Increased Expression of Estrogen Receptor α-36 by Breast Cancer Oncogene IKKε Promotes Growth of ER-Negative Breast Cancer Cells

Abstract

Background/Aims: The expression of estrogen receptor-α (ERα) is one of the most important diagnostic and prognostic factors of breast cancer. Recently, ERα-36 has been identified as a novel variant of ER-α. ERα-36 lacks intrinsic transcription activity and mainly mediates non-genomic estrogen signaling. The noncanonical IKK family member IKKε is essential for regulating antiviral signaling pathways and is recently discovered as a breast cancer oncogene. IKKε interacts with and phosphorylates ERα on serine 167, induces ERα transactivation activity and enhances ERα binding to DNA in ER-positive breast cancer cells. However, the correlation between IKKε and the ERα-36 signaling pathway in ER-negative breast cancer cells remains unclear. Methods and Results: In this study, we show that IKKε interacts with ERα-36 and increases its expression in breast cancer cells. As shown by western blot assays, the upregulation of ERα-36 by IKKε was significant. In MDA-MB-231 cells which are ER-negative, IKKε was able to increase the expression of ERα-36 in a dose-dependent manner, and the RNA interference assay indicated the correlation between IKKε and ERα-36 expression. Moreover, IKKε enhanced the growth of MDA-MB-231 and MDA-MB-436 cells. Conclusions: These results suggest that IKKε increases ERα-36 expression and is involved in ERα-36 mediated non-genomic estrogen signaling.