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

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

doi:10.1038/s41467-021-23052-9

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.

Highlights

Resistance to Herceptin represents a significant challenge for successful treatment of HER2positive breast cancer
We detected significantly higher protein levels of IGF2, but not IGF1 in the conditioned medium (CM) of pool[2] and HR20 cells than that of SKBR3 and BT474 cells, respectively (Fig. 1b). These data suggest that post-transcriptional upregulation of IGF2 may play a role in the activation of insulin-like growth factor (IGF)-1R/Akt/mammalian target of rapamycin (mTOR) signaling in Herceptin-resistant breast cancer cells
While the importance of insulin-like growth factor-1 receptor (IGF-1R)-initiated signaling in Herceptin resistance has been well documented, the precise mechanism leading to the signaling activation remains elusive

Summary

Introduction

Resistance to Herceptin represents a significant challenge for successful treatment of HER2positive breast cancer. We demonstrate that the IGF2/IGF-1R/IRS1 signaling is aberrantly activated in Herceptinresistant 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. Herceptin (or trastuzumab), a humanized anti-HER2 monoclonal antibody (Ab), is an effective HER2-targeted therapy against early and metastatic HER2-positive breast cancers. We seek to investigate the contributions of IGF2 and the insulin receptor substrate-1 (IRS1) to Herceptin resistance and elucidate the underlying mechanism of increased expression of both IGF2 and IRS1 and aberrant activation of IGF-1R signaling in Herceptin-resistant breast cancer

Methods

Results

Conclusion