American Association for Cancer Research
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10780432ccr151900-sup-153811_1_supp_3223932_nxny3l.png (1.05 MB)

Supplementary Figure 1 from Expression and Function of Phosphodiesterase Type 5 in Human Breast Cancer Cell Lines and Tissues: Implications for Targeted Therapy

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posted on 2023-03-31, 18:23 authored by Stefania Catalano, Antonella Campana, Cinzia Giordano, Balázs Győrffy, Roberta Tarallo, Antonio Rinaldi, Giuseppina Bruno, Aurora Ferraro, Francesco Romeo, Marilena Lanzino, Fabio Naro, Daniela Bonofiglio, Sebastiano Andò, Ines Barone

Molecule activity predictor analysis of Ingenuity Pathway Analysis performed on Cdc42 signaling and Rac signaling in PDE5-overexpressing MCF-7 cells compared to vector-transfected cells.

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PROGRAMMA “FUTURO IN RICERCA”

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ARTICLE ABSTRACT

Purpose: By catalyzing cGMP hydrolysis, phosphodiesterase (PDE) 5 is a critical regulator of its concentration and effects in different (patho)physiologic processes, including cancers. As PDE5 is a known druggable target, we investigated the clinical significance of its expression in breast cancer and the underlying mechanisms by which it may contribute to tumor progression.Experimental Design: PDE5 expression was evaluated in seven breast cancer cell lines by RT-PCR and immunoblotting. To examine the impact of PDE5 on cancer phenotype, MCF-7 cells expressing lower levels of the enzyme were engineered to stably overexpress PDE5. Proliferation was evaluated by MTT assays, motility and invasion by wound-healing/transmigration/invasion assays, transcriptome-profiling by RNA-sequencing, and Rho GTPase signaling activation by GST-pulldown assays and immunoblotting. Clinical relevance was investigated by IHC on tissues and retrospective studies from METABRIC cohort.Results: PDE5 is differentially expressed in each molecular subtype of both breast cancer cell lines and tissues, with higher levels representing a startling feature of HER2-positive and triple-negative breast cancers. A positive correlation was established between elevated PDE5 levels and cancers of high histologic grade. Higher PDE5 expression correlated with shorter patient survival in retrospective analyses. On molecular level, stable PDE5 overexpression in Luminal-A–like MCF-7 cells resulted in enhanced motility and invasion through Rho GTPase signaling activation. Treatment of PDE5-stable clones with selective ROCK or PDE5 inhibitors completely restored the less motile and weak invasive behavior of control vector cells.Conclusions: PDE5 expression enhances breast cancer cell invasive potential, highlighting this enzyme as a novel prognostic candidate and an attractive target for future therapy in breast cancers. Clin Cancer Res; 22(9); 2271–82. ©2015 AACR.

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