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

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. Resistance to Herceptin represents a major challenge for successful treatment of HER2-positive breast cancer. Here, the authors demonstrate that the activation of the IGF2/IRS1 signal caused by disruption of a negative feedback loop between FOXO3a-miR-128/miR-30/miR-193 induces Herceptin resistance.

Automated summary

Resistance to Herceptin in HER2-positive breast cancer is a major challenge, with aberrant activation of the IGF2/IRS1 signaling pathway due to disruption of the negative feedback loop between FOXO3a and miRNAs. Detecting increased levels of IGF2 and IRS1 in patients with poor response to Herceptin-containing regimens provides insights for identifying predictive biomarkers and strategies to overcome resistance to Herceptin.