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New perspectives in triple-negative breast cancer therapy based on treatments with TGFβ1 siRNA and doxorubicin

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Abstract

Triple-negative breast cancer (TNBC), which accounts for 10–20% of all breast cancers, has the worst prognosis. Although chemotherapy treatment is a standard for TNBC, it lacks a specific target. Therefore, new therapeutic strategies are required to be investigated. In this study, a combined doxorubicin (DOX) and small interfering RNA (siRNA) therapy is proposed as therapeutic strategy for targeting TGFβ1 gene. Hs578T cell line is used as in vitro model for TNBC, wherein TGFβ1siRNA therapy is employed to enhance therapeutic effects. Cell proliferation rate is measured using an MTT test, and morphological alterations are assed using microscopically approached, while gene expression is determined by qRT-PCR analysis. The combined treatment of TGFβ1siRNA and DOX reduced levels of cell proliferation and mitochondrial activity and promoted the alteration of cell morphology (dark-field microscopy). DOX treatment caused downregulation of six genes and upregulation of another six genes. The combined effects of DOX and TGFβ1siRNA resulted in upregulation of 13 genes and downregulation of four genes. Silencing of TGFβ1 resulted in activation of cell death mechanisms in Hs578T cells, to potentiate the effects of DOX, but not in an additive manner, due to the activation of genes involved in resistance to therapy (ABCB1 and IL-6).

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Abbreviations

2-HER2:

Human epidermal growth factor

ABCB1:

ATP-binding cassette sub-family B member 1

cDNA:

Complementary DNA

DFS:

Disease-free survival

DNA:

Deoxyribonucleic acid

DOX:

Doxorubicin

ER:

Estrogen receptor

FC:

Fold change

IC50:

Half maximal inhibitory concentration

IL-6/IL-8:

Interleukin 6/interleukin 8

MGMT:

Methylation of O6-methylguanine-DssNA methyltransferase

Ml:

Milliliter

μM:

Micromolar

nM:

Nanomolar

OS:

Overall survival

PR:

Progesterone receptor

PTEN:

Phosphatase and tensin homolog

RNAi:

RNA interference

SD:

Standard deviation

siRNA:

Small interfering RNA

TCGA:

The cancer genome atlas

TGFβ1:

Transforming growth factor beta 1

TMRE:

Tetra methylrhodamine ethyl ester

TNBC:

Triple-negative breast cancer

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Funding

This paper was published under the frame of European Social Found, Human Capital Operational Programme 2014–2020, Project No. POCU/380/6/13/125171, and PNCDI III 2015–2020 “Increasing the performance of scientific research and technology transfer in translational medicine through the formation of a new generation of young researchers”—ECHITAS, no. 29PFE/ 18.10. 2018. Cristina Alexandra Ciocan-Cȃrtiţă received a grant for doctoral research Grant Number 1300/11/13.01.2017.

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Authors and Affiliations

  1. Research Center for Functional Genomics Biomedicine and Translational Medicine, “Iuliu Haţieganu” University of Medicine and Pharmacy, 23 Marinescu Street, 400337, Cluj-Napoca, Romania

    Cristina Alexandra Ciocan-Cȃrtiţă, Ancuţa Jurj, Lajos Raduly, Roxana Cojocneanu, Valentina Pileczki, Laura-Ancuta Pop, Liviuţa Budişan, Cornelia Braicu & Ioana Berindan-Neagoe

  2. MedFuture Research Center for Advanced Medicine, “Iuliu Haţieganu” University of Medicine and Pharmacy, 4-6 Louis Pasteur Street, 400349, Cluj-Napoca, Romania

    Alin Moldovan

  3. Department of Functional Genomics and Experimental Pathology, “Prof. Dr. Ion Chiricuţă” Oncology Institute, 34-36 Republicii Street, 400015, Cluj-Napoca, Romania

    Ioana Berindan-Neagoe

  4. Department of Natural and Environmental Sciences, University of Illinois At Urbana-Champaign, Urbana, IL, 61801, USA

    Schuyler S. Korban

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  1. Cristina Alexandra Ciocan-Cȃrtiţă
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Conceptualization was done by CACC, IBN, CB; contributions to methodology were done by AJ, CACC, LR, RC, AM, VP, LB; software was provided by RC, LAP, CB; validation was done by AJ, CB; formal analysis was carried out LAP, CB; investigation was done by IBN.; resources were gathered by IBN, CB; data curation was performed by RC; writing—original draft preparation—was done by AJ, CACC; writing—review and editing—was done by CB, IBN, SSK; visualization was carried out by CB, RC; supervision was done by IBN; editing was done by SSK; project administration was done by IBN; funding was acquired by IBN, CACC, CB.

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Correspondence to Cornelia Braicu or Ioana Berindan-Neagoe.

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Ciocan-Cȃrtiţă, C.A., Jurj, A., Raduly, L. et al. New perspectives in triple-negative breast cancer therapy based on treatments with TGFβ1 siRNA and doxorubicin. Mol Cell Biochem 475, 285–299 (2020). https://doi.org/10.1007/s11010-020-03881-w

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