Abstract 4141: PDE3A promotes ER positive beast cancer progression by preventing ERα ubiquitination degradation

Background: ER+ breast cancer (ER+BC) is the most common subtype, which characterized by high risk of recurrence and metastasis after treatment. ERα is considered to be a key driver in the malignant progression of ER+BC, and it is necessary to understand the signaling mechanism of ERα. PDE3A, a member of the phosphodiesterases (PDEs) family, can hydrolyze the cAMP and cGMP, and is an important regulator of intracellular signaling. However, there are few studies on the effect of PDE3A on the malignant progression of ER+BC, and the specific mechanism is still unclear. Aim: (i) To investigate the prognostic role of PDE3A in ER+BC and its links with breast cancer proliferation and metastasis; (ii) to explore the regulatory mechanism of PDE3Ain ER+BC biological process; (iii) to screen effective molecule inhibitor targetingPDE3A. Methods: The expression level of PDE3A in ER+BC was determined by immunohistochemical staining and the mRNA expression profiles from the TCGA database. Roles of PDE3Ain cancer cell growth, metastasis were determined by molecular and cell biology methods. Co-Immunoprecipitation (CO-IP) was used to examine the binding of PDE3Aand ERα. Chromatin immunoprecipitation (ChIP) and promoter luciferase reporter assay were included for detecting the transcription of PDE3A in ER+BC. ER+BC xenograft mice were used to study the inhibition of tumor development. Results: PDE3A is a novel ER+BC target, which is overexpressed in ER+BC tissues and significantly associated with clinical pathology of advanced TNM stage and poor prognosis of patients. In vitro and in vivo studies have demonstrated that PDE3Apromotes ER+BC proliferation and metastasis. Mechanically, PDE3A regulates ERαproteasome degradation through competitive binding to ERα with its E3 ligase SPOP, independently of the catalytic activity of PDE3A. In addition, ERα directly facilitates the transcription of PDE3A and up-regulate the expression level of PDE3A.Furthermore, we screened out brequinar, a small molecule inhibitor targeting PDE3A, can inhibit breast cancer cell proliferation and metastasis, and reverse endocrine resistance. Conclusion: We identified an important role of PDE3A-ERα feedback loop in the ER+BC progress and resistance to endocrine therapy, representing a future biomarker and therapeutic target of ER+BC. Citation Format: Shengyu Pu, Heyan Chen, Bohong Chen, Jianjun He, Na Hao. PDE3A promotes ER positive beast cancer progression by preventing ERα ubiquitination degradation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4141.