p53 is a potential mediator of pregnancy and hormone-induced resistance to mammary carcinogenesis

Full-term pregnancy early in reproductive life is protective against breast cancer in women. Pregnancy also provides protection in animals against carcinogen-induced breast cancer, and this protection can be mimicked by using the hormones estrogen and progesterone. The molecular mechanisms that form the basis for this protective effect have not been elucidated. On the basis of our results, we propose a cell-fate hypothesis. At a critical period in adolescence the hormonal milieu of pregnancy affects the developmental fate of a subset of mammary epithelial cells and its progeny, which results in persistent differences in molecular pathways between the epithelial cells of hormone-treated and mature virgin mammary glands. These changes in turn dictate the proliferative response to carcinogen challenge and include a block in carcinogen-induced increase in mammary epithelial cell proliferation and an increased and sustained expression of nuclear p53 in the hormone-treated mammary gland. This hormone-induced nuclear p53 is transcriptionally active as evidenced by increased expression of mdm2 and p21 (CIP1/WAF1). Importantly, exposure to perphenazine, a compound that induces mammary gland differentiation but does not confer protection, does not induce p53 expression, indicating that p53 is not a differentiation marker. The proliferative block and induction of p53 are operative in both rats and mice, results that support the generality of the proposed hypothesis.

[1]  Leif E. Peterson,et al.  Short-term exposure to estrogen and progesterone induces partial protection against N-nitroso-N-methylurea-induced mammary tumorigenesis in Wistar--Furth rats. , 2001, Cancer letters.

[2]  M. Kulesz-Martin,et al.  p53 protein at the hub of cellular DNA damage response pathways through sequence-specific and non-sequence-specific DNA binding. , 2001, Carcinogenesis.

[3]  J. Pietenpol,et al.  p53 Signaling and cell cycle checkpoints. , 2001, Chemical research in toxicology.

[4]  J. Russo,et al.  Cancer risk related to mammary gland structure and development , 2001, Microscopy research and technique.

[5]  F. Kittrell,et al.  Development of spontaneous mammary tumors in BALB/c p53 heterozygous mice. A model for Li-Fraumeni syndrome. , 2000, The American journal of pathology.

[6]  R. Ullrich,et al.  Progesterone facilitates chromosome instability (aneuploidy) in p53 null , 2000, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[7]  B. Weber,et al.  Genetic and hormonal risk factors in breast cancer. , 2000, Journal of the National Cancer Institute.

[8]  S. Naber,et al.  Cytoplasmic sequestration and functional repression of p53 in the mammary epithelium is reversed by hormonal treatment. , 2000, Cancer research.

[9]  F. Kittrell,et al.  A mammary-specific model demonstrates the role of the p53 tumor suppressor gene in tumor development , 2000, Oncogene.

[10]  P. Hanawalt,et al.  p53-dependent global genomic repair of benzo[a]pyrene-7,8-diol-9,10-epoxide adducts in human cells. , 2000, Cancer research.

[11]  J. Ferlay,et al.  Estimates of the worldwide mortality from 25 cancers in 1990 , 1999, International journal of cancer.

[12]  D. Medina,et al.  Chemical carcinogen-induced tumorigenesis in parous, involuted mouse mammary glands. , 1999, Journal of the National Cancer Institute.

[13]  H. Gardner,et al.  Mammary gland development, reproductive history, and breast cancer risk. , 1999, Cancer research.

[14]  R. Guzman,et al.  Hormonal prevention of breast cancer: mimicking the protective effect of pregnancy. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[15]  B. O’Malley,et al.  Hormone-induced refractoriness to mammary carcinogenesis in Wistar-Furth rats. , 1998, Carcinogenesis.

[16]  D. Evans,et al.  Germ-line mutations of TP53 in Li-Fraumeni families: an extended study of 39 families. , 1997, Cancer research.

[17]  J. Russo,et al.  Differentiation and breast cancer. , 1997, Medicina.

[18]  J. Russo,et al.  Mammary gland neoplasia in long-term rodent studies. , 1996, Environmental health perspectives.

