RADIATION-INDUCED APOPTOSIS IN NORMAL AND PRENEOPLASTIC MAMMARY-GLANDS IN-VIVO - SIGNIFICANCE OF GLAND DIFFERENTIATION AND P53 STATUS

The tumor suppressor gene p53 maintains the integrity of the genome by stimulating apoptosis in cells that have sustained DNA damage. The p5 3 gene is frequently altered in human cancers, including breast cancer , and such alterations are thought to result in genomic instability an d aneuploidy, 2 hallmarks of anaplastic cells. We used radiation as a DNA-damaging agent to test the role of p53 in controlling apoptosis pr opensity in pre-neoplastic mammary lesions in mice. Four different pre -neoplastic mammary outgrowth lines, D1, TM2H, TM4 and TM12, were main tained by serial transplantation in the cleared mammary fat pads of sy ngeneic BALB/c mice. These lines have known alterations in p53 express ion: TM12 has normal expression, D1 over-produces wild-type protein, T M2H contains a deletion resulting in a null phenotype and TM4 produces a mutant protein. Mice bearing the various outgrowths were irradiated with 5 Gy, and apoptosis was scored by examination of histological se ctions prepared from the outgrowths 6 hr after irradiation. The TM12 o utgrowths, but not the TM2H outgrowths, exhibited radiation-induced ap optosis. The D1 and TM4 lines expressed radiation-induced apoptosis wh ile the fat pads were being repopulated; however, the induced apoptosi s declined to low levels as the mice aged. These results are consisten t with the hypothesis that normal p53 function is important if mammary cells with DNA damage are to be deleted by apoptosis. (C) 1996 Wiley- Liss, Inc.