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

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

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)1047-1058
Number of pages12
JournalNeoplasia (United States)
Volume16
Issue number12
DOIs
Publication statusPublished - 2014

ASJC Scopus subject areas

  • Cancer Research

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    Ferrari-Amorotti, G., Chiodoni, C., Shen, F., Cattelani, S., Soliera, A. R., Manzotti, G., Grisendi, G., Dominici, M., Rivasi, F., Colombo, M. P., Fatatis, A., & Calabretta, B. (2014). Suppression of Invasion and Metastasis of Triple-Negative Breast Cancer Lines by Pharmacological or Genetic Inhibition of Slug Activity. Neoplasia (United States), 16(12), 1047-1058. https://doi.org/10.1016/j.neo.2014.10.006