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Relevance and mechanism of STAT3/miR-221-3p/Fascin-1 axis in EGFR TKI resistance of triple-negative breast cancer

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Abstract

The epidermal growth factor receptor 1 (EGFR) plays a crucial role in the progression of various malignant tumors and is considered a potential target for treating triple-negative breast cancer (TNBC). However, the effectiveness of representative tyrosine kinase inhibitors (TKIs) used in EGFR-targeted therapy is limited in TNBC patients. In our study, we observed that the TNBC cell lines MDA-MB-231 and MDA-MB-468 exhibited resistance to Gefitinib. Treatment with Gefitinib caused an upregulation of Fascin-1 (FSCN1) protein expression and a downregulation of miR-221-3p in these cell lines. However, sensitivity to Gefitinib was significantly improved in both cell lines with either inhibition of FSCN1 expression or overexpression of miR-221-3p. Our luciferase reporter assay confirmed that FSCN1 is a target of miR-221-3p. Moreover, Gefitinib treatment resulted in an upregulation of phosphorylated signal transducer and activator of transcription 3 (p-STAT3) in MDA-MB-231 cells. Using Stattic, a small-molecule inhibitor of STAT3, we observed a significant enhancement in the inhibitory effect of Gefitinib on the growth, migration, and invasion of MDA-MB-231 cells. Additionally, Stattic treatment upregulated miR-221-3p expression and downregulated FSCN1 mRNA and protein expression. A strong positive correlation was noted between the expression of STAT3 and FSCN1 in breast cancer tissues. Furthermore, patients with high expression levels of both STAT3 and FSCN1 had a worse prognosis. Our findings suggest that elevated FSCN1 expression is linked to primary resistance to EGFR TKIs in TNBC. Moreover, we propose that STAT3 regulates the expression of miR-221-3p/FSCN1 and therefore modulates resistance to EGFR TKI therapy in TNBC. Combining EGFR TKI therapy with inhibition of FSCN1 or STAT3 may offer a promising new therapeutic option for TNBC.

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Data availability

All the datasets used and/or analyzed in the study are available from the corresponding author on reasonable request.

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Funding

This work was supported by grants from the National Natural Science Foundation of China (No. 81802660).

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Author notes

  1. Lu-Lu Jin and Hua-Jun Lu have contributed equally to this work.

Authors and Affiliations

  1. Department of Biomedical Sciences Laboratory, Affiliated Dongyang Hospital of Wenzhou Medical University, Dongyang, Zhejiang, China

    Lu-Lu Jin

  2. Department of Oncological Radiotherapy, Affiliated Dongyang Hospital of Wenzhou Medical University, Dongyang, Zhejiang, China

    Hua-Jun Lu

  3. Department of Pathology, Affiliated Dongyang Hospital of Wenzhou Medical University, 60 Wu Ning Xi Road, Dongyang, Zhejiang, China

    Jun-Kang Shao, Shi-Ping Lu, Bi-Fei Huang & Chao-Qun Wang

  4. Department of Medical Oncology, Affiliated Dongyang Hospital of Wenzhou Medical University, Dongyang, Zhejiang, China

    Yan Wang

  5. Department of Surgical Oncology, Affiliated Dongyang Hospital of Wenzhou Medical University, Dongyang, Zhejiang, China

    Gui-Nv Hu

  6. Laboratory of Cancer Biology, Key Laboratory of Biotherapy in Zhejiang Province, Sir Run Run Shaw Hospital, Medical School of Zhejiang University, Hangzhou, Zhejiang, China

    Hong-Chuan Jin

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Contributions

CQW: designed the experiments. LLJ, HJL, JKS, and YW: performed the experiments. CQW, LLJ, HJL, and SPL: analyzed the data. BFH and GNH: were responsible for management of the clinical samples. The manuscript was written by CQW and revised by HCJ. All authors have read and approved the final manuscript.

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Correspondence to Chao-Qun Wang.

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Jin, LL., Lu, HJ., Shao, JK. et al. Relevance and mechanism of STAT3/miR-221-3p/Fascin-1 axis in EGFR TKI resistance of triple-negative breast cancer. Mol Cell Biochem (2023). https://doi.org/10.1007/s11010-023-04907-9

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