Suppression of Invasion and Metastasis of Triple-Negative Breast Cancer Lines by Pharmacological or Genetic Inhibition of Slug Activity

Most triple-negative breast cancers (TNBCs) exhibit gene expression patterns associated with epithelial-to-mesenchymal transition (EMT), a feature that correlates with a propensity for metastatic spread. Overexpression of the EMT regulator Slug is detected in basal and mesenchymal-type TNBCs and is...

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Main Authors: Giovanna Ferrari-Amorotti, Claudia Chiodoni, Fei Shen, Sara Cattelani, Angela Rachele Soliera, Gloria Manzotti, Giulia Grisendi, Massimo Dominici, Francesco Rivasi, Mario Paolo Colombo, Alessandro Fatatis, Bruno Calabretta
Format: Article
Language:English
Published: Elsevier 2014-12-01
Series:Neoplasia: An International Journal for Oncology Research
Online Access:http://www.sciencedirect.com/science/article/pii/S1476558614001626
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author Giovanna Ferrari-Amorotti
Claudia Chiodoni
Fei Shen
Sara Cattelani
Angela Rachele Soliera
Gloria Manzotti
Giulia Grisendi
Massimo Dominici
Francesco Rivasi
Mario Paolo Colombo
Alessandro Fatatis
Bruno Calabretta
author_facet Giovanna Ferrari-Amorotti
Claudia Chiodoni
Fei Shen
Sara Cattelani
Angela Rachele Soliera
Gloria Manzotti
Giulia Grisendi
Massimo Dominici
Francesco Rivasi
Mario Paolo Colombo
Alessandro Fatatis
Bruno Calabretta
author_sort Giovanna Ferrari-Amorotti
collection DOAJ
description Most triple-negative breast cancers (TNBCs) exhibit gene expression patterns associated with epithelial-to-mesenchymal transition (EMT), a feature that correlates with a propensity for metastatic spread. Overexpression of the EMT regulator Slug is detected in basal and mesenchymal-type TNBCs and is associated with reduced E-cadherin expression and aggressive disease. The effects of Slug depend, in part, on the interaction of its N-terminal SNAG repressor domain with the chromatin-modifying protein lysine demethylase 1 (LSD1); thus, we investigated whether tranylcypromine [also known as trans-2-phenylcyclopropylamine hydrochloride (PCPA) or Parnate], an inhibitor of LSD1 that blocks its interaction with Slug, suppresses the migration, invasion, and metastatic spread of TNBC cell lines. We show here that PCPA treatment induces the expression of E-cadherin and other epithelial markers and markedly suppresses migration and invasion of TNBC cell lines MDA-MB-231 and BT-549. These effects were phenocopied by Slug or LSD1 silencing. In two models of orthotopic breast cancer, PCPA treatment reduced local tumor growth and the number of lung metastases. In mice injected directly in the blood circulation with MDA-MB-231 cells, PCPA treatment or Slug silencing markedly inhibited bone metastases but had no effect on lung infiltration. Thus, blocking Slug activity may suppress the metastatic spread of TNBC and, perhaps, specifically inhibit homing/colonization to the bone.
