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NFκBP65 transcription factor modulates resistance to doxorubicin through ABC transporters in breast cancer

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Abstract

Background

Shedding light on chemoresistance biology of breast cancer could contribute to enhance the clinical outcome. Intrinsic or acquired resistance to chemotherapy is a major problem in breast cancer treatment.

Methods and materials

The NFκB pathway by siRNAP65 and JSH-23 as a translocational inhibitor of NFκBP65 in the doxorubicin-resistant MCF-7 (MCF-7/Dox) and MCF-7 cells was blocked. Then, the ABC transporter expression and function were assessed by real-time qRT-PCR and flow cytometry, respectively. Induction of apoptosis was evaluated after inhibition of the NFΚB pathway as well.

Results

Our study underlined the upregulation of NFκBP65 and anti-apoptotic Bcl-2 and downregulation of pro-apoptotic Bax in the MCF-7/Dox cells compared with control MCF-7 cells. Here, we showed that interplay between nuclear factor kappa B P65 (NFkBP65) as a transcriptional regulator and ABC transporters in the MCF-7/Dox cancer cells. We found that inhibition of the elevated expression of NFκBP65 in the resistant breast cancer, whether translocational inhibition or silencing by siRNA, decreased the expression and function of MDR1 and MRP1 efflux pumps. Furthermore, the blockade of NFκBP65 promoted apoptosis via modulating Bcl-2 and BAX expression. After inhibition of the NFκBP65 signaling pathway, elevated baseline expression of survival Bcl-2 gene in the resistant breast cells significantly decreased.

Conclusion

Suppression of the NFκB pathway has a profound dual impact on promoting the intrinsic apoptotic pathway and reducing ABC transporter function and expression, which are some of the chemoresistance features. It was speculated that the NFκB pathway directly acts on doxorubicin-induced MDR1 and MRP1 expression in MCF-7/Dox cells.

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Acknowledgements

We are grateful to all members of the Stem Cell Research Center for technical assistance and/or advice.

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Authors and Affiliations

  1. Department of Anatomical Science, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran

    Kobra Velaei, Balal Barazvan & Jafar Soleimani Rad

  2. Department of Clinical Biochemistry and Laboratory Medicine, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran

    Nasser Samadi

  3. Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran

    Kobra Velaei & Sina Soltani

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  1. Kobra Velaei
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  2. Nasser Samadi
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  3. Sina Soltani
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Correspondence to Jafar Soleimani Rad.

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Velaei, K., Samadi, N., Soltani, S. et al. NFκBP65 transcription factor modulates resistance to doxorubicin through ABC transporters in breast cancer. Breast Cancer 24, 552–561 (2017). https://doi.org/10.1007/s12282-016-0738-8

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  • DOI: https://doi.org/10.1007/s12282-016-0738-8

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