Abstract
Proliferating cells within the terminal end buds of the virgin female rat mammary gland are the most susceptible to chemical carcinogen induced tumorigenesis. We hypothesized that selective ablation of proliferating cells in the mammary gland would reduce mammary tumor incidence upon carcinogen challenge. Selective ablation of proliferating cells was achieved by intraductal injections of Adv-RSV-tk and gancyclovir administration. Despite efficient viral transduction of the thymidine kinase protein and the apparent elimination of >90% of the prolif-erating cells, the rats exhibited a higher incidence of MNU induced mammary tumors arising with shorter latency as compared to control animals. Several possible explanations of the puzzling relationship between elimination of cycling cells and increased tumor incidence are discussed and alternative strategies for the prevention of breast cancer are proposed.
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Kelsey JL, Gammon MD: The epidemiology of breast cancer. CA Cancer J Clin 41: 146–165, 1991
Peto R, Boreham J, Clarke M, Davies C, Beral V: UK and USA breast cancer deaths down 25% in year 2000 at ages 20–69 years [letter] [see comments]. Lancet 355: 1822, 2000
Greenlee RT, Hill-Harmon MB, Thun M: Cancer Statistics, 2001. CA Cancer J Clin 51: 15–36, 2001
Newman B, Austin MA, Lee M, King MC: Inheritance of human breast cancer: evidence for autosomal dominant transmission in high-risk families. Proc Natl Acad Sci USA 85: 3044–3048, 1988
Leris C, Mokbel K: The prevention of breast cancer: an overview. Curr Med Res Opin 16: 252–257, 2001
Hartmann LC, Schaid DJ, McDonnell SK: Contralateral prophylactic mastectomy in women with a personal and family history of breast cancer. In: Proceedings of the American Society of Clinical Oncology 2000. Abstract no 298, pp 77a
Hartmann LC, Schaid DJ, Woods JE, Crotty TP, Myers JL, Arnold PG, Petty PM, Sellers TA, Johnson JL, McDonnell SK, Frost MH, Jenkins RB: Efficacy of bilateral prophylactic mastectomy in women with a family history of breast cancer. N Engl J Med 340: 77–84, 1999
O'Regan RM, Jordan VC: Tamoxifen to raloxifene and beyond. Semin Oncol 28: 260–273, 2001
Rhodes DJ, Hartmann LC, Perez EA: Breast cancer prevention trials. Curr Oncol Rep 2: 558–565, 2000
Fisher B, Costantino JP, Wickerham DL, Redmond CK, Kavanah M, Cronin WM, Vogel V, Robidoux A, Dimitrov N, Atkins J, Daly M, Wieand S, Tan-Chiu E, Ford L, Wolmark N: Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J Natl Cancer Inst 90: 1371–1388, 1998
Cauley JA, Norton L, Lippman ME, Eckert S, Krueger KA, Purdie DW, Farrerons J, Karasik A, Mellstrom D, Ng KW, Stepan JJ, Powles TJ, Morrow M, Costa A, Silfen SL, Walls EL, Schmitt H, Muchmore DB, Jordan VC: Continued breast cancer risk reduction in postmenopausal women treated with raloxifene: 4-year results from the MORE trial. Multiple outcomes of raloxifene evaluation. Breast Cancer Res Treat 65: 125–134, 2001
Cummings SR, Eckert S, Krueger KA, Grady D, Powles TJ, Cauley JA, Norton L, Nickelsen T, Bjarnason NH, Morrow M, Lippman ME, Black D, Glusman JE, Costa A, Jordan VC: The effect of raloxifene on risk of breast cancer in postmenopausal women: results from the MORE randomized trial. Multiple outcomes of raloxifene evaluation. Jama 281: 2189–2197, 1999
Jeng MH, Kao C, Sivaraman L, Krnacik S, Chung LW, Medina D, Conneely OM, O'Malley BW: Reconstitution of estrogendependent transcriptional activation of an adenoviral target gene in select regions of the rat mammary gland. Endocrinology 139: 2916–2925, 1998
Russo J, Russo IH: Susceptibility of the mammary gland to carcinogenesis. II. Pregnancy interruption as a risk factor in tumor incidence. Am J Pathol 100: 497–512, 1980
Russo J, Russo IH: Influence of differentiation and cell kinetics on the susceptibility of the rat mammary gland to carcinogenesis. Cancer Res 40: 2677–2687, 1980
Medina D: The mammary gland: a unique organ for the study of development and tumorigenesis. J Mammary Gland Biol Neoplasia 1: 5–19, 1996
Cheng YC, Huang ES, Lin JC, Mar EC, Pagano JS, Dutschman GE, Grill SP: Unique spectrum of activity of 9-[(1,3-dihydroxy-2-propoxy)methyl]-guanine against herpesviruses in vitro and its mode of action against herpes simplex virus type 1. Proc Natl Acad Sci USA 80: 2767–2770, 1983
Wei SJ, Chao Y, Hung YM, Lin WC, Yang DM, Shih YL, Ch'ang LY, Whang-Peng J, Yang WK: S-and G2-phase cell cycle arrests and apoptosis induced by ganciclovir in murine melanoma cells transduced with herpes simplex virus thymidine kinase. Exp Cell Res 241: 66–75, 1998
Halloran PJ, Fenton RG: Irreversible G2-M arrest and cytoskeletal reorganization induced by cytotoxic nucleoside analogues. Cancer Res 58: 3855–3865, 1998
