title: Suppression of invasion and metastasis of triple-negative breast cancer lines by pharmacological or genetic inhibition of slug activity.
abstract: 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.
authors.affiliation: Dipartimento di Medicina Diagnostica, Clinica a di Sanità Pubblica, University of Modena and Reggio Emilia, Modena, Italy. Electronic address: ferrariamorotti@hotmail.it.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Ferrari-Amorotti
authors.affiliation: Istituto Tumori Milano, Milano, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Chiodoni
authors.affiliation: Department of Pharmacology and Physiology, Drexel University, Philadelphia, PA, USA.
authors.forename: Fei
authors.initials: F
authors.lastname: Shen
authors.affiliation: Dipartimento di Medicina Diagnostica, Clinica a di Sanità Pubblica, University of Modena and Reggio Emilia, Modena, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Cattelani
authors.affiliation: Dipartimento di Medicina Diagnostica, Clinica a di Sanità Pubblica, University of Modena and Reggio Emilia, Modena, Italy.
authors.forename: Angela Rachele
authors.initials: AR
authors.lastname: Soliera
authors.affiliation: Dipartimento di Medicina Diagnostica, Clinica a di Sanità Pubblica, University of Modena and Reggio Emilia, Modena, Italy.
authors.forename: Gloria
authors.initials: G
authors.lastname: Manzotti
authors.affiliation: Dipartimento di Scienze Mediche e Chirurgiche Materno-Infantili e dell'Adulto, Modena, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Grisendi
authors.affiliation: Dipartimento di Scienze Mediche e Chirurgiche Materno-Infantili e dell'Adulto, Modena, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Dominici
authors.affiliation: Dipartimento di Anatomia Patologica e Medicina Legale, University of Modena and Reggio Emilia, Modena, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Rivasi
authors.affiliation: Istituto Tumori Milano, Milano, Italy.
authors.forename: Mario Paolo
authors.initials: MP
authors.lastname: Colombo
authors.affiliation: Department of Pharmacology and Physiology, Drexel University, Philadelphia, PA, USA; Department of Pathology, Drexel University, Philadelphia, PA, USA; Program in Biology of Prostate Cancer, Kimmel Cancer Center, Philadelphia, PA, USA.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Fatatis
authors.affiliation: Dipartimento di Medicina Diagnostica, Clinica a di Sanità Pubblica, University of Modena and Reggio Emilia, Modena, Italy; Department of Cancer Biology and Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA. Electronic address: Calabretta@jefferson.edu.
authors.forename: Bruno
authors.initials: B
authors.lastname: Calabretta
mesh_terms: D000818:Animals; D015820:Cadherins / Q000235:genetics; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D020868:Gene Silencing / Q000502:physiology*; D056466:Histone Demethylases / Q000037:antagonists & inhibitors; D051379:Mice; D008807:Mice, Inbred BALB C; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008856:Microscopy, Fluorescence; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis / Q000517:prevention & control; D010957:Plasmids; D060888:Real-Time Polymerase Chain Reaction; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000235:genetics*; D014191:Tranylcypromine / Q000494:pharmacology*; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*
chemical_list: D015820:Cadherins; D008996:Monoamine Oxidase Inhibitors; C000604407:SNAI1 protein, human; C000604449:Snai2 protein, mouse; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D014191:Tranylcypromine; D056466:Histone Demethylases; C495195:KDM1A protein, human