Expression and function of phosphodiesterase type 5 in human breast cancer cell lines and tissues: Implications for targeted therapy

Stefania Catalano, Antonella Campana, Cinzia Giordano, B. Györffy, Roberta Tarallo, Antonio Rinaldi, Giuseppina Bruno, Aurora Ferraro, Francesco Romeo, Marilena Lanzino, Fabio Naro, Daniela Bonofiglio, Sebastiano Andò, Ines Barone

Research output: Contribution to journalArticle

21 Citations (Scopus)

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 triplenegative 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.

Original languageEnglish
Pages (from-to)2271-2282
Number of pages12
JournalClinical Cancer Research
Volume22
Issue number9
DOIs
Publication statusPublished - May 1 2016

Fingerprint

Type 5 Cyclic Nucleotide Phosphodiesterases
Breast Neoplasms
Cell Line
rho GTP-Binding Proteins
MCF-7 Cells
Immunoblotting
Neoplasms
Therapeutics
RNA Sequence Analysis
Phosphodiesterase 5 Inhibitors
Behavior Control
Gene Expression Profiling
Enzymes
Phenobarbital
Wound Healing
Hydrolysis
Research Design
Retrospective Studies
Clone Cells
Phenotype

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Expression and function of phosphodiesterase type 5 in human breast cancer cell lines and tissues : Implications for targeted therapy. / Catalano, Stefania; Campana, Antonella; Giordano, Cinzia; Györffy, B.; Tarallo, Roberta; Rinaldi, Antonio; Bruno, Giuseppina; Ferraro, Aurora; Romeo, Francesco; Lanzino, Marilena; Naro, Fabio; Bonofiglio, Daniela; Andò, Sebastiano; Barone, Ines.

In: Clinical Cancer Research, Vol. 22, No. 9, 01.05.2016, p. 2271-2282.

Research output: Contribution to journalArticle

Catalano, S, Campana, A, Giordano, C, Györffy, B, Tarallo, R, Rinaldi, A, Bruno, G, Ferraro, A, Romeo, F, Lanzino, M, Naro, F, Bonofiglio, D, Andò, S & Barone, I 2016, 'Expression and function of phosphodiesterase type 5 in human breast cancer cell lines and tissues: Implications for targeted therapy', Clinical Cancer Research, vol. 22, no. 9, pp. 2271-2282. https://doi.org/10.1158/1078-0432.CCR-15-1900
Catalano, Stefania ; Campana, Antonella ; Giordano, Cinzia ; Györffy, B. ; Tarallo, Roberta ; Rinaldi, Antonio ; Bruno, Giuseppina ; Ferraro, Aurora ; Romeo, Francesco ; Lanzino, Marilena ; Naro, Fabio ; Bonofiglio, Daniela ; Andò, Sebastiano ; Barone, Ines. / Expression and function of phosphodiesterase type 5 in human breast cancer cell lines and tissues : Implications for targeted therapy. In: Clinical Cancer Research. 2016 ; Vol. 22, No. 9. pp. 2271-2282.
@article{031a3d0f05ba40099b4d0a561ca258b2,
title = "Expression and function of phosphodiesterase type 5 in human breast cancer cell lines and tissues: Implications for targeted therapy",
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 triplenegative 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.",
author = "Stefania Catalano and Antonella Campana and Cinzia Giordano and B. Gy{\"o}rffy and Roberta Tarallo and Antonio Rinaldi and Giuseppina Bruno and Aurora Ferraro and Francesco Romeo and Marilena Lanzino and Fabio Naro and Daniela Bonofiglio and Sebastiano And{\`o} and Ines Barone",
year = "2016",
month = "5",
day = "1",
doi = "10.1158/1078-0432.CCR-15-1900",
language = "English",
volume = "22",
pages = "2271--2282",
journal = "Clinical Cancer Research",
issn = "1078-0432",
publisher = "American Association for Cancer Research Inc.",
number = "9",

}

TY - JOUR

T1 - Expression and function of phosphodiesterase type 5 in human breast cancer cell lines and tissues

T2 - Implications for targeted therapy

AU - Catalano, Stefania

AU - Campana, Antonella

AU - Giordano, Cinzia

AU - Györffy, B.

AU - Tarallo, Roberta

AU - Rinaldi, Antonio

AU - Bruno, Giuseppina

AU - Ferraro, Aurora

AU - Romeo, Francesco

AU - Lanzino, Marilena

AU - Naro, Fabio

AU - Bonofiglio, Daniela

AU - Andò, Sebastiano

AU - Barone, Ines

PY - 2016/5/1

Y1 - 2016/5/1

N2 - 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 triplenegative 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.

AB - 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 triplenegative 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.

UR - http://www.scopus.com/inward/record.url?scp=84969248061&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84969248061&partnerID=8YFLogxK

U2 - 10.1158/1078-0432.CCR-15-1900

DO - 10.1158/1078-0432.CCR-15-1900

M3 - Article

C2 - 26667489

AN - SCOPUS:84969248061

VL - 22

SP - 2271

EP - 2282

JO - Clinical Cancer Research

JF - Clinical Cancer Research

SN - 1078-0432

IS - 9

ER -