2. Academic Validation
  3. Regulatory Crosstalk of Doxorubicin, Estradiol and TNFα Combined Treatment in Breast Cancer-derived Cell Lines

Regulatory Crosstalk of Doxorubicin, Estradiol and TNFα Combined Treatment in Breast Cancer-derived Cell Lines

  • Sci Rep. 2019 Oct 23;9(1):15172. doi: 10.1038/s41598-019-51349-9.
Isar Nassiri 1 2,  Alberto Inga 3,  Erna Marija Meškytė 4 5,  Federica Alessandrini 4,  Yari Ciribilli 4,  Corrado Priami 6 7
Affiliations

Affiliations

  • 1 Department of Oncology, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.
  • 2 The Microsoft Research - University of Trento Centre for Computational and Systems Biology (COSBI), Rovereto, TN, Italy.
  • 3 Laboratory of Transcriptional Networks, Department CIBIO, University of Trento, 38123, Trento, Italy.
  • 4 Laboratory of Molecular Cancer Genetics, Department CIBIO, University of Trento, 38123, Trento, Italy.
  • 5 Department of Biological Models, Life Sciences Centre, Institute of Biochemistry, Vilnius University, Vilnius, Lithuania.
  • 6 The Microsoft Research - University of Trento Centre for Computational and Systems Biology (COSBI), Rovereto, TN, Italy. [email protected].
  • 7 Dipartimento di Informatica, Università di Pisa, Pisa, Italy. [email protected].
PMID: 31645610 DOI: 10.1038/s41598-019-51349-9
Abstract

We present a new model of ESR1 network regulation based on analysis of Doxorubicin, Estradiol, and TNFα combination treatment in MCF-7. We used Doxorubicin as a therapeutic agent, TNFα as marker and mediator of an inflammatory microenvironment and 17β-Estradiol (E2) as an agonist of Estrogen Receptors, known predisposing factor for hormone-driven breast Cancer, whose pharmacological inhibition reduces the risk of breast Cancer recurrence. Based on the results of transcriptomics analysis, we found 71 differentially expressed genes that are specific for the combination treatment with Doxorubicin + Estradiol + TNFα in comparison with single or double treatments. The responsiveness to the triple treatment was examined for seven genes by qPCR, of which six were validated, and then extended to four additional cell lines differing for p53 and/or ER status. The results of differential regulation enrichment analysis highlight the role of the ESR1 network that included 36 of 71 specific differentially expressed genes. We propose that the combined activation of p53 and NF-kB transcription factors significantly influences ligand-dependent, ER-driven transcriptional responses, also of the ESR1 gene itself. These results provide a model of coordinated interaction of TFs to explain the Doxorubicin, E2 and TNFα induced repression mechanisms.

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