Bi WL, Parysek LM, Warnick R, Stambrook PJ: In vitro evidence that metabolic cooperation is responsible for the bystander effect observed with HSV tk retroviral gene therapy. Hum Gene Ther 4: 725–731, 1993
Elshami AA, Saavedra A, Zhang H, Kucharczuk JC, Spray DC, Fishman GI, Amin KM, Kaiser LR, Albelda SM: Gap junctions play a role in the 'bystander effect' of the herpes simplex virus thymidine kinase/ganciclovir system in vitro. Gene Ther 3: 85–92, 1996
Freeman SM, Abboud CN, Whartenby KA, Packman CH, Koeplin DS, Moolten FL, Abraham GN: The 'bystander effect': tumor regression when a fraction of the tumor mass is genetically modified. Cancer Res 53: 5274–5283, 1993
Anderson LM, Swaminathan S, Zackon I, Tajuddin AK, Thimmapaya B, Weitzman SA: Adenovirus-mediated tissuetargeted expression of the HSVtk gene for the treatment of breast cancer. Gene Ther 6: 854–864, 1999
Borrelli E, Heyman RA, Arias C, Sawchenko PE, Evans RM: Transgenic mice with inducible dwarfism. Nature 339: 538–541, 1989
Canfield V, West AB, Goldenring JR, Levenson R: Genetic ablation of parietal cells in transgenic mice: a new model for analyzing cell lineage relationships in the gastric mucosa. Proc Natl Acad Sci USA 93: 2431–2435, 1996
Kendall SK, Saunders TL, Jin L, Lloyd RV, Glode LM, Nett TM, Keri RA, Nilson JH, Camper SA: Targeted ablation of pituitary gonadotropes in transgenic mice. Mol Endocrinol 5: 2025–2036, 1991
Clark AJ, Iwobi M, Cui W, Crompton M, Harold G, Hobbs S, Kamalati T, Knox R, Neil C, Yull F, Gusterson B: Selective cell ablation in transgenic mice expression E. coli nitroreductase [see comments]. Gene Ther 4: 101–110, 1997
Cui W, Gusterson B, Clark AJ: Nitroreductase-mediated cell ablation is very rapid and mediated by a p53-independent apoptotic pathway. Gene Ther 6: 764–770, 1999
Pansera F: Accessibility and possibility of elimination of breast epithelium: the theoretical possibility of preventing breast carcinoma through destruction of the epithelium of origin. Med Hypotheses 33: 107–111, 1990
Ankerst J, Jonsson N: Adenovirus type 9-induced tumorigenesis in the rat mammary gland related to sex hormonal state. J Natl Cancer Inst 81: 294–298, 1989
Kohlhepp RL, Hegge LF, Nett JE, Moser AR: ROSA26 mice carry a modifier of Min-induced mammary and intestinal tumor development. Mamm Genome 11: 1058–1062, 2000
Medina D, Shepherd F, Gropp T: Enhancement of the tumorigenicity of preneoplastic mammary nodule lines by enzymatic dissociation. J Natl Cancer Inst 60: 1121–1126, 1978
Morral N, O'Neal W, Rice K, Leland M, Kaplan J, Piedra PA, Zhou H, Parks RJ, Velji R, Aguilar-Cordova E, Wadsworth S, Graham FL, Kochanek S, Carey KD, Beaudet AL: Administration of helper-dependent adenoviral vectors and sequential delivery of different vector serotype for long-term liver-directed gene transfer in baboons. Proc Natl Acad Sci USA 96: 12816–12821, 1999
Isaacs JT: Genetic control of resistance to chemically induced mammary adenocarcinogenesis in the rat. Cancer Res 46: 3958–3963, 1986
Schiedner G, Morral N, Parks RJ, Wu Y, Koopmans SC, Langston C, Graham FL, Beaudet AL, Kochanek S: Genomic DNA transfer with a high-capacity adenovirus vector results in improved in vivo gene expression and decreased toxicity [published erratum appears in Nat Genet 1998 Mar; 18(3): 298]. Nat Genet 18: 180–183, 1998
Chen SH, Shine HD, Goodman JC, Grossman RG, Woo SL: Gene therapy for brain tumors: regression of experimental gliomas by adenovirus-mediated gene transfer in vivo. Proc Natl Acad Sci USA 91: 3054–3057, 1994
Garnier A, Cote J, Nadeau I, Kamen A, Massie B: Scale-up of the adenovirus expression system for the production of recombinant protein in human 293S cells. Cytotechnology 15: 145–155, 1994
Jani A, Lochmuller H, Acsadi G, Simoneau M, Huard J, Garnier A, Karpati G, Massie B: Generation, validation, and large scale production of adenoviral recombinants with large size inserts such as a 6.3 kb human dystrophin cDNA. J Virol Methods 64: 111–124, 1997
Graham F, Prevec L: Vol 7, Humana, Clifton, NJ, 1991
Rasmussen SB, Young LJT, Smith GH: Preparing Mammary Gland Whole Mounts from Mice. Vol 1, Kluwer Academic/ Plenum Publishers, New York, NY 10013–1578, 2000, pp 75–86
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Sivaraman, L., Gay, J., Hilsenbeck, S.G. et al. Effect of Selective Ablation of Proliferating Mammary Epithelial Cells on MNU Induced Rat Mammary Tumorigenesis. Breast Cancer Res Treat 73, 75–83 (2002). https://doi.org/10.1023/A:1015227719105
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DOI: https://doi.org/10.1023/A:1015227719105