Abstract PS2-11-07: Linc00152-regulated pde4d is a mediator of drug resistance and metastasis in highly aggressive breast cancer

Abstract Resistance to anti-cancer therapies is one of the major challenges against effective cancer treatment that is frequently accompanied by metastatic recurrence, the major cause of cancer-related death. Here, we identified the Phosphodiesterase 4D (PDE4D) and its novel upstream long non-coding RNA (lncRNA) LINC00152 as critical mediators of drug resistance and metastasis in aggressive breast cancers. We showed that LINC00152 interacts with and stabilizes PDE4D mRNA, thus driving resistance to standard of care endocrine therapy. Mechanistically, LINC00152/PDE4D deactivates the downstream cAMP/PKA/CREB axis, leading to reduced intracellular calcium and iron accumulation, preventing drug-induced ferroptosis. Inhibiting LINC00152 restores sensitivity by activating cAMP/PKA/ferroptosis axis which is reversed by PDE4D overexpression. In addition, we demonstrated that PDE4D promotes migration and metastasis via triggering luminal-to-basal transition in highly aggressive drug resistant models. Inhibiting LINC00152 or PDE4D reduces cancer cell migration upon PKA-mediated blockage of TGF-β signaling and reduction of mesenchymal gene expression. Targeting PDE4D using the clinically-tested PDE4D selective inhibitor, BPN14770 significantly reduces the number of circulating tumor cells and 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 PDE4D and its highly oncogenic upstream lncRNA, LINC00152 as mediators of endocrine resistance and metastasis in the highly aggressive ER+ breast cancer. Citation Format: O. Saatci, R. Alam, K. Huynh-Dam, A. Isik, M. Uner, N. Belder, P. G. Ersan, U. M. Tokat, B. Ulukan, M. Cetin, K. Calisir, M. E. Gedik, H. Bal, O. Sener Sahin, Y. Riazalhosseini, D. Thieffry, D. Gautheret, B. Ogretmen, S. Aksoy, A. Uner, A. Akyol, O. Sahin. Linc00152-regulated pde4d is a mediator of drug resistance and metastasis in highly aggressive breast cancer abstract. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS2-11-07.