Stat3/Oct-4/c-Myc signal circuit for regulating stemness-mediated doxorubicin resistance of triple-negative breast cancer cells and inhibitory effects of WP1066

  • Authors:
    • Cong-Cong Cheng
    • Li-Hong Shi
    • Xue-Jian Wang
    • Shu-Xiao Wang
    • Xiao-Qing Wan
    • Shu-Rong Liu
    • Yi-Fei Wang
    • Zhong Lu
    • Li-Hua Wang
    • Yi Ding
  • View Affiliations

  • Published online on: May 8, 2018     https://doi.org/10.3892/ijo.2018.4399
  • Pages: 339-348
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Abstract

Doxorubicin (Dox) is widely used in the treatment of triple-negative breast cancer cells (TNBCs), however resistance limits its effectiveness. Cancer stem cells (CSCs) are associated with Dox resistance in MCF-7 estrogen receptor positive breast cancer cells. Signal transducer and activator of transcription 3 (Stat3) may functionally shift non-CSCs towards CSCs. However, whether Stat3 drives the formation of CSCs during the development of resistance in TNBC, and whether a Stat3 inhibitor reverses CSC-mediated Dox resistance, remains to be elucidated. In the present study, human MDA-MB-468 and murine 4T1 mammary carcinoma cell lines with the typical characteristics of TNBCs, were compared with estrogen receptor-positive MCF-7 cells as a model system. The MTT assay was used to detect cytotoxicity of Dox. In addition, the expression levels of CSC-specific markers and transcriptional factors were measured by western blotting, immunofluorescence staining and flow cytometry. The mammosphere formation assay was used to detect stem cell activity. Under long-term continuous treatment with Dox at a low concentration, TNBC cultures not only exhibited a drug-resistant phenotype, but also showed CSC properties. These Dox-resistant TNBC cells showed activation of Stat3 and high expression levels of pluripotency transcription factors octamer-binding transcription factor-4 (Oct-4) and c-Myc, which was different from the high expression of superoxide dismutase 2 (Sox2) in Dox-resistant MCF-7 cells. WP1066 inhibited the phosphorylation of Stat3, and decreased the expression of Oct-4 and c-Myc, leading to a reduction in the CD44-positive cell population, and restoring the sensitivity of the cells to Dox. Taken together, a novel signal circuit of Stat3/Oct-4/c-Myc was identified for regulating stemness-mediated Dox resistance in TNBC. The Stat3 inhibitor WP1066 was able to overcome the resistance to Dox through decreasing the enrichment of CSCs, highlighting the therapeutic potential of WP1066 as a novel sensitizer of Dox-resistant TNBC.
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July 2018
Volume 53 Issue 1

Print ISSN: 1019-6439
Online ISSN:1791-2423

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Copy and paste a formatted citation
APA
Cheng, C., Shi, L., Wang, X., Wang, S., Wan, X., Liu, S. ... Ding, Y. (2018). Stat3/Oct-4/c-Myc signal circuit for regulating stemness-mediated doxorubicin resistance of triple-negative breast cancer cells and inhibitory effects of WP1066. International Journal of Oncology, 53, 339-348. https://doi.org/10.3892/ijo.2018.4399
MLA
Cheng, C., Shi, L., Wang, X., Wang, S., Wan, X., Liu, S., Wang, Y., Lu, Z., Wang, L., Ding, Y."Stat3/Oct-4/c-Myc signal circuit for regulating stemness-mediated doxorubicin resistance of triple-negative breast cancer cells and inhibitory effects of WP1066". International Journal of Oncology 53.1 (2018): 339-348.
Chicago
Cheng, C., Shi, L., Wang, X., Wang, S., Wan, X., Liu, S., Wang, Y., Lu, Z., Wang, L., Ding, Y."Stat3/Oct-4/c-Myc signal circuit for regulating stemness-mediated doxorubicin resistance of triple-negative breast cancer cells and inhibitory effects of WP1066". International Journal of Oncology 53, no. 1 (2018): 339-348. https://doi.org/10.3892/ijo.2018.4399