The Journal of Cell Biology, Vol 129, 1363-1378, Copyright © 1995 by The Rockefeller University Press

ARTICLES

bcl-2 overexpression inhibits cell death and promotes the morphogenesis, but not tumorigenesis of human mammary epithelial cells [published erratum appears in J Cell Biol 1995 Nov;131(4):following 1121]

PJ Lu, QL Lu, A Rughetti and J Taylor-Papadimitriou
Department of Epithelial Cell Biology, Imperial Cancer Research Fund, London, United Kingdom.

Overexpression of the B cell leukemia/lymphoma-2 (bcl-2) gene has been shown to confer a survival advantage on cells by inhibiting apoptosis. In epithelia, the bcl-2 gene is also related to development and differentiation, and the protein is strongly expressed in the embryo in the epithelial cells of the developing mammary gland. To investigate directly the effect of bcl-2 on human epithelial cells, we used an amphotropic recombinant retrovirus to introduce the gene into nontumorigenic cell lines developed from luminal epithelial cells cultured from milk. Here we demonstrate that while bcl-2 overexpression does not directly induce the tumorigenic phenotype, it provides a survival advantage to the mammary epithelial cells by inhibiting cell death at confluence or under conditions of serum starvation, bcl-2 can also affect the phenotype of the original epithelial cells, and promote epithelial-mesenchymal conversion, accompanied by loss of the cell adhesion molecules E-cadherin and alpha 2 beta 1 integrin. The extent of the epithelial-mesenchymal conversion varies with small differences in the phenotype of the parental line and with the level of expression of Bcl-2 and in some cases cell lines emerge with a mixed phenotype. The increased survival of Bcl-2-expressing cells at confluence results in multilayering, and the development of three- dimensional structures. Where a mixed phenotype is observed these structures consist of an outer layer of polarized epithelial cells separated by a basement membrane-like layer from an inner mass of fibroblastoid cells. Branching morphogenesis of bcl-2 transfectants is also observed in collagen gels (in the absence of fibroblast growth factors). The results strongly indicate that by increasing their survival under restrictive growth conditions, and by modifying the epithelial phenotype, bcl-2 can influence the specific morphogenetic behavior of mammary epithelial cells.
CiteULike    Complore    Connotea    Del.icio.us    Digg    Facebook    Reddit    Technorati    Twitter    What's this?

This article has been cited by other articles:

• Imamov, O., Morani, A., Shim, G.-J., Omoto, Y., Thulin-Andersson, C., Warner, M., Gustafsson, J.-A. (2004). Estrogen receptor {beta} regulates epithelial cellular differentiation in the mouse ventral prostate. Proc. Natl. Acad. Sci. USA 101: 9375-9380 [Abstract] [Full Text]  
• Sorenson, C. M. (2004). Interaction of bcl-2 with Paxillin through Its BH4 Domain Is Important during Ureteric Bud Branching. J. Biol. Chem. 279: 11368-11374 [Abstract] [Full Text]  
• Li, L., Backer, J., Wong, A. S. K., Schwanke, E. L., Stewart, B. G., Pasdar, M. (2003). Bcl-2 expression decreases cadherin-mediated cell-cell adhesion. J. Cell Sci. 116: 3687-3700 [Abstract] [Full Text]  
• Decary, S., Decesse, J. T., Ogryzko, V., Reed, J. C., Naguibneva, I., Harel-Bellan, A., Cremisi, C. E. (2002). The Retinoblastoma Protein Binds the Promoter of the Survival Gene bcl-2 and Regulates Its Transcription in Epithelial Cells through Transcription Factor AP-2. Mol. Cell. Biol. 22: 7877-7888 [Abstract] [Full Text]  
• Sorenson, C. M., Sheibani, N. (2002). Sustained activation of MAPK/ERKs signaling pathway in cystic kidneys from bcl-2 -/- mice. Am. J. Physiol. Renal Physiol. 283: F1085-F1090 [Abstract] [Full Text]  
• Lu, P. J., Sundquist, K., Baeckstrom, D., Poulsom, R., Hanby, A., Meier-Ewert, S., Jones, T., Mitchell, M., Pitha-Rowe, P., Freemont, P., Taylor-Papadimitriou, J. (1999). A Novel Gene (PLU-1) Containing Highly Conserved Putative DNA/Chromatin Binding Motifs Is Specifically Up-regulated in Breast Cancer. J. Biol. Chem. 274: 15633-15645 [Abstract] [Full Text]  
• Deugnier, M., Faraldo, M., Rousselle, P, Thiery, J., Glukhova, M. (1999). Cell-extracellular matrix interactions and EGF are important regulators of the basal mammary epithelial cell phenotype. J. Cell Sci. 112: 1035-1044 [Abstract]  
• Tang, M.-J., Hu, J.-J., Lin, H.-H., Chiu, W.-T., Jiang, S.-T. (1998). Collagen gel overlay induces apoptosis of polarized cells in cultures: disoriented cell death. Am. J. Physiol. Cell Physiol. 275: C921-C931 [Abstract] [Full Text]  
• Khwaja, A., Lehmann, K., Marte, B. M., Downward, J. (1998). Phosphoinositide 3-Kinase Induces Scattering and Tubulogenesis in Epithelial Cells through a Novel Pathway. J. Biol. Chem. 273: 18793-18801 [Abstract] [Full Text]  
• Elstner, E., Muller, C., Koshizuka, K., Williamson, E. A., Park, D., Asou, H., Shintaku, P., Said, J. W., Heber, D., Koeffler, H. P. (1998). Ligands for peroxisome proliferator-activated receptorgamma and retinoic acid receptor inhibit growth and induce apoptosis of human breast cancer cells in vitro and in BNX mice. Proc. Natl. Acad. Sci. USA 95: 8806-8811 [Abstract] [Full Text]  
• Whitehouse, C., Burchell, J., Gschmeissner, S., Brockhausen, I., Lloyd, K. O., Taylor-Papadimitriou, J. (1997). A Transfected Sialyltransferase That Is Elevated in Breast Cancer and Localizes to the medial/trans-Golgi Apparatus Inhibits the Development of core-2-based O-Glycans. JCB 137: 1229-1241 [Abstract] [Full Text]  

Home | Help | Feedback | Subscriptions | Archive | Search | Table of Contents