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

Liyun Luo, Zhijie Zhang, Ni Qiu, Li Ling, Xiaoting Jia, Ying Song, Hongsheng Li, Jiansheng Li, Hui Lyu, Hao Liu, Zhimin He (), Bolin Liu () and Guopei Zheng ()
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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

Nature Communications, 2021, vol. 12, issue 1, 1-16

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-23052-9

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