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spelling doaj.art-a77b33130f67494ab68695c56d8e7eaa2022-12-21T18:00:39ZengElsevierNeoplasia: An International Journal for Oncology Research1476-55862014-12-0116121047105810.1016/j.neo.2014.10.006Suppression of Invasion and Metastasis of Triple-Negative Breast Cancer Lines by Pharmacological or Genetic Inhibition of Slug ActivityGiovanna Ferrari-Amorotti0Claudia Chiodoni1Fei Shen2Sara Cattelani3Angela Rachele Soliera4Gloria Manzotti5Giulia Grisendi6Massimo Dominici7Francesco Rivasi8Mario Paolo Colombo9Alessandro Fatatis10Bruno Calabretta11Dipartimento di Medicina Diagnostica, Clinica a di Sanità Pubblica, University of Modena and Reggio Emilia, Modena, ItalyIstituto Tumori Milano, Milano, ItalyDepartment of Pharmacology and Physiology, Drexel University, Philadelphia, PA, USADipartimento di Medicina Diagnostica, Clinica a di Sanità Pubblica, University of Modena and Reggio Emilia, Modena, ItalyDipartimento di Medicina Diagnostica, Clinica a di Sanità Pubblica, University of Modena and Reggio Emilia, Modena, ItalyDipartimento di Medicina Diagnostica, Clinica a di Sanità Pubblica, University of Modena and Reggio Emilia, Modena, ItalyDipartimento di Scienze Mediche e Chirurgiche Materno-Infantili e dell’Adulto, Modena, ItalyDipartimento di Scienze Mediche e Chirurgiche Materno-Infantili e dell’Adulto, Modena, ItalyDipartimento di Anatomia Patologica e Medicina Legale, University of Modena and Reggio Emilia, Modena, ItalyIstituto Tumori Milano, Milano, ItalyDepartment of Pharmacology and Physiology, Drexel University, Philadelphia, PA, USADipartimento di Medicina Diagnostica, Clinica a di Sanità Pubblica, University of Modena and Reggio Emilia, Modena, ItalyMost triple-negative breast cancers (TNBCs) exhibit gene expression patterns associated with epithelial-to-mesenchymal transition (EMT), a feature that correlates with a propensity for metastatic spread. Overexpression of the EMT regulator Slug is detected in basal and mesenchymal-type TNBCs and is associated with reduced E-cadherin expression and aggressive disease. The effects of Slug depend, in part, on the interaction of its N-terminal SNAG repressor domain with the chromatin-modifying protein lysine demethylase 1 (LSD1); thus, we investigated whether tranylcypromine [also known as trans-2-phenylcyclopropylamine hydrochloride (PCPA) or Parnate], an inhibitor of LSD1 that blocks its interaction with Slug, suppresses the migration, invasion, and metastatic spread of TNBC cell lines. We show here that PCPA treatment induces the expression of E-cadherin and other epithelial markers and markedly suppresses migration and invasion of TNBC cell lines MDA-MB-231 and BT-549. These effects were phenocopied by Slug or LSD1 silencing. In two models of orthotopic breast cancer, PCPA treatment reduced local tumor growth and the number of lung metastases. In mice injected directly in the blood circulation with MDA-MB-231 cells, PCPA treatment or Slug silencing markedly inhibited bone metastases but had no effect on lung infiltration. Thus, blocking Slug activity may suppress the metastatic spread of TNBC and, perhaps, specifically inhibit homing/colonization to the bone.http://www.sciencedirect.com/science/article/pii/S1476558614001626
spellingShingle Giovanna Ferrari-Amorotti
Claudia Chiodoni
Fei Shen
Sara Cattelani
Angela Rachele Soliera
Gloria Manzotti
Giulia Grisendi
Massimo Dominici
Francesco Rivasi
Mario Paolo Colombo
Alessandro Fatatis
Bruno Calabretta
Suppression of Invasion and Metastasis of Triple-Negative Breast Cancer Lines by Pharmacological or Genetic Inhibition of Slug Activity
Neoplasia: An International Journal for Oncology Research
title Suppression of Invasion and Metastasis of Triple-Negative Breast Cancer Lines by Pharmacological or Genetic Inhibition of Slug Activity
title_full Suppression of Invasion and Metastasis of Triple-Negative Breast Cancer Lines by Pharmacological or Genetic Inhibition of Slug Activity
title_fullStr Suppression of Invasion and Metastasis of Triple-Negative Breast Cancer Lines by Pharmacological or Genetic Inhibition of Slug Activity
title_full_unstemmed Suppression of Invasion and Metastasis of Triple-Negative Breast Cancer Lines by Pharmacological or Genetic Inhibition of Slug Activity
title_short Suppression of Invasion and Metastasis of Triple-Negative Breast Cancer Lines by Pharmacological or Genetic Inhibition of Slug Activity
title_sort suppression of invasion and metastasis of triple negative breast cancer lines by pharmacological or genetic inhibition of slug activity
url http://www.sciencedirect.com/science/article/pii/S1476558614001626
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