Abstract Retinoic acid signaling, mediated through its receptors (RARs and RXRs), plays a fundamental role in regulating cell differentiation, proliferation, and apoptosis. While well established in hematologic malignancies, particularly acute promyelocytic leukemia, its therapeutic potential in breast cancer remains underexplored. Emerging evidence has identified aberrant epigenetic regulation of retinoic acid receptors as a central mechanism of resistance to retinoic acid. This review integrates recent advances in epigenetic control, receptor biology, and translational studies to re-evaluate the therapeutic potential of retinoic acid in breast cancer. Among the many factors that influence retinoic acid signaling are reduced receptor expression and altered intracellular delivery of retinoic acid. Promoter hypermethylation and histone deacetylation silence RARβ2 and disrupt canonical retinoic acid transcriptional networks, while imbalanced intracellular routing via CRABP2 and FABP5 and subtype-specific expression of RAR isoforms further determine therapeutic outcomes. Luminal tumors with preserved RARα and CRABP2 expression display strong retinoic acid sensitivity, in contrast to HER2-enriched and triple-negative subtypes, where MYC -driven CRABP2 suppression and DNA hypermethylation confer retinoid resistance. Epigenetic therapies using DNMT or HDAC inhibitors can restore RARβ2 expression and resensitize tumors. Combination regimens such as retinoic acid with entinostat and doxorubicin achieve potent antitumor synergy in preclinical models. Retinoic acid also remodels the tumor microenvironment by modulating angiogenesis, fibroblast activation, and immune responses, although stromal RARβ signaling can paradoxically promote tumor progression. Early clinical trials lacked biomarker stratification and were limited by unfavorable pharmacokinetics, likely obscuring therapeutic benefit. Future clinical development should focus on biomarker-driven patient stratification, pharmacological optimization, and rational combination strategies that integrate retinoids with targeted or immune-based therapies. Notably, emerging methylation-based classifiers that identify retinoid-responsive triple-negative breast cancer subsets, together with the paradoxical pro-tumorigenic effects of stromal RARβ, underscore the novelty and translational significance of integrating tumor-intrinsic and microenvironmental determinants of retinoid sensitivity. Together, these approaches may help re-establish functional retinoid signaling and realize the therapeutic potential of retinoic acid in breast cancer.
Szymański et al. (Fri,) studied this question.