Abstract 5683: lncRNA-protein interactions that predict response to endocrine therapy in HR+ breast cancer

Abstract Hormone receptor positive (HR+) breast cancer (BCa) is the most frequently diagnosed BCa type accounting for 70% of all breast cancer cases. A large population of HR+ BCa patients (30-40%) are resistant to mainstay endocrine therapy and develop incurable metastatic disease. Hence, it is imperative to identify viable biomarkers that stratify patients as drug responders or non-responders. Emerging scientific literature highlights the essential role of long non-coding RNAs (lncRNA) in cancer drug resistance and metastatic transformation; lncRNA include RNAs over 200 nucleotides in length that do not encode protein. Major biological functions of lncRNA rely on association with select protein interactors. As lncRNA equally bind proteins with and without canonical RNA-binding motifs, it is unclear what facilitates this lncRNA-protein interaction. Our recent studies show that SUMO post-translational modification (or SUMOylation) of target proteins potentiates binding with lncRNA, particularly at the chromatin. Using a small-scale screening, we see that SUMO-modification works to enhance association with lncRNAs for proteins with and without a canonical RNA binding domain (RBD). SUMOylation of RBD-expressing heterochromatin protein 1 α (HP1α) drives interaction with multiple chromatin-associated lncRNA both within and outside canonical heterochromatin foci. Interaction with lncRNA supports SUMOylated HP1α’s unconventional function as a transcriptional repressor at select euchromatic loci. We now report an inverse relationship in which SUMOylated HP1α directs the stability of its lncRNA binding partner. Specifically, SUMO-modified HP1α directs cell-cycle dependent recruitment of the RNA degradation machinery to the chromatin and facilitates clearance of chromatin-bound lncRNA. This dynamic lncRNA degradation process is disturbed with cancer onset and instead favors aberrant cancer cell transformation. Consistently, restoring lncRNA degradation homeostasis decreases metastatic properties of HR+ BCa cells and increases sensitivity to targeted therapeutics currently in clinical trials. Our studies define a fundamental mechanism that dictates lncRNA stability and/or degradation in BCa cells. In addition, we present viable biomarkers that predict sensitivity to ET and alternative targeted therapies. Citation Format: Kacie D. Waiters, Maram Quttina, Ashfia F. Khan, Samaneh Karami, Anthony S. Peidl, Funmi Babajide, Tasneem Bawa-Khalfe. lncRNA-protein interactions that predict response to endocrine therapy in HR+ breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5683.