P53VAL135 TEMPERATURE-SENSITIVE MUTANT SUPPRESSES GROWTH OF HUMAN BREAST-CANCER CELLS

One common step in the malignant progression of a wide variety of human cancers seems to be inactivation of the p53 gene, via point mutation or deletion or both; or overexpression of mutated protein with dominant transforming activity. This study shows a suppressive effect of wild type p53 on the growth of human breast cancer cells. Introduction of wild type p53 versus mutant into five human breast cancer cell lines containing mutant p53 resulted in a marked reduction in colony formation. Two of these were transfected with human wt p53 expression vectors and the other three were infected with retroviruses packaging human wt p53, both showing similar reduction in the number of surviving colonies, suggesting a role for wt p53 in suppression of breast cancer cell growth. Direct evidence for growth suppression was obtained by introduction of the temperature sensitive p53Val135 into Hs578T human breast cancer cells containing a mutant p53. This murine mutant allele p53Va1135 functions as an oncogene at 37 degrees C and as a tumor suppressor at 32 degrees C. The cell line generated was strongly growth inhibited at the restrictive temperature (31.5 degrees C), at which temperature the suppressor form is expressed. This inhibition of proliferation was reversible upon a temperature upshift. Analysis of the cell cycle distribution shows these growth suppressed cells to be inhibited in the G1 phase of the cell cycle. Thus wt p53 may have an important role in breast cancer tumorigenesis.