Increased Expression of Phosphodiesterase Type 5 Promotes the Invasive Potential of Breast Cancer Cells: Implications for Targeted Therapy.. Increased Expression of Phosphodiesterase Type 5 Promotes the Invasive Potential of Breast Cancer Cells: Implications for Targeted Therapy.

Purpose: By catalyzing hydrolysis of cyclic guanosine monophosphate, phosphodiesterase (PDE) 5 is a critical regulator of its concentration and biological effects in different (patho)physiological processes, including cancers. Being PDE5 a known druggable target, we investigated the clinical significance of its expression in breast cancers and the underlying molecular mechanisms by which it may contribute to breast cancer progression. Experimental Design: RT-PCR and immunoblotting analyses were used for PDE5 expression in eight breast cancer cell lines. To examine PDE5’s impact on cancer phenotype, MCF-7 cells, expressing the lowest levels of PDE5, were engineered to stably overexpress PDE5. Cell proliferation was assessed by MTT assays, motility and invasion by wound-healing, transmigration, matrigel-based invasion assays. RNA sequencing identified differentially-expressed genes. Clinical relevance of PDE5 was investigated by immunohistochemistry on tissues and retrospective studies from the Metabric cohort. Results: PDE5 was expressed at lower levels in luminal A-type breast cancer cells (MCF-7) compared to luminal B-like, HER2-overexpressing and basal-like cells. MCF-7 cells stably overexpressing PDE5 exhibited an increased cell motility and invasion through activation of Rho family of GTPases. Treatment of PDE5 clones with selective ROCK or PDE5 inhibitors completely restored the less motile and weak invasive behavior of control cells. In patients, PDE5 expression was found in ~85% of tumor entities analyzed, with the highest intensity staining in high-grade tumors. Retrospective analyses showed that higher PDE5 levels correlated with poorer survival. Conclusion: PDE5 expression enhances breast cancer cell invasive potential, highlighting its role as a novel molecular candidate with prognostic significance and a potential target in the treatment of breast cancers.