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dc.contributor.authorSantiago-Gómez, Angélica
dc.contributor.authorKedward, T
dc.contributor.authorSimoes, Bruno M
dc.contributor.authorDragoni, I
dc.contributor.authorNicAmhlaoibh, R
dc.contributor.authorTrivier, E
dc.contributor.authorSabin, V
dc.contributor.authorGee, J
dc.contributor.authorSims, A
dc.contributor.authorHowell, Sacha J
dc.contributor.authorClarke, Robert B
dc.date.accessioned2019-06-25T09:32:52Z
dc.date.available2019-06-25T09:32:52Z
dc.date.issued2019en
dc.identifier.citationSantiago-Gomez A, Kedward T, Simoes BM, Dragoni I, NicAmhlaoibh R, Trivier E, et al. PAK4 regulates stemness and progression in endocrine resistant ER-positive metastatic breast cancer. Cancer Lett. 2019;458:66-75.en
dc.identifier.pmid31121213en
dc.identifier.doi10.1016/j.canlet.2019.05.014en
dc.identifier.urihttp://hdl.handle.net/10541/621878
dc.description.abstractDespite 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.en
dc.language.isoenen
dc.relation.urlhttps://dx.doi.org/10.1016/j.canlet.2019.05.014en
dc.titlePAK4 regulates stemness and progression in endocrine resistant ER-positive metastatic breast canceren
dc.typeArticleen
dc.contributor.departmentBreast Biology Group, Manchester Breast Centre, Division of Cancer Sciences, Oglesby Cancer Research Building, University of Manchester, Manchester, M20 4GJen
dc.identifier.journalCancer Lettersen
dc.description.noteen]
refterms.dateFOA2019-06-27T14:46:16Z


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