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Disruption of FOXO3a-miRNA feedback inhibition of IGF2/IGF-1R/IRS1 signaling confers Herceptin resistance in HER2-positive breast cancer

Author

Listed:
  • Liyun Luo

    (Affiliated Cancer Hospital & Institute of Guangzhou Medical University)

  • Zhijie Zhang

    (Affiliated Cancer Hospital & Institute of Guangzhou Medical University)

  • Ni Qiu

    (Affiliated Cancer Hospital & Institute of Guangzhou Medical University)

  • Li Ling

    (Affiliated Cancer Hospital & Institute of Guangzhou Medical University)

  • Xiaoting Jia

    (Affiliated Cancer Hospital & Institute of Guangzhou Medical University)

  • Ying Song

    (Affiliated Cancer Hospital & Institute of Guangzhou Medical University)

  • Hongsheng Li

    (Affiliated Cancer Hospital & Institute of Guangzhou Medical University)

  • Jiansheng Li

    (Affiliated Cancer Hospital & Institute of Guangzhou Medical University)

  • Hui Lyu

    (Louisiana State University (LSU) Health Sciences Center)

  • Hao Liu

    (Affiliated Cancer Hospital & Institute of Guangzhou Medical University)

  • Zhimin He

    (Affiliated Cancer Hospital & Institute of Guangzhou Medical University)

  • Bolin Liu

    (Louisiana State University (LSU) Health Sciences Center)

  • Guopei Zheng

    (Affiliated Cancer Hospital & Institute of Guangzhou Medical University
    Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation)

Abstract

Resistance to Herceptin represents a significant challenge for successful treatment of HER2-positive breast cancer. Here, we show that in Herceptin-sensitive cells, FOXO3a regulates specific miRNAs to control IGF2 and IRS1 expression, retaining basic IGF2/IGF-1R/IRS1 signaling. The basic activity maintains expression of PPP3CB, a subunit of the serine/threonine-protein phosphatase 2B, to restrict FOXO3a phosphorylation (p-FOXO3a), inducing IGF2- and IRS1-targeting miRNAs. However, in Herceptin-resistant cells, p-FOXO3a levels are elevated due to transcriptional suppression of PPP3CB, disrupting the negative feedback inhibition loop formed by FOXO3a and the miRNAs, thereby upregulating IGF2 and IRS1. Moreover, we detect significantly increased IGF2 in blood and IRS1 in the tumors of breast cancer patients with poor response to Herceptin-containing regimens. Collectively, we demonstrate that the IGF2/IGF-1R/IRS1 signaling is aberrantly activated in Herceptin-resistant breast cancer via disruption of the FOXO3a-miRNA negative feedback inhibition. Such insights provide avenues to identify predictive biomarkers and effective strategies overcoming Herceptin resistance.

Suggested Citation

  • Liyun Luo & Zhijie Zhang & Ni Qiu & Li Ling & Xiaoting Jia & Ying Song & Hongsheng Li & Jiansheng Li & Hui Lyu & Hao Liu & Zhimin He & Bolin Liu & Guopei Zheng, 2021. "Disruption of FOXO3a-miRNA feedback inhibition of IGF2/IGF-1R/IRS1 signaling confers Herceptin resistance in HER2-positive breast cancer," Nature Communications, Nature, vol. 12(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-23052-9
    DOI: 10.1038/s41467-021-23052-9
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    Cited by:

    1. Yutian Zou & Shaoquan Zheng & Xinhua Xie & Feng Ye & Xiaoqian Hu & Zhi Tian & Shu-Mei Yan & Lu Yang & Yanan Kong & Yuhui Tang & Wenwen Tian & Jindong Xie & Xinpei Deng & Yan Zeng & Zhe-Sheng Chen & Ha, 2022. "N6-methyladenosine regulated FGFR4 attenuates ferroptotic cell death in recalcitrant HER2-positive breast cancer," Nature Communications, Nature, vol. 13(1), pages 1-18, December.

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