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Hokkaido University Collection of Scholarly and Academic Papers >
Institute for Chemical Reaction Design and Discovery : ICReDD >
Peer-reviewed Journal Articles, etc >
ERK MAP Kinase Signaling Regulates RAR Signaling to Confer Retinoid Resistance on Breast Cancer Cells
| Title: | ERK MAP Kinase Signaling Regulates RAR Signaling to Confer Retinoid Resistance on Breast Cancer Cells |
| Authors: | Hirota, Akira Browse this author →KAKEN DB | | Clement, Jean-Emmanuel Browse this author →KAKEN DB | | Tanikawa, Satoshi Browse this author →KAKEN DB | | Nonoyama, Takayuki Browse this author →KAKEN DB | | Komatsuzaki, Tamiki Browse this author →KAKEN DB | | Gong, Jian Ping Browse this author →KAKEN DB | | Tanaka, Shinya Browse this author →KAKEN DB | | Imajo, Masamichi Browse this author →KAKEN DB |
| Keywords: | breast cancer | | retinoids | | retinoic acid receptor (RAR) | | ERK MAP kinase | | breast cancer subtypes |
| Issue Date: | Dec-2022 |
| Publisher: | MDPI |
| Journal Title: | Cancers |
| Volume: | 14 |
| Issue: | 23 |
| Start Page: | 5890 |
| Publisher DOI: | 10.3390/cancers14235890 |
| Abstract: | 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. 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. |
| Type: | article |
| URI: | http://hdl.handle.net/2115/87763 |
| Appears in Collections: | 化学反応創成研究拠点：ICReDD (Institute for Chemical Reaction Design and Discovery : ICReDD) > 雑誌発表論文等 (Peer-reviewed Journal Articles, etc)
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