Interactions of apoptosis, proliferation and host age in the regression ofthe mouse mammary preneoplasia, TM3, carrying an unusual mutation in p53

We have developed an in vivo model system of mouse mammary preneoplasias in order to examine the cell and molecular changes that occur during tumorige nesis. Most of these preneoplasias are characterized by an alveolar hyperpl asia morphologically similar to that present in normal pregnant mammary gla nd, but have tumor forming capabilities ranging from very low to high. One of these hyperplasias, the TM3 HOG (transformed mammary hyperplastic outgro wth), forms tumors infrequently and has the unusual characteristic of spont aneous regression, We have observed that 7-8 months post-transplantation in to the cleared mammary fat pad of a BALB/c mouse, the TM3 hyperplasia will begin to regress, leaving only a sparse ductal tree with remnant alveolar s tructures by 10-12 months post-transplantation. We have sought to elucidate the mechanism of this regression by determining the apoptotic and prolifer ative rates of the alveolar cells during TM3 HOG development. Studies show that apoptotic rates in the TM3 HOG are consistently high (4-7%) at all tim es after transplantation. This apoptotic rate is higher than the rates foun d in other preneoplasias in our system and approach the rates observed in t he normal involuting gland, An unusual p53 mutation, a serine insertion at codon 233, may be causally related to the high spontaneous apoptotic freque ncies as well as elevated inducible apoptotic frequencies in TM3. In additi on, a sudden decrease (similar to 63%) in proliferation occurs around 8 mon ths post-transplantation. Furthermore, transplantation experiments indicate that the ability of the 8-month-old host and/or mammary gland to support g rowth of preneoplastic mammary tissues is markedly diminished compared with 3- or 6-month-old hosts. The results presented here suggest that the persi stent high apoptotic rates, concomitant with decreased proliferation rates, may be responsible for TM3's regression and implicate a unique mutant p53 as a causal factor, Additionally, the results suggest that host determinant s can interact with specific molecular changes in the preneoplastic cells t o influence growth and progression of the preneopiastic populations.