt:

WEB-based Gene SeT AnaLysis Toolkit

KEGG:

Kyoto encyclopedia of genes and genomes

DAVID:

Database for annotation, visualization, and integrated discovery

PPI:

Protein–protein interaction

SERD:

Selective estrogen receptor down regulator

EMT:

Epithelial to mesenchymal transition

ERα:

Estrogen receptor alpha

ROS:

Reactive oxygen species

CTGs:

Potential cinnamaldehyde target genes against fulvestrant-resistant breast cancer

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Authors and Affiliations

  1. Laboratory of Macromolecular Engineering, Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Universitas Gadjah Mada Sekip Utara II, Yogyakarta, 55281, Indonesia

    Adam Hermawan

  2. Cancer Chemoprevention Research Center, Faculty of Pharmacy, Universitas Gadjah Mada Sekip Utara II, Yogyakarta, 55281, Indonesia

    Herwandhani Putri

  3. Laboratory of Medicinal Chemistry, Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Universitas Gadjah Mada Sekip Utara II, Yogyakarta, 55281, Indonesia

    Rohmad Yudi Utomo

Authors
  1. Adam Hermawan
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  2. Herwandhani Putri
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  3. Rohmad Yudi Utomo
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Contributions

AH contributed to the design, acquisition, review and evaluation of the data, the writing and revision of the article and the final approval of the version to bepublished. HP contributed to the analysis of the results, drafted the article and finalized the version to be published. RYU contributed to the data acquisition and drafted the article. The final manuscript was read and accepted by all contributors.

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Correspondence to Adam Hermawan.

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Hermawan, A., Putri, H. & Utomo, R.Y. Exploration of targets and molecular mechanisms of cinnamaldehyde in overcoming fulvestrant-resistant breast cancer: a bioinformatics study. Netw Model Anal Health Inform Bioinforma 10, 30 (2021). https://doi.org/10.1007/s13721-021-00303-9

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  • DOI: https://doi.org/10.1007/s13721-021-00303-9

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