Abstract
Mammary tumorigenesis was analysed in transgenic mice which overexpress des(1-3)hIGF-I (WAP-DES) and/or a mutant form of p53 (p53172R-H). Nonlactating, multiparous WAP-DES mice exhibited hyperplastic lesions termed mammary interepithelial neoplasia (MIN) which constitutively expressed WAP-DES. By 23 months of age, 53% of the WAP-DES mice developed mammary adenocarcinomas. A 75% reduction in both apoptosis and proliferation was observed in the normal mammary glands of WAP-DES mice. Mammary tumor incidence in WAP-DES/p53 bitransgenic mice was similar to that of WAP-DES and 2–3-fold greater than that of nontransgenic and p53172R-H females. Tumor latency, however, was reduced by 8 months in bitransgenic mice as compared to mice of the other three genotypes. Aneuploidy was frequently observed in tumors from bitransgenic and p53172R-H mice, but not from mice expressing only the WAP-DES transgene. Expression of IGFBP3 was elevated in tumors from WAP-DES, but not bitransgenic mice, indicating an alteration in the p53/IGF-I axis. These studies indicate that overexpression of des(1-3)hIGF-I increases the frequency of MIN and stochastic mammary tumors and that the appearance of tumors displaying genomic instability is accelerated by mutant p53172R-H.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 50 print issues and online access
$259.00 per year
only $5.18 per issue
Rent or buy this article
Prices vary by article type
from$1.95
to$39.95
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Aas T, Borresen AL, Geisler S, Smith-Sorensen B, Johnsen H, Varhaug JE, Akslen LA and Lonning PE. . 1996 Nature Med. 2: 811–814.
Amundadottir LT, Nass SJ, Berchem GJ, Johnson MD and Dickson RB. . 1996 Oncogene 13: 757–765.
Arteaga CL. . 1992 Br. Cancer Res. Treat. 22: 101–106.
Bates P, Fisher R, Ward A, Richardson L, Hill DJ and Graham CF. . 1996 Br. J. Cancer 72: 1189–1193.
Ben-David Y and Berstein A. . 1991 Cell 66: 831–834.
Buckbinder L, Talbott R, Velasco-Miguel S, Takenaka I, Faha B, Seizinger BR and Kley N. . 1995 Nature 377: 646–649.
Cardiff RD, Anver MR, Gusterson BA, Henninghausen L, Jensen RA, Merino MJ, Rehn S, Russo J, Tavbassoli FA, Wakefield LM, Ward JM and Green JE. . 2000 Oncogene in press.
Christofori G, Naik P and Hanahan D. . 1994 Nature 369: 414–418.
Conover CA and Bale LK. . 1992 Endocrinology 131: 608–614.
Conover CA and Powell DR. . 1991 Endocrinology 129: 710–716.
Cullen KJ, Yee D, Sly WS, Perdue J, Hampton B, Lippman ME and Rosen N. . 1990 Cancer Res. 50: 48–53.
Dittmer D, Pati S, Zambetti G, Chu S, Teresky AK, Moore M, Finlay C and Levine AJ. . 1993 Nature Genetics 4: 42–46.
Dunn T. . 1959 Physiopathology of Cancer. Homburger F. (ed.) A.J. Phiebig: New York. pp38–83.
Fukasawa K, Choi T, Kuriyama R, Rulong S and Vande Woude GF. . 1996 Science 271: 1744–1747.
Gai XX, Rizzo MG, Lee J, Ullrich A and Baserga R. . 1988 Oncogene Res. 3: 377–386.
Gill ZP, Perks CM, Newcomb PV and Holly JMP. . 1997 J. Biol. Chem. 272: 25602–25607.
Gualberto A, Aldape K, Kozakiewics K and Tlsty TD. . 1998 Proc. Natl. Acad. Sci. (USA) 95: 5166–5171.
Hachiya M, Chumakov A, Miller CW, Akashi M, Said J and Koeffler HP. . 1994 Anticancer Res. 14: 1853–1860.
Hadsell DL, Greenberg NM, Fligger JM, Baumrucker CR and Rosen JM. . 1996 Endocrinology 137: 321–330.
Hainaut P, Soussi T, Shomer B, Hollstein M, Greenblatt M, Hovig E, Harris CC and Montesano R. . 1997 Nucleic Acids Res. 25: 151–157.
Hollstein M, Sidransky D, Vogelstein B and Harris CC. . 1991 Science 253: 49–53.
Kern SE, Pietenpol JA, Thiagalingam S, Seymour A, Kinzler KW and Vogelstein B. . 1992 Science 256: 827–830.
Kleinberg DI. . 1997 J. Mamm. Gland Biol. Neoplas. 2: 49–57.
Li B, Murphy KL, Laucirica R, Kittrell F, Medina D and Rosen JM. . 1998 Oncogene 16: 997–1007.
Li B, Rosen JM, McMenamin-Balano J, Muller WJ and Perkins AS. . 1997 Mol. Cell Biol. 17: 3155–3163.
Livingstone LR, White A, Sprouse J, Livanos E, Jacks T and Tlsty TD. . 1992 Cell 70: 923–935.
