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Regulation of Breast Cancer Cell Chemotaxis by the Phosphoinositide 3-Kinase p110¹

Cell Signalling Group, The Ludwig Institute for Cancer Research, University College and Royal Free Medical School Branch, London, W1W 7BS [C. S., B. V.]; The Randall Centre for Molecular Mechanisms of Cell Function, King’s College, London, SE1 1UL [J. S., G. E. J.]; Department of Anatomy and Developmental Biology, St. George’s Hospital Medical School, London, SW17 0RE [D. C. B.]; Ludwig Institute for Cancer Research-University College London Breast Cancer Laboratory, Department of Surgery, Royal Free and University College School of Medicine, London, W1W 7EJ [M. J. O.]; Department of Clinical Biochemistry, Institute of Clinical Science, Queens University, Belfast, BT12 6BJ [W. E. A.]; Division of Signal Transduction Therapy, School of Life Sciences, University of Dundee, Dundee, DD1 5EH [J. B.]; and Department of Biochemistry and Molecular Biology, University College London, London, WC1E 6BT [B. V.], United Kingdom

Class IA phosphoinositide 3'-kinases (PI3Ks) regulate many cellular processes downstream of tyrosine kinases and Ras. Despite a clear implication of PI3K in cancer, little is known about the distribution of the different PI3K isoforms in malignant cells. We screened a large panel of tissues and cell lines for expression of class IA PI3Ks, and document a ubiquitous expression of the p110 and p110ß isoforms but a variable and more restricted tissue distribution of the p110 isoform. Originally found in WBCs, p110 was also detected in some nonhematopoietic cell types especially those of breast or melanocytic origin, both in the untransformed and transformed state. Isoform-specific neutralization of PI3K isoforms in breast cancer cell lines (by PI3K antibody microinjection or a p110-selective pharmacological inhibitor) demonstrated that p110 is the most important class IA PI3K in the regulation of epidermal growth factor-driven motility in vitro, controlling the directionality and, to a lesser extent, the speed of migration. In contrast, p110ß was required for the direction but not the speed of migration, whereas p110 did not impact on either of these parameters. These results show a nonredundant function of PI3K isoforms downstream of the epidermal growth factor receptor and indicate that the presence of p110 may confer breast cancer cells with selective migratory capacities. The potential clinical implications of p110 expression in non-WBC-derived tumors are discussed.

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