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Published on: June 9, 2023
Expression and Function of Phosphodiesterase Type 5 in Human Breast Cancer Cell Lines and Tissues: Implications for
Stefania Catalano1, Antonella Campana1, Cinzia Giordano2
1Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende (CS), Italy.
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.
Insights
Phosphodiesterase (PDE) 5 expression enhances breast cancer cell invasion, particularly in HER2-positive and triple-negative subtypes. Targeting PDE5 may offer a novel therapeutic strategy for breast cancer patients.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Phosphodiesterase type 5 (PDE5) regulates cyclic guanosine monophosphate (cGMP) levels.
- PDE5 plays a role in various physiological and pathological processes, including cancer.
- PDE5 is a validated drug target.
Purpose of the Study:
- To investigate the clinical significance of PDE5 expression in breast cancer.
- To elucidate the mechanisms by which PDE5 contributes to tumor progression.
Main Methods:
- PDE5 expression was assessed in breast cancer cell lines and patient tissues using RT-PCR, immunoblotting, and immunohistochemistry (IHC).
- Functional assays (proliferation, motility, invasion) were performed on engineered MCF-7 cells overexpressing PDE5.
- Transcriptome profiling and Rho GTPase signaling activation assays were conducted.
- Clinical relevance was evaluated using the METABRIC cohort.
Main Results:
- PDE5 is differentially expressed across breast cancer subtypes, with higher levels in HER2-positive and triple-negative cancers.
- Elevated PDE5 expression correlates with high histologic grade and shorter patient survival.
- PDE5 overexpression enhanced cell motility and invasion, mediated by Rho GTPase signaling.
- Inhibitors of ROCK or PDE5 reversed the invasive phenotype.
Conclusions:
- PDE5 expression promotes breast cancer cell invasion.
- PDE5 is a potential prognostic marker for breast cancer.
- PDE5 represents an attractive therapeutic target for breast cancer treatment.
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