Absence of p53 in a mouse mammary tumor model promotes tumor cell proliferation without affecting apoptosis.

Loss or mutation of p53 may have multiple biological and genetic effects that result in accelerated tumor progression. Loss of p53 in some tumors has been correlated with a marked decrease in tumor cell apoptosis. p53 loss may also accelerate tumor growth through an increase in cell proliferation rates. To examine the effects of p53 loss on tumor progression in a controlled experimental context, we previously crossed p53-deficient mice to mammary tumor-susceptible Wnt-1 transgenic (TG) mice. The resulting female Wnt-1 TG offspring of this cross all developed mammary tumors, regardless of p53 status (p53+/+, p53+/-, or p53-/-). However, female p53-/- Wnt-1 TG mice developed tumors much sooner than their p53+/+ counterparts. In this report, we demonstrate that the average growth rates of tumors missing (p53-/-) or losing p53 (p53+/- with loss of heterozygosity) are accelerated compared to tumors with both wild-type p53 alleles (p53+/+). This accelerated growth rate appears to be due primarily to increases in rates of tumor cell proliferation. Tumor cell apoptotic levels were modest and were not measurably different in the presence or absence of wild-type p53. These results differ substantially from other mouse tumor models in which p53 loss was closely correlated with accelerated growth rates through attenuated apoptosis. Thus, the mechanisms by which p53 loss influences tumor progression may differ, depending on the tissue type and/or the oncogenic pathways involved.