Murphy KL and Rosen JM. . 2000 Oncogene in press.
Morgan WF, Corcoran J, Hartmann A, Kaplan MI, Limoli CL and Ponnaiya B. . 1998 Mutat. Res. 404: 125–128.
Neiman PE, Blish C, Heydt C, Loring G and Thomas SJ. . 1994 Mol. Biol. Cell 5: 763–772.
Neuenschwander S, Schwartz A, Wood TL, Roberts Jr CT, Hennighausen L and Leroith D. . 1996 J. Clin. Invest. 97: 2225–2232.
Ohlsson C, Kley N, Werner H and LeRoith D. . 1998 Endocrinology 139: 1101–1107.
Ory K, Legros Y, Auguin C and Soussi T. . 1994 EMBO J. 13: 3496–3504.
Pravtcheva DD and Wise TL. . 1999 J. Exp. Zool. 281: 43–57.
Quarrie LH, Addey CV and Wilde CJ. . 1996 J. Cell Physiol. 168: 559–569.
Schuller AGP, Groffen C, van Neck JW and Drop SLS. . 1994 Mol. Cell Endocrinol. 104: 57–66.
Sell C, Rubini M, Rubin R, Liu JP, Efstratiadis A and Baserga R. . 1993 Proc. Natl. Acad. Sci. USA 90: 11217–11221.
Starbog M, Gell K, Brundell E and Höög C. . 1996 J. Cell Sci. 109: 143–153.
Strange R, Li F, Saurer S, Burkhardt A and Friis RR. . 1992 Development 115: 49–58.
Symonds H, Krall L, Remington L, Saenz-Robles M, Lowe S, Jacks T and Van Dyke T. . 1994 Cell 78: 703–711.
Turner BC, Haffty BG, Narayanan L, Yuan J, Havre PA, Gumbs AA, Kaplan L, Burgaud JL, Carter D, Baserga R and Glazer PM. . 1997 Cancer Res. 57: 3079–3083.
Valentinis B, Bhala A, Deangelis T, Baserga R and Cohen P. . 1995 Mol. Endocrinol. 9: 361–367.
Villafuerte BC, Zhang WN and Phillips LS. . 1996 Mol. Endocrinol. 10: 622–630.
Wada J, Liu ZZ, Alvares K, Kumar A, Wallner E, Makino H and Kanwar YS. . 1993 Proc. Natl. Acad. Sci. (USA) 90: 10360–10364.
Wang XJ, Greenhalgh DA, Jiang A, He D, Zhong L, Medina D, Brinkley BR and Roop DR. . 1998 Oncogene 17: 35–45.
Webster NG, Resnik JL, Reichart DB, Strauss B, Haas M and Seely L. . 1996 Cancer Res. 56: 2781–2788.
Werner H, Karnieli E, Rauscher III FJ, and LeRoith D. . 1996 Proc. Natl. Acad. Sci. (USA) 93: 8318–8323.
Yee D, Cullen KJ, Paik S, Perdue JF, Hampton B, Schwartz A, Lippman ME and Rosen N. . 1988 Cancer Res. 48: 6691–6696.
Yee D, Paik S, Lebovic GS, Marcus RR, Favoni RE, Cullen KJ, Lippman ME and Rosen N. . 1989 Mol. Endocrinol. 3: 509–517.
Acknowledgements
The authors would like to thank Dr O'Brian Smith for help with statistical analysis of the data, Dr Daniel Medina for help in evaluating tumor pathology and a critical review of the manuscript, Liz Hopkins for processing of tissue sections, and Louise Hadsell for help in reading immunohistochemistry results. Thank also to Dr Yasphal Kanwar for providing the murine IGF-IR cDNA, and Dr Han vanNeck for providing the murine IGFBP3 cDNA. This work is a publication of the USDA/ARS Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine and Texas Children's Hospital, Houston, TX, USA. This project has been funded with federal funds from the National Institutes of Health grants #DK52197-01 (DH) and #CA16303 (J Rosen), and in part with federal funds from the US Department of Agriculture/Agricultural Research Service under Cooperative Agreement #58-6250-6001 (D Hadsell). The contents of this publication do not necessarily reflect the views or policies of the USDA nor does the mention of trade names, commercial products or organizations imply endorsement by the US Government.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Hadsell, D., Murphy, K., Bonnette, S. et al. Cooperative interaction between mutant p53 and des(1-3)IGF-I accelerates mammary tumorigenesis. Oncogene 19, 889–898 (2000). https://doi.org/10.1038/sj.onc.1203386
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.onc.1203386
Keywords
This article is cited by
-
Expression of IGF1R in normal breast tissue and subsequent risk of breast cancer
Breast Cancer Research and Treatment (2011)
-
Preneoplastic changes persist after IGF-IR downregulation and tumor regression
Oncogene (2010)
-
The insulin-like growth factor pathway as a target for cancer therapy
Clinical and Translational Oncology (2010)
-
Insulin resistance and hepatocarcinogenesis
Clinical Journal of Gastroenterology (2010)
-
Reversibility and recurrence of IGF-IR-induced mammary tumors
Oncogene (2009)