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Crosstalk between IGF-1 and estrogen receptor non-genomic signaling pathway in breast cancer

Abstract : Breast cancer is a major health problem currently affecting 1 out of 5 women. Seventy percent of breast cancers are hormone-dependent, and are treated by hormonal therapies targeting estrogen receptor and consequently the inhibition of its pro-tumorigenic effects. In parallel to the genomic estrogen signaling, non-genomic signaling has been described, where ERa recruits Src kinase and PI3K at the plasma membrane and thus activates downstream phosphorylation cascades like AKT, which in turn leads to survival and proliferation of cancer cells. Our team has found that estrogen-induced methylation of arginine 260 of ERa is a prerequisite for the formation of this non-genomic complex, regulating cell proliferation. In 2012, we have shown that this pathway is activated in aggressive breast tumors representing a new potential target for breast cancer therapy. Crosstalk between estrogen and growth factors signaling involving phosphorylation has been largely described. For this reason, we investigated if ERa R260 methylation could be involved in this crosstalk. Among several growth factors, we found that IGF-1 was the only one able to induce methylation of ERa in an estrogen-independent manner. Similarly to estrogen, IGF-1 induces a rapid and transient methylation of ERa by the Protein Arginine Methyltransferase (PRMT1) concomitant with the formation of ERa/Src/PI3K complex. Using several approaches, we found significant results showing that PRMT1 probably via ERa methylation plays a crucial role in IGF-1 signaling. Interestingly, we have recently found also that receptor tyrosine kinase IGF-1R phosphorylates the DNA binding domain (DBD) of ERa that could modulate the latter downstream signaling. In line with these results, we found on TMAs of a cohort of 440 breast tumors that IGF-1 expression is correlated with ERa non-genomic signaling. These results report new insight into estrogen and IGF-1 interference, which open new perspectives of combining therapies targeting the two pathways
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Submitted on : Monday, October 15, 2018 - 6:42:07 PM
Last modification on : Friday, October 23, 2020 - 5:03:16 PM
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  • HAL Id : tel-01896107, version 1



Ali Choucair. Crosstalk between IGF-1 and estrogen receptor non-genomic signaling pathway in breast cancer. Cancer. Université de Lyon, 2018. English. ⟨NNT : 2018LYSE1074⟩. ⟨tel-01896107⟩



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