[19]  C. Prives,et al.  p53: puzzle and paradigm. , 1996, Genes & development.

[20]  F. Talamantes,et al.  Refractoriness to mammary tumorigenesis in parous rats: is it caused by persistent changes in the hormonal environment or permanent biochemical alterations in the mammary epithelia? , 1995, Carcinogenesis.

[21]  G. Stark,et al.  p53 controls both the G2/M and the G1 cell cycle checkpoints and mediates reversible growth arrest in human fibroblasts. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[22]  V. Rotter,et al.  Accumulation of wild‐type p53 protein upon gamma‐irradiation induces a G2 arrest‐dependent immunoglobulin kappa light chain gene expression. , 1995, EMBO Journal.

[23]  P. O'Connor,et al.  Interaction of the p53-regulated protein Gadd45 with proliferating cell nuclear antigen. , 1994, Science.

[24]  John Calvin Reed,et al.  Tumor suppressor p53 is a regulator of bcl-2 and bax gene expression in vitro and in vivo. , 1994, Oncogene.

[25]  B Rosner,et al.  Reproductive risk factors in a prospective study of breast cancer: the Nurses' Health Study. , 1994, American journal of epidemiology.

[26]  J. Trent,et al.  WAF1, a potential mediator of p53 tumor suppression , 1993, Cell.

[27]  B. Vogelstein,et al.  A mammalian cell cycle checkpoint pathway utilizing p53 and GADD45 is defective in ataxia-telangiectasia , 1992, Cell.

[28]  H. J. Evans,et al.  p53 mutations in breast cancer. , 1992, Cancer research.

[29]  A. Levine,et al.  Two distinct mechanisms alter p53 in breast cancer: mutation and nuclear exclusion. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[30]  J. Russo,et al.  Comparative study of the influence of pregnancy and hormonal treatment on mammary carcinogenesis. , 1991, British Journal of Cancer.

[31]  A. Kimchi,et al.  Wild-type p53 induces apoptosis of myeloid leukaemic cells that is inhibited by interleukin-6 , 1991, Nature.

[32]  B. Vogelstein,et al.  p53 mutations in human cancers. , 1991, Science.

[33]  J. Kelsey,et al.  Epidemiology of breast cancer. , 1990, Epidemiologic reviews.

[34]  L. Strong,et al.  Germ line p53 mutations in a familial syndrome of breast cancer, sarcomas, and other neoplasms. , 1990, Science.

[35]  J. Russo,et al.  Effect of human chorionic gonadotropin on mammary gland differentiation and carcinogenesis. , 1990, Carcinogenesis.

[36]  J. Russo,et al.  Human chorionic gonadotropin and rat mammary cancer prevention. , 1990, Journal of the National Cancer Institute.

[37]  D. Sinha,et al.  Prevention of mammary carcinogenesis in rats by pregnancy: effect of full-term and interrupted pregnancy. , 1988, British Journal of Cancer.

[38]  M. Juliana,et al.  Short-term hormone treatment as a chemopreventive method against mammary cancer initiation in rats. , 1988, Anticancer research.

[39]  J. Russo,et al.  Biological and molecular bases of mammary carcinogenesis. , 1987, Laboratory investigation; a journal of technical methods and pathology.

[40]  C. Grubbs,et al.  Chemoprevention of N-Nitroso-N-methylurea-Induced Mammary Cancers by Pretreatment with 17β-Estradiol and Progesterone , 1985 .

[41]  L. Tay,et al.  Formation and removal of 7,12-dimethylbenz[a]anthracene--nucleic acid adducts in rat mammary epithelial cells with different susceptibility to carcinogenesis. , 1981, Carcinogenesis.

[42]  J. Russo,et al.  Susceptibility of the mammary gland to carcinogenesis. II. Pregnancy interruption as a risk factor in tumor incidence. , 1980, The American journal of pathology.

[43]  C. Lowe,et al.  Age at first birth and breast cancer risk. , 1970, Bulletin of the World Health Organization.

[44]  R. Moon.  Relationship between previous reproductive history and chemically induced mammary cancer in rats , 1969, International journal of cancer.