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ERK MAP Kinase Signaling Regulates RAR Signaling to Confer Retinoid Resistance on Breast Cancer Cells
Akira Hirota1, Jean-Emmanuel Clément1,2, Satoshi Tanikawa1
1Institute for Chemical Reaction Design and Discovery (WPI-ICReDD), Hokkaido University, Sapporo 001-0021, Japan.
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.
Insights
Retinoid resistance in cancer is linked to activated ERK signaling suppressing retinoic acid receptor (RAR) activity. Inhibiting ERK can restore retinoid therapy effectiveness and improve breast cancer prognosis.
Area of Science:
- Oncology
- Molecular Biology
- Cell Signaling
Background:
- Retinoids, including retinoic acid (RA), show anticancer potential by regulating cell proliferation and survival.
- Cancer cells frequently develop resistance to retinoid therapy, hindering treatment efficacy.
- Understanding retinoid resistance mechanisms is crucial for improving cancer treatment strategies.
Purpose of the Study:
- To investigate the role of ERK MAP kinase signaling in retinoid resistance in breast cancer.
- To determine if ERK pathway activation suppresses retinoic acid receptor (RAR) signaling.
- To evaluate the therapeutic potential of inhibiting ERK signaling in overcoming retinoid resistance.
Main Methods:
- Investigated the effect of ERK MAP kinase signaling on RAR transcriptional activity in breast cancer cells.
- Utilized gene expression analysis to assess RAR-target gene upregulation.
- Correlated RAR and ERK signaling status with patient prognosis and breast cancer subtypes.
Main Results:
- Constitutive activation of ERK signaling, often due to RAS/RAF mutations, suppresses RAR signaling in breast cancer.
- ERK pathway activation inhibits RA-induced RAR transcriptional activity and target gene expression.
- Inhibition of ERK signaling potentiates the tumor-suppressive effects of RA.
- Suppressed RAR signaling and activated ERK signaling are associated with poor prognosis in breast cancer subtypes (basal-like, HER2-enriched, luminal B).
Conclusions:
- ERK-dependent suppression of RAR activity is a key mechanism underlying retinoid resistance in breast cancer.
- Targeting the ERK pathway offers a potential strategy to overcome retinoid resistance.
- The interplay between ERK and RAR signaling is linked to specific breast cancer subtypes and patient outcomes.
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