PAK4 regulates stemness and progression in endocrine resistant ERpositive metastatic breast cancer

Research output: Contribution to journalArticle

  • External authors:
  • Thomas Kedward
  • Illaria Dragoni
  • Roisin NicAmhlaoibh
  • Elisabeth Trivier
  • Verity Sabin
  • Julia M Gee
  • Andrew H Sims

Abstract

Despite the effectiveness of endocrine therapies to treat estrogen receptor-positive (ER+) breast tumours, two thirds of patients will eventually relapse due to de novo or acquired resistance to these agents. Cancer Stem-like Cells (CSCs), a rare cell population within the tumour, accumulate after anti-estrogen treatments and are likely to contribute to their failure. Here we studied the role of p21-activated kinase 4 (PAK4) as a promising target to overcome endocrine resistance and disease progression in ER+ breast cancers. PAK4 predicts for resistance to tamoxifen and poor prognosis in 2 independent cohorts of ER+ tumours. We observed that PAK4 strongly correlates with CSC activity in metastatic patient-derived samples irrespective of breast cancer subtype. However, PAK4-driven mammosphere-forming CSC activity increases alongside progression only in ER+ metastatic samples. PAK4 activity increases in ER+ models during acquired resistance to endocrine therapies. Targeting PAK4 with either CRT PAKi, a small molecule inhibitor of PAK4, or with specific siRNAs abrogates CSC activity/self-renewal in clinical samples and endocrine-resistant cells. Together, our findings establish that PAK4 regulates stemness during disease progression and that its inhibition reverses endocrine resistance in ER+ breast cancers.

Bibliographical metadata

Original languageEnglish
Article number10.1016/j.canlet.2019.05.014
Number of pages11
JournalCancer Letters
Early online date20 May 2019
DOIs
Publication statusPublished - 28 Aug 2019