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Reduction of E-Cadherin Levels and Deletion of the -Catenin Gene in Human Prostate Cancer Cells¹

Brady Urological Institute, Research Laboratories [R. A. M., C. M. E., W. B. I.] and Oncology Center [W. B. I.], The Johns Hopkins Medical Institutions, Baltimore, Maryland 21205, and Department of Information Physiology, National Institute for Physiological Sciences, Myodaiji, Okazaki, Aichi 444, Japan [A. N., S. T.]

The cadherins are a family of transmembrane glycoproteins responsible for calcium-dependent cell-cell adhesion. This adhesion is mediated by a group of cytoplasmic proteins, the catenins, which act inside the cell to couple the cadherin molecule to the microfilament cytoskeleton. Dysfunction of E-cadherin-dependent cell-cell adhesion has been demonstrated to contribute to the acquisition of invasive potential of malignant adenocarcinoma cells. The potential role of alterations of catenin expression in tumor cell invasion is largely unexplored. We have previously found that E-cadherin is frequently down-regulated in clinical samples of prostate cancer (Umbas, R., Schalken, J. A., Aalders, T. W., Carter, B. S., Karthaus, H. F. M., Schaafsma, H. E., Debruyne, F. M. J., and Isaacs, W. B. Cancer Res., 52: 5104–5109, 1992). In this study, we further investigate this adhesion system in both benign and malignant human prostate cells in culture. Using antibodies to E-cadherin and its cytoplasmic accessory protein, -catenin, we find that 5 of 6 human prostate cancer cell lines have reduced or absent levels of one or the other or both of these molecules when compared to normal prostatic epithelial cells. Only the LNCaP prostate cancer cell line is indistinguishable from normal prostate epithelium with respect to its E-cadherin--catenin complement. Interestingly, the PC-3 line is characterized by the presence of E-cadherin, but the complete lack of -catenin found at both the RNA and protein level. This lack of -catenin gene expression is explained by Southern analysis, which reveals a homozygous deletion of a large portion of the -catenin gene in PC-3 cells. This loss of -catenin is functionally manifested by negligible Ca²⁺-dependent aggregation of these cells in vitro, when compared to LNCaP cells. These results confirm that E-cadherin-dependent cell-cell adhesion is frequently aberrant in prostate cancer cells, and suggest that in a subset of prostate cancers, this adhesion may be inactivated by loss of -catenin rather than E-cadherin itself. Furthermore, these results demonstrate that mutational inactivation of the -catenin gene is one mechanism responsible for the loss of normal cell-cell adhesion in prostate cancer.

¹ Grants from USPHS (CA55231 and CA58236) to W. B. I. and from the R. W. Johnson Foundation to R. A. M. supported these studies.

² To whom requests for reprints should be addressed, at Department of Urology, Marburg 105, The Johns Hopkins Hospital, 600 North Wolfe Street, Baltimore, MD 21205.

Received 2/16/93. Accepted 5/20/93.

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