Abstract LB452: The role of dysregulated retinoid receptors in colorectal cancer

Abstract The retinoic acid (RA) signaling pathway plays an essential role in regulating cell differentiation in the colon. Our Goal is to determine how aberrant retinoid receptor expression might promote colorectal cancer (CRC) development through dysregulated retinoic acid signaling. Rationale: Retinoid receptors are often abnormally expressed or mutated in human CRCs. So, aberrant expression or mutation of RA receptors could lead to incomplete differentiation and increase CRC growth. Indeed, we previously reported that CRC cell lines harboring mutations in RA receptors (RAR, RXR) have drug resistance to all-trans RA (ATRA). Hypothesis: Aberrant RA receptor expression leads to dysregulated RA signaling that contributes to CRC development. Accordingly, we investigated RA receptor components of the RA signaling pathway including RARs, RXRs, PPARs and determined if aberrant RA expression predicts CRC patient survival. We discovered a signature of six RA receptor genes that are differentially expressed between normal colon and CRC, and that also predicts poor CRC patient survival. We found that up to 22% of CRCs have RA receptor mutations, but mutation status did not predict patient survival. However, we did find that frequency of retinoid receptor mutation was higher (>2X-fold) in early-onset CRC (EOCRC, age < 45) compared to late-onset CRC. NanoString profiling experiments revealed: i). induction of wild-type APC expression in APC-mutant CRC cells increases expression of RA receptors in response to ATRA; ii). A specific RA receptor expression profile characterizes ALDH+ versus LGR5+ stem cells. Conclusions Since RA receptor expression predicts CRC patient survival, it provides a mechanism by which dysregulated RA signaling could promote tumor behavior and drive colon tumorigenesis. Since the rate of retinoid receptor mutation was increased in EOCRC, this indicates that aberrant RA signaling may be a predisposing factor for early CRC development. Citation Format: Bruce M. Boman, Brooke Coulbourne, Anh Nguyen, Caroline Facey, Chi Zhang. The role of dysregulated retinoid receptors in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB452.