This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Jerry, D. J. Articles by Butel, J. S. Search for Related Content PubMed PubMed Citation Articles by Jerry, D. J. Articles by Butel, J. S.

Mutations in p53 Are Frequent in the Preneoplastic Stage of Mouse Mammary Tumor Development¹

Division of Molecular Virology [D. J. J., M. A. O., J. S. B.] and Department of Cell Biology [F. S. K., D. M.], Baylor College of Medicine, Houston, Texas 77030; and Department of Biochemistry, Medical Sciences Institute, The University of Dundee, Dundee DD1 4HN, United Kingdom [D. P. L.]

Preneoplastic lesions in the mammary gland represent a population of cells at increased risk of progression to tumors. Because p53 is the most commonly mutated gene in human breast cancer, we sought to determine whether mutations in p53 were present in preneoplastic lesions or were acquired during progression to overt tumors. In the mouse mammary gland, hyperplastic alveolar nodules (HAN) are the most common preneoplastic lesion. Analysis of the TM series of transplantable murine HAN outgrowths and tumors allowed the status of p53 to be determined at distinct stages of mammary tumorigenesis. Alterations in the p53 gene or in the pattern of p53 protein expression were observed in all five HAN outgrowth lines examined. Altered expression of p53 protein was detected in 3 of 5 TM HAN outgrowth lines as determined by immunohistochemistry. Overexpression of nuclear p53 was detected in only a fraction of the cells (10–50%) in TM3 and TM4 HAN outgrowths, whereas in tumors that arose from TM4 HAN outgrowths, the proportion of cells overexpressing p53 protein approached 100%. Despite overexpression of p53 in TM3 HAN outgrowths, no tumors have developed in this line. The TM9 outgrowth line exhibited a different pattern of p53 expression by immunohistochemistry: p53 protein was overexpressed in the cytoplasm of virtually all cells in the HAN outgrowths but was localized to the nuclei of TM9 tumor cells. Direct sequencing of p53 transcripts from tumors and cell lines revealed various genetic changes: point mutations in exons 4 and 5 (TM2H, nonsense; TM4, missense); a deletion in exon 5 (TM4); and an insertion in exon 7 (TM3). Although p53 protein was overexpressed in TM9 tumors, it was shown to be wild-type both by immunoprecipitation and direct sequencing of the entire coding region of the cDNA. TM4 cells were homogeneous with respect to mutant p53 genotype and uniformly expressed p53 by immunohistochemical staining in vitro, but transplantation of TM4 cells to fat pads of BALB/c hosts resulted in HAN outgrowths in situ in which <50% of the cells expressed the mutant p53 at detectable levels. In summary, mutation of the p53 gene and overexpression of p53 protein can occur in preneoplastic mammary epithelial cells, and those mutations are maintained in tumors that arise from the HAN. It appears that mutation of p53 conferred a biologically relevant growth advantage to cells in vivo. Overexpression of p53 in one outgrowth line in the absence of mutations in the coding sequence suggests the presence of cellular factors that can enhance accumulation of wild-type p53 protein. Conversely, expression of mutant p53 was decreased when cells were grown in situ, implicating the presence of cellular factors that can suppress p53 expression in vivo. These observations demonstrate that the p53 pathway may be a common target for mutation in murine mammary tumorigenesis.

¹ This publication was supported in part by research grants CA25215 and CA47112 from the National Cancer Institute. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the National Cancer Institute.

² To whom requests for reprints should be addressed.

Received 2/ 1/93. Accepted 5/ 6/93.

This article has been cited by other articles:

				A. Bruning, E. Stickeler, D. Diederich, L. Walz, H. Rohleder, K. Friese, and I. B. Runnebaum Coxsackie and Adenovirus Receptor Promotes Adenocarcinoma Cell Survival and Is Expressionally Activated after Transition from Preneoplastic Precursor Lesions to Invasive Adenocarcinomas Clin. Cancer Res., June 15, 2005; 11(12): 4316 - 4320. [Abstract] [Full Text] [PDF]

				G. Zhang, B. He, and G. F. Weber Growth Factor Signaling Induces Metastasis Genes in Transformed Cells: Molecular Connection between Akt Kinase and Osteopontin in Breast Cancer Mol. Cell. Biol., September 15, 2003; 23(18): 6507 - 6519. [Abstract] [Full Text] [PDF]

				C. A. Zahnow, R. D. Cardiff, R. Laucirica, D. Medina, and J. M. Rosen A Role for CCAAT/Enhancer Binding Protein {beta}-Liver-enriched Inhibitory Protein in Mammary Epithelial Cell Proliferation Cancer Res., January 1, 2001; 61(1): 261 - 269. [Abstract] [Full Text]

				C. J. Fabian, B. F. Kimler, C. M. Zalles, J. R. Klemp, S. Kamel, S. Zeiger, and M. S. Mayo Short-Term Breast Cancer Prediction by Random Periareolar Fine-Needle Aspiration Cytology and the Gail Risk Model J Natl Cancer Inst, August 2, 2000; 92(15): 1217 - 1227. [Abstract] [Full Text] [PDF]

				M. H. Barcellos-Hoff and S. A. Ravani Irradiated Mammary Gland Stroma Promotes the Expression of Tumorigenic Potential by Unirradiated Epithelial Cells Cancer Res., March 1, 2000; 60(5): 1254 - 1260. [Abstract] [Full Text]

				S. G. Bonnette, F. S. Kittrell, L.C. Stephens, R. E. Meyn, and D. Medina Interactions of apoptosis, proliferation and host age in the regression of the mouse mammary preneoplasia, TM3, carrying an unusual mutation in p53 Carcinogenesis, September 1, 1999; 20(9): 1715 - 1720. [Abstract] [Full Text] [PDF]