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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., 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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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: 29 Jul 2019 14:56

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