ANKRd44 gene silencing: A putative role in trastuzumab resistance in HER2-like breast cancer

Marco La Ferla, Francesca Lessi*, Paolo Aretini, Davide Pellegrini, Sara Franceschi, Elena Tantillo, Michele Menicagli, Ivo Marchetti, Claudia Scopelliti, Prospero Civita, Claudia De Angelis, Lucrezia Diodati, Ilaria Bertolini, Manuela Roncella, Liam A. McDonnell, Jacob Hochman, Marzia Del Re, Cristian Scatena, Antonio G. Naccarato, Andrea FontanaChiara M. Mazzanti

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

Abstract

Trastuzumab is an effective therapeutic treatment for Her2-like breast cancer; despite this most of these tumors develop resistance to therapy due to specific gene mutations or alterations in gene expression. Understanding the mechanisms of resistance to Trastuzumab could be a useful tool in order to identify combinations of drugs that elude resistance and allow a better response for the treated patients. Twelve primary biopsies of Her2+/hormone receptor negative (ER-/PgR-) breast cancer patients were selected based on the specific response to neoadjuvant therapy with Trastuzumab and their whole exome was sequenced leading to the identification of 18 informative gene mutations that discriminate patients selectively based on response to treatment. Among these genes, we focused on the study of the ANKRD44 gene to understand its role in the mechanism of resistance to Trastuzumab. The ANKRD44 gene was silenced in Her2-like breast cancer cell line (BT474), obtaining a partially Trastuzumab-resistant breast cancer cell line that constitutively activates the NF-kb protein via the TAK1/AKT pathway. Following this activation an increase in the level of glycolysis in resistant cells is promoted, also confirmed by the up-regulation of the LDHB protein and by an increased TROP2 protein expression, found generally associated with aggressive tumors. These results allow us to consider the ANKRD44 gene as a potential gene involved in Trastuzumab resistance.

Original languageEnglish
Article number547
JournalFrontiers in Oncology
Volume9
Issue numberJUN
DOIs
StatePublished - 2019

Bibliographical note

Publisher Copyright:
Copyright © 2019 La Ferla, Lessi, Aretini, Pellegrini, Franceschi, Tantillo, Menicagli, Marchetti, Scopelliti, Civita, De Angelis, Diodati, Bertolini, Roncella, McDonnell, Hochman, Del Re, Scatena, Naccarato, Fontana and Mazzanti. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

Keywords

  • ANKRD44
  • Gene silencing
  • Her2+ breast cancer
  • LC-MS/MS
  • Next generation sequencing
  • Trastuzumab resistance

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