© 2002 by Oxford University Press
Journal of the National Cancer Institute, Vol. 94, No. 19, 1494-1503,
October 2, 2002
© 2002 Oxford University Press
ARTICLE |
Phenotypic Reversion or Death of Cancer Cells by Altering Signaling Pathways in Three-Dimensional Contexts
Affiliations of authors: F. Wang, R. K. Hansen, D. Radisky, M. H. Barcellos-Hoff, M. J. Bissell, Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA; T. Yoneda, University of Texas Health Science Center, Department of Medicine, San Antonio, TX; O. W. Petersen, Structural Cell Biology Unit, Institute of Medical Anatomy, The Panum Institute, Copenhagen, Denmark; E. A. Turley, London Regional Cancer Center, London, Ontario, Canada.
Correspondence to: M. J. Bissell, Ph.D., Life Sciences Division, Lawrence Berkeley National Laboratory, One Cyclotron Rd., 83–101, Berkeley, CA 94720 (e-mail: mjbissell{at}lbl.gov).
Background: We previously used a three-dimensional (3D) reconstituted basement membrane (rBM) assay to demonstrate that tumorigenic HMT-3522 T4–2 human breast cells can be induced to form morphologically normal structures ("reversion") by treatment with inhibitors of 
1 integrin, the epidermal growth factor receptor (EGFR), or mitogen-activated protein kinase (MAPK). We have now used this assay to identify reversion and/or death requirements of several more aggressive human breast cancer cell lines. Methods: Breast tumor cell lines MCF7, Hs578T, and MDA-MB-231 were cultured in 3D rBM and treated with inhibitors of 1 integrin, MAPK, or phosphatidylinositol 3-kinase (PI3K). MDA-MB-231 cells, which lack E-cadherin, were transfected with an E-cadherin cDNA. The extent of reversion was assessed by changes in morphology and polarity, growth in 3D rBM or soft agar, level of invasiveness, and tumor formation in nude mice. Results: All three cell lines showed partial reversion (MCF7 the greatest and Hs578T the least) of tumorigenic properties treated with a single 1 integrin, MAPK, or PI3K inhibitor. Combined inhibition of 1 integrin and either PI3K or MAPK resulted in nearly complete phenotypic reversion (MDA-MB-231, MCF7) or in cell death (Hs578T). E-cadherin-transfected MDA-MB-231 cells showed partial reversion, but exposure of the transfectants to an inhibitor of 1 integrin, PI3K, or MAPK led to nearly complete reversion. Conclusion: The 3D rBM assay can be used to identify signaling pathways that, when manipulated in concert, can lead to the restoration of morphologically normal breast structures or to death of the tumor cells, even highly metastatic cells. This approach may be useful to design therapeutic intervention strategies for aggressive breast cancers.
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