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Failure of RB1 to Reverse the Malignant Phenotype of Human Tumor Cell Lines¹

Departments of Molecular and Medical Genetics [M. M. M., R. A. P., B. L. G.], Ophthalmology [B. L. G.], and Immunology [R. A. P.], University of Toronto, and Division of Immunology and Cancer Research [M. M. M., B. L. C., R. A. P., B. L. G.], the Hospital for Sick Children, Toronto, Ontario, Canada M5G 1X8

In addition to retinoblastoma and osteosarcoma, mutation of both alleles of the RB1 gene occurs frequently in several other types of tumors. In order to evaluate the role of RB1 in cancer, the wild type RB1 gene was introduced into the RB1-deleted breast cancer cell line MDA-468-S4 and retinoblastoma cell lines WERI-Rb1 and Y-79. The RB1 complementary DNA was under control of the inducible murine metallothionein promoter in MDA-468-S4 and the thymidine kinase promoter in the retinoblastoma lines. The protein, p110^RB1, produced from the exogenously introduced gene appeared normal by immunoprecipitation, Western blot analysis, and nuclear localization and also showed normal cell cycle-dependent phosphorylation and an ability to bind to E1a protein. No changes in growth rate or morphology were observed in either of the reconstituted cell types. Expression of p110^RB1 in MDA-468-S4 did not affect anchorage-independent growth when measured by colony formation in soft agar. Although the ability of WERI-Rb1 cells expressing p110^RB1 to form colonies in methylcellulose was reduced, the reconstituted retinoblastoma cell lines formed intraocular tumors in immunodeficient mice with the same efficiency as the RB1-negative parent cell lines and the tumors produced by the RB1-reconstituted cells continued to express p110^RB1. These experimental results suggest that the malignant phenotype is little affected by the replacement of p110^RB1 and that RB1 is a relatively weak tumor suppressor gene.

¹ This work was supported by the Terry Fox Program Project Grant from the National Cancer Institute of Canada, the Medical Research Council of Canada Grant MA6491, the Retinoblastoma Family Association, and the Royal Arch Masons of Canada. M. M. M. was funded by National Sciences and Engineering Research Council of Canada. B. L. G. is a Research Associate of the Ontario Cancer Treatment and Research Foundation.

² To whom requests for reprints should be addressed, at Division of Immunology and Cancer, Hospital for Sick Children, 555 University Ave., Toronto, Ontario, Canada M5G 1X8.

³ The first two authors have contributed equally to this work.

Received 11/20/91. Accepted 12/ 2/91.

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