PAK4 regulates stemness and progression in endocrine resistant ER-positive metastatic breast cancer

Santiago-Gómez, Angélica, Kedward, Thomas, Simões, Bruno M., Dragoni, Ilaria, NicAmhlaoibh, Roisin, Trivier, Elisabeth, Sabin, Verity, Gee, Julia M. ORCID: https://orcid.org/0000-0001-6483-2015, Sims, Andrew H., Howell, Sacha J. and Clarke, Robert B. 2019. PAK4 regulates stemness and progression in endocrine resistant ER-positive metastatic breast cancer. Cancer Letters 458 , pp. 66-75. 10.1016/j.canlet.2019.05.014

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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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Pharmacy
Publisher:	Elsevier
ISSN:	0304-3835
Date of First Compliant Deposit:	29 May 2019
Date of Acceptance:	14 May 2019
Last Modified:	02 May 2023 23:54
URI:	https://orca.cardiff.ac.uk/id/eprint/122947

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