Carcinogenesis, Vol. 20, No. 9, 1715-1720,
September 1999
© 1999 Oxford University Press
Cancer Biology |
Interactions of apoptosis, proliferation and host age in the regression of the mouse mammary preneoplasia, TM3, carrying an unusual mutation in p53
Department of Cell Biology, Baylor College of Medicine, One Baylor Plaza,
1 Department of Veterinary Medicine and Surgery and
2 Department of Experimental Radiation Oncology, University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA
We have developed an in vivo model system of mouse mammary preneoplasias in order to examine the cell and molecular changes that occur during tumorigenesis. Most of these preneoplasias are characterized by an alveolar hyperplasia morphologically similar to that present in normal pregnant mammary gland, but have tumor forming capabilities ranging from very low to high. One of these hyperplasias, the TM3 HOG (transformed mammary hyperplastic outgrowth), forms tumors infrequently and has the unusual characteristic of spontaneous regression. We have observed that 7–8 months post-transplantation into 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 structures by 10–12 months post-transplantation. We have sought to elucidate the mechanism of this regression by determining the apoptotic and proliferative 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 times after transplantation. This apoptotic rate is higher than the rates found in other preneoplasias in our system and approach the rates observed in the normal involuting gland. An unusual p53 mutation, a serine insertion at codon 233, may be causally related to the high spontaneous apoptotic frequencies as well as elevated inducible apoptotic frequencies in TM3. In addition, a sudden decrease (~63%) in proliferation occurs around 8 months post-transplantation. Furthermore, transplantation experiments indicate that the ability of the 8-month-old host and/or mammary gland to support growth of preneoplastic mammary tissues is markedly diminished compared with 3- or 6-month-old hosts. The results presented here suggest that the persistent 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 determinants can interact with specific molecular changes in the preneoplastic cells to influence growth and progression of the preneoplastic populations.
Abbreviations: AI, apoptotic index; TM HOG, transformed mammary hyperplastic outgrowth.
3 To whom correspondence should be addressed Email: dmedina{at}bcm.tmc.edu
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