ERα/PR crosstalk is altered in the context of the ERα Y537S mutation and contributes to endocrine therapy-resistant tumor proliferation

The constitutively active ESR1 Y537S mutation is associated with endocrine therapy (ET) resistance and progression of metastatic breast cancer through its effects on estrogen receptor (ER alpha) gene regulatory functions. However, the complex relationship between ER alpha and the progesterone receptor (PR), known as ER alpha/PR crosstalk, has yet to be characterized in the context of the ER alpha Y537S mutation. Using proximity ligation assays, we identify an increased physical interaction of ER alpha and PR in the context of the ER alpha Y537S mutation, including in the nucleus where this interaction may translate to altered gene expression. As such, more than 30 genes were differentially expressed in both patient tumor and cell line data (MCF7 and/or T47D cells) in the context of the ER alpha Y537S mutation compared to ER alpha WT. Of these, IRS1 stood out as a gene of interest, and ER alpha and PR occupancy at chromatin binding sites along IRS1 were uniquely altered in the context of ER alpha Y537S. Furthermore, siRNA knockdown of IRS1 or treatment with the IRS1 inhibitor NT-157 had a significant anti-proliferative effect in ER alpha Y537S cell lines, implicating IRS1 as a potential therapeutic target for restoring treatment sensitivity to patients with breast cancers harboring ER alpha Y537S mutations.

Automated summary

The constitutively active ESR1 Y537S mutation is associated with increased physical interaction of ER alpha and PR, altered gene expression, and potential therapeutic targeting of IRS1 for restoring treatment sensitivity in breast cancers harboring ER alpha Y537S mutations.