Inhibition of phosphodiesterase 4 and 7 regulates breast cancer cell proliferation

• Published in: Biochimica et biophysica acta. General subjects Vol. 1869; no. 11; p. 130850
• Main Authors: Mayora Justel, Carla, Valladares, Tamara, Gargiulo, Lucía, González-Pardo, Verónica, De Sousa, Maximiliano, Esandi, María del Carmen, Davio, Carlos, Lüthy, Isabel, Bruzzone, Ariana
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.10.2025
• Subjects: Breast neoplasm; Cell line; Cyclic AMP; Gene expression; Phosphodiesterase 4 inhibitor; Roflumilast; Cyclic AMP; Cell line; Roflumilast; Phosphodiesterase 4 inhibitor; Gene expression; Breast neoplasm
• ISSN: 0304-4165; 1872-8006; 1872-8006
• DOI: 10.1016/j.bbagen.2025.130850

cAMP regulates key processes in mammary cell biology. Previous studies suggested reduced cAMP production in more malignant cells. This study investigates the role of cAMP in mammary biology using non-tumor (MCF-10A  and HBL-100) and tumor (MCF-7 and MDA-MB-231) human breast cell lines. cAMP levels were quantified using a competitive radio-binding assay. Cell proliferation and viability were assessed by cell counting and MTT assay. Gene expression was analyzed by real-time PCR and immunofluorescence. Additional assays included migration, colony formation, annexin V/IP staining, comet assay, and caspase-3 activity. Public datasets were consulted. Phosphodiesterase (PDE) inhibitors were tested: the broad-spectrum PDE inhibitor IBMX (3-Isobutyl-1-methylxanthine), the PDE4-selective inhibitor roflumilast, and the PDE7-selective inhibitor BRL-50481. Non-tumor cells produced more cAMP than tumor cells, with or without IBMX. IBMX decreases cell proliferation and viability in all cell lines. Gene expression data revealed higher ADCY2, 3, 4, 5, 6, and 8 expression in normal tissues. Roflumilast reduced cell viability in all tested cells, while the PDE7-specific inhibitor BRL-50481 only affected MCF-7 cells. All PDE inhibitors exhibited an additive effect with tamoxifen, reducing MCF-7 cell viability. In tumor cells roflumilast decreased cell migration. In MDA-MB-231 cells, although IBMX and roflumilast showed a trend toward further decreasing viability compared to doxorubicin or paclitaxel alone, the differences were not statistically significant. The selective PDE4 inhibitor roflumilast demonstrated potential as a therapeutic agent when combined with specific breast cancer treatments, offering a novel approach in breast cancer therapy. •cAMP levels are higher in non-tumor breast cells compared to breast cancer cells.•ADCY gene expression is lower in tumor tissues compared to normal tissues.•PDE4D expression is elevated in MDA-MB-231 breast cancer cells.•Roflumilast reduces migration and cell viability in breast cancer cell lines.•PDE inhibitors enhance tamoxifen effects in MCF-7 breast cancer cells.