ERα36-GPER1 Collaboration Inhibits TLR4/NFκB-Induced Pro-Inflammatory Activity in Breast Cancer Cells

Inflammation is important for the initiation and progression of breast cancer. We have previously reported that in monocytes, estrogen regulates TLR4/NF kappa B-mediated inflammation via the interaction of the Er alpha isoform ER alpha 36 with GPER1. We therefore investigated whether a similar mechanism is present in breast cancer epithelial cells, and the effect of ER alpha 36 expression on the classic 66 kD ER alpha isoform (ER alpha 66) functions. We report that estrogen inhibits LPS-induced NF kappa B activity and the expression of downstream molecules TNF alpha and IL-6. In the absence of ER alpha 66, ER alpha 36 and GPER1 are both indispensable for this effect. In the presence of ER alpha 66, ER alpha 36 or GPER1 knock-down partially inhibits NF kappa B-mediated inflammation. In both cases, ER alpha 36 overexpression enhances the inhibitory effect of estrogen on inflammation. We also verify that ER alpha 36 and GPER1 physically interact, especially after LPS treatment, and that GPER1 interacts directly with NF kappa B. When both ER alpha 66 and ER alpha 36 are expressed, the latter acts as an inhibitor of ER alpha 66 via its binding to estrogen response elements. We also report that the activation of ER alpha 36 leads to the inhibition of breast cancer cell proliferation. Our data support that ER alpha 36 is an inhibitory estrogen receptor that, in collaboration with GPER1, inhibits NF kappa B-mediated inflammation and ER alpha 66 actions in breast cancer cells.

Automated summary

ER alpha 36 collaborates with GPER1 to inhibit NF kappa B-mediated inflammation and ER alpha 66 actions in breast cancer cells. Particularly, this effect is more significant in the absence of ER alpha 66. Moreover, overexpression of ER alpha 36 enhances the inhibitory effect of estrogen on inflammation.