title: Focal adhesion kinase and Wnt signaling regulate human ductal carcinoma in situ stem cell activity and response to radiotherapy.
abstract: Cancer stem cells (CSCs) can avoid or efficiently repair DNA damage from radio and chemotherapy, which suggests they play a role in disease recurrence. Twenty percentage of patients treated with surgery and radiotherapy for ductal carcinoma in situ (DCIS) of the breast recur and our previous data show that high grade DCIS have increased numbers of CSCs. Here, we investigate the role of focal adhesion kinase (FAK) and Wnt pathways in DCIS stem cells and their capacity to survive irradiation. Using DCIS cell lines and patient samples, we demonstrate that CSC-enriched populations are relatively radioresistant and possess high FAK activity. Immunohistochemical studies of active FAK in DCIS tissue show high expression was associated with a shorter median time to recurrence. Treatment with a FAK inhibitor or FAK siRNA in nonadherent and three-dimensional matrigel culture reduced mammosphere formation, and potentiated the effect of 2 Gy irradiation. Moreover, inhibition of FAK in vitro and in vivo decreased self-renewal capacity, levels of Wnt3a and B-Catenin revealing a novel FAK-Wnt axis regulating DCIS stem cell activity. Overall, these data establish that the FAK-Wnt axis is a promising target to eradicate self-renewal capacity and progression of human breast cancers.
authors.affiliation: Surgical Oncology, University Hospital of South Manchester NHS Foundation Trust, Wythenshawe Hospital, Education and Research Centre, Manchester, United Kingdom; Cancer Stem Cell Research, University of Manchester, Institute of Cancer Sciences, Manchester Academic Health Science Centre, The Christie NHS Foundation Trust, Manchester, United Kingdom.
authors.forename: Kathryn E
authors.initials: KE
authors.lastname: Williams
authors.forename: Nigel J
authors.initials: NJ
authors.lastname: Bundred
authors.forename: Göran
authors.initials: G
authors.lastname: Landberg
authors.forename: Robert B
authors.initials: RB
authors.lastname: Clarke
authors.forename: Gillian
authors.initials: G
authors.lastname: Farnie
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000201:enzymology / Q000473:pathology / Q000532:radiotherapy; D018270:Carcinoma, Ductal, Breast / Q000201:enzymology / Q000473:pathology / Q000532:radiotherapy; D045744:Cell Line, Tumor; D005260:Female; D051417:Focal Adhesion Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000528:radiation effects; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D014411:Neoplastic Stem Cells / Q000201:enzymology / Q000473:pathology; D034741:RNA, Small Interfering / Q000494:pharmacology; D011836:Radiation Tolerance / Q000187:drug effects / Q000528:radiation effects*; D060449:Wnt Signaling Pathway / Q000528:radiation effects*; D060509:Wnt3A Protein / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism
chemical_list: D009363:Neoplasm Proteins; D034741:RNA, Small Interfering; C555510:WNT3A protein, human; D060509:Wnt3A Protein; D051176:beta Catenin; D051417:Focal Adhesion Kinase 1; C496050:PTK2 protein, human
keywords: Breast; Cancer stem cells; Focal adhesion kinase; Radiotherapy; Spheres; Wnt