ERK MAP Kinase Signaling Regulates RAR Signaling to Confer Retinoid Resistance on Breast Cancer Cells

SIMPLE SUMMARY: Breast cancer is among the most common cancers and the leading cause of cancer-related death in women worldwide. Among potential anticancer drugs considered promising in breast cancer treatment are retinoids that act mainly through nuclear retinoic acid receptors (RARs). Clinical trials, however, showed that cancer cells often acquire resistance to retinoid therapy. Therefore, elucidation of underlying mechanisms of retinoid resistance is needed to develop more effective use of retinoids in cancer treatment. In this study, we identify activation of ERK MAP kinase signaling as a novel mechanism for retinoid resistance of breast cancer cells. We show that ERK signaling regulates RAR signaling and inhibition of ERK potentiates tumor-suppressive functions of RARs in breast cancer cells. Moreover, we also reveal that suppression of RAR signaling coincides with activation of ERK signaling in specific subtypes of breast cancers and that these changes are associated with poor prognoses of breast cancer patients. ABSTRACT: Retinoic acid (RA) and its synthetic derivatives, retinoids, have been established as promising anticancer agents based on their ability to regulate cell proliferation and survival. Clinical trials, however, have revealed that cancer cells often acquire resistance to retinoid therapy. Therefore, elucidation of underlying mechanisms of retinoid resistance has been considered key to developing more effective use of retinoids in cancer treatment. In this study, we show that constitutive activation of ERK MAP kinase signaling, which is often caused by oncogenic mutations in RAS or RAF genes, suppresses RA receptor (RAR) signaling in breast cancer cells. We show that activation of the ERK pathway suppresses, whereas its inhibition promotes, RA-induced transcriptional activation of RAR and the resultant upregulation of RAR-target genes in breast cancer cells. Importantly, ERK inhibition potentiates the tumor-suppressive activity of RA in breast cancer cells. Moreover, we also reveal that suppression of RAR signaling and activation of ERK signaling are associated with poor prognoses in breast cancer patients and represent hallmarks of specific subtypes of breast cancers, such as basal-like, HER2-enriched and luminal B. These results indicate that ERK-dependent suppression of RAR activity underlies retinoid resistance and is associated with cancer subtypes and patient prognosis in breast cancers.