Abstract LB019: LINC00152-regulated PDE4D mediates drug resistance and metastasis in highly aggressive breast cancer

Abstract Phosphodiesterase 4D (PDE4D) is a member of the phosphodiesterase family of enzymes, catalyzing the hydrolysis of cAMP second messenger and inhibiting cAMP signaling. Targeting PDE4D raises the intracellular cAMP levels, leading to apoptosis and cell cycle arrest in different tumor types. However, its contribution to drug resistance and metastasis is still elusive. lncRNAs are more than 200 nucleotides in length and carry out diverse functions including transcriptional regulation, and regulation of proteins or RNA molecules by direct binding and stabilization. LINC00152 is an oncogenic lncRNA that promotes survival, proliferation, epithelial-mesenchymal transition (EMT) and invasiveness in cancer cells. Despite being a driver in several key oncogenic processes, whether LINC00152 is an upstream regulator of PDE4D to drive endocrine resistance and metastasis in ER+ breast cancer remains to be elucidated. Here we showed that LINC00152 stabilizes PDE4D mRNA, thus driving tamoxifen resistance upon deactivation of the cAMP/PKA/CREB axis. Overexpressing PDE4D rescues LINC00152-mediated tamoxifen resistance by blocking tamoxifen-induced ferroptosis. In addition, we demonstrated that inhibiting LINC00152 or PDE4D reduces the migration of endocrine resistant cells upon PKA-mediated blockage of TGF-β signaling. Targeting PDE4D using the clinically-tested PDE4D selective inhibitor, BPN14770 significantly reduces spontaneous metastasis in the highly aggressive, endocrine resistant-mimicking MMTV-PyMT model in vivo. Importantly, we showed that high levels of PDE4D mRNA is associated with worse metastasis-free survival in endocrine-treated ER+ breast cancer patients. Overall, we identified the highly oncogenic lncRNA, LINC00152 as an upstream regulator of PDE4D, which drives endocrine resistance and metastasis in the highly aggressive ER+ breast cancer. Citation Format: Ozge Saatci, Rashedul Alam, Kim-Tuyen Huynh-Dam, Aynur Isik, Meral Uner, Nevin Belder, Pelin Ersan, Unal M. Tokat, Burge Ulukan, Metin Cetin, Kubra Calisir, Mustafa E. Gedik, Hilal Bal, Ozlem Sener Sahin, Yasser Riazalhosseini, Denis Thieffry, Daniel Gautheret, Besim Ogretmen, Sercan Aksoy, Aysegul Uner, Aytekin Akyol, Ozgur Sahin. LINC00152-regulated PDE4D mediates drug resistance and metastasis in highly aggressive breast 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 LB019.