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Nat Commun: FOXO3a-miRNA negative feedback inhibition affects Herceptin resistance in HER2-positive breast cancer

 Last Update: 2021-06-16
 Source: Internet
 Author: User

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anti mitochondrial ab

her2 pathway

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Breast cancer, as one of the leading causes of cancer-related deaths in women worldwide, is a heterogeneous disease and has been divided into several molecular subtypes

Previous studies have shown that HER2 amplification/overexpression is observed in approximately 20-25% of breast cancer patients, and it is significantly related to the poor prognosis of patients

Herceptin (or trastuzumab), as a humanized anti-HER2 monoclonal antibody (Ab), is an effective HER2 targeted therapy for early and metastatic HER2-positive breast cancer

However, not all patients with HER2-positive breast cancer respond to Herceptin-based treatment regimens

There is an urgent need to develop new therapies to overcome Herceptin resistance to reduce the mortality of patients with metastatic HER2-positive breast cancer

IGF2/IGF-1R/IRS1/Akt/mTOR signaling pathway is involved in Herceptin resistance in HER2-positive breast cancer cells

In this study, the researchers found that in Herceptin-sensitive cells, FOXO3a can regulate the expression of IGF2 and IRS1 by regulating specific miRNAs to maintain the most basic level of IGF2/IGF-1R/IRS1 signal transduction

The expression and maintenance of PPP3CB (a subunit of serine/threonine protein phosphatase 2B) can inhibit the phosphorylation of FOXO3a (p-FOXO3a), and p-FOXO3a can induce miRNAs targeting IGF2 and IRS1

The PPP3CB/FOXO3a/IRS1 signaling pathway can cause a poor response to Herceptin

Researchers found that in Herceptin-resistant cells, the transcription of PPP3CB was inhibited, leading to an increase in the level of p-FOXO3a, thereby destroying the negative feedback inhibition loop formed by FOXO3a and miRNA, and finally upregulating the levels of IGF2 and IRS1.

The expression levels of IGF2 and IRS1 were significantly increased in the tumor tissues and blood of breast cancer patients who responded poorly to Herceptin treatment regimens

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

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