Oncogenic activation of FAK drives apoptosis suppression in a 3D-culture model of breast cancer initiation.
A key hallmark of cancer cells is the loss of positional control over growth and survival. Focal adhesion kinase (FAK) is a tyrosine kinase localised at sites of integrin-mediated cell adhesion to the extracellular matrix. FAK controls a number of adhesion-dependent cellular functions, including migration, proliferation and survival. Although FAK is overexpressed and activated in metastatic tumours, where it promotes invasion, it can also be elevated in cancers that have yet to become invasive. The contribution of FAK to the early stages of tumourigenesis is not known. We have examined the effect of activating FAK in non-transformed mammary epithelial cells (MECs) to understand its role in tumour initiation. In agreement with previous studies, we find FAK activation in 2D-culture promotes proliferation, migration, and epithelial-to-mesenchymal transition. However in 3D-cultures that better resemble normal tissue morphology, mammary cells largely respond to FAK activation via suppression of apoptosis, promoting aberrant acinar morphogenesis. This is an acquired function of FAK, because endogenous FAK signalling is not required for normal morphogenesis in 3D-culture or in vivo. Thus, FAK activation may facilitate tumour initiation by causing resistance to apoptosis. We suggest that aberrant FAK activation in breast epithelia is dependent upon the tissue context in which it occurs.
Wellcome Trust Centre for Cell-Matrix Research, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK.
Scott
S
Walker
Wellcome Trust Centre for Cell-Matrix Research, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK.
Fiona
F
Foster
Wellcome Trust Centre for Cell-Matrix Research, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK.
Amber
A
Wood
Wellcome Trust Centre for Cell-Matrix Research, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK.
Thomas
T
Owens
Wellcome Trust Centre for Cell-Matrix Research, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK.
Keith
K
Brennan
Wellcome Trust Centre for Cell-Matrix Research, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK.
Charles H
CH
Streuli
Wellcome Trust Centre for Cell-Matrix Research, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK.
Andrew P
AP
Gilmore
D000818:Animals; D017209:Apoptosis; D001940:Breast / Q000473:pathology; D001943:Breast Neoplasms / Q000209:etiology* / Q000473:pathology; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D051417:Focal Adhesion Kinase 1 / Q000037:antagonists & inhibitors / Q000502:physiology*; D006801:Humans; D006965:Hyperplasia; D051379:Mice
D051417:Focal Adhesion Kinase 1; C496050:PTK2 protein, human
Focal adhesion kinase; anoikis; apoptosis; breast cancer