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

• Published in: Cancer letters 2019-08, Vol.458, p.66-75
• Main Authors: 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., Clarke, Robert B.
• Format: Article
• Language: English
• Subjects: Antiestrogens; Antineoplastic Agents, Hormonal - pharmacology; Biomarkers; Breast cancer; Breast Neoplasms - drug therapy; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cancer stem cells; Cell cycle; Cell growth; Cell self-renewal; Disease Progression; Disease resistance; Down-Regulation; Drug Resistance, Neoplasm; Endocrine resistance; Endocrine therapy; Estrogen Receptor Antagonists - pharmacology; Estrogen receptors; Estrogens; Female; Fulvestrant - pharmacology; Gene Expression; Growth factors; Humans; Kinases; MCF-7 Cells; Medical prognosis; Medical research; Meta-Analysis as Topic; Metabolism; Metastases; Metastasis; Neoplasm Metastasis; Neoplastic Stem Cells - drug effects; Neoplastic Stem Cells - metabolism; Neoplastic Stem Cells - pathology; p21-activated kinase; p21-Activated Kinases - antagonists & inhibitors; p21-Activated Kinases - biosynthesis; p21-Activated Kinases - genetics; p21-Activated Kinases - metabolism; PAK4; Phenols; Prognosis; Receptors, Estrogen - metabolism; siRNA; Small Molecule Libraries - pharmacology; Tamoxifen; Tamoxifen - pharmacology; Tumors
• ISSN: 0304-3835; 1872-7980
• DOI: 10.1016/j.canlet.2019.05.014

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 of 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. •PAK4 predicts for failure of endocrine therapies and poor prognosis.•PAK4 drives stemness and progression in ER + metastatic breast cancer.•Targeting PAK4 abrogates breast CSC activity and restores sensitivity to endocrine treatments.•Targeting PAK4 will improve outcome of ER + breast cancer patients.