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bioRxiv · 10.1101/558528

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

Santiago-Gomez, A.·Dragoni, I.·NicAmhlaoibh, R.·Trivier, E.·Sabin, V.·Simoes, B. M.·Gee, J. M.·Sims, A. H.·Howell, S. J.·Clarke, R.
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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. HighlightsO_LIPAK4 predicts for failure of endocrine therapies and poor prognosis C_LIO_LIPAK4 drives stemness and progression in ER+ metastatic breast cancer C_LIO_LITargeting PAK4 abrogates breast CSC activity and restores sensitivity to endocrine treatments C_LIO_LITargeting PAK4 will improve outcome of ER+ breast cancer patients C_LI List of Abbreviations that appeared in abstractCancer Stem-like Cells (CSCs) p21-activated kinase 4 (PAK4) Estrogen Receptor (ER)

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Santiago-Gomez, A., Dragoni, I., NicAmhlaoibh, R., Trivier, E., Sabin, V., Simoes, B. M., Gee, J. M., Sims, A. H., Howell, S. J., Clarke, R.. 2019-02-22. PAK4 regulates stemness and progression in endocrine resistant ER-positive metastatic breast cancer. https://doi.org/10.1101/558528

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