Abstract
In the present study, competitive cDNA library screening (CCLS) and cDNA microarray analyses were employed to identify differentially expressed genes in methylnitrosourea-induced rat mammary adenocarcinomas. The preliminary screening of 100 000 plaques by CCLS identified 1217 clones with differential expression. Dot–blot analysis of the isolated clones verified differential expression in 471 distinct genes. Confirmation of these 471 genes was conducted by performing reverse transcription-polymerase chain reactions, and a total of 160 genes were confirmed after comparing six rat mammary adenocarcinomas and three normal rat mammary glands. Fifty-nine of these showed lower expression in the adenocarcinomas while the remaining 101 were overexpressed in the tumors. Employing a cDNA microarray containing 588 known genes revealed an additional 33 differentially expressed genes in these tumors. Importantly, most of the identified genes demonstrated relatively reproducible overexpression or underexpression in individual tumors. Many of the altered genes determined by cDNA microarray analysis were oncogenes, tumor suppressor genes, or genes involved in cell cycle control and apoptosis. CCLS identified many others not previously associated with mammary carcinogenesis, including a novel gene named RMT-7. Preliminary studies to determine the applicability of this gene expression approach for detecting potential biomarkers for cancer chemoprevention was evaluated in rat mammary tumors obtained from animals treated with vorozole, a potent aromatase inhibitor. When genes exhibiting differential expression as determined by CCLS or cDNA microarray analysis were examined in control and vorozole-treated tumors, expression of 19 genes was found to be modulated significantly in tumors treated with vorozole. Further investigations into these identified genes should contribute significantly to our understanding of the molecular mechanisms of rat mammary tumorigenesis. In addition, the identified genes may become useful targets for drug development and potential biomarkers for monitoring treatment and prevention of breast cancer in humans.
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Bertucci F, Houlgatte R, Benziane A, Granjeaud S, Adelaide J, Tagett R, Loriod B, Jacquemier J, Viens P, Jordan B, Birnbaum D, Nguyen C . 2000 Hum. Mol. Genet. 9: 2981–2991
Burk R, Hill KE, Boeglin ME, Ebner FF, Chittum HS . 1997 Histochem. Cell Biol. 108: 11–15
Chen H, Liu J, Merrick BA, Waalkes MP . 2001 Mol. Carcinog. 30: 79–87
Christov K, Shilkaitis A, Green A, Mehta RG, Grubbs CJ, Kelloff G, Lubet RA . 2000 Breast Cancer Res. Treat. 60: 117–128
Cole PA, Robinson CH . 1990 J. Med. Chem. 33: 2933–2942
De Coster R, Van Ginckel RF, Callens MJ, Goeminne NK, Janssens BL . 1992 Cancer Res. 52: 1240–1244
Devilee P, Schuuring E, van de Vijver MJ, Cornelisse CJ . 1994 Crit. Rev. Oncog. 5: 247–270
Dukes M . 1997 Oncology 54: 6–10
Easton DF, Bishop DT, Ford D, Crockford GP . 1993 Am. J. Hum. Genet. 52: 678–701
Ekholm SV, Reed SI . 2000 Curr. Opin. Cell Biol. 12: 676–684
Filmus J, Robles AI, Shi W, Wong MJ, Colombo LL, Conti CJ . 1994 Oncogene 9: 3627–3633
Gilles C, Polette M, Birembaut P, Brunner N, Thompson EW . 1997 Clin. Exp. Metastasis 15: 519–526
Gould MN . 1995 Semin.Cancer Biol. 6: 147–152
Grubbs CJ, Moon RC . 1974 Eur. J. Cancer 10: 707–712
Hannon GJ, Beach D . 1994 Nature 371: 257–261
Hu L, Lin L, Crist KA, Kelloff GJ, Steele VE, Lubet RA, You M, Wang Y . 1997 J. Cell. Biochem 28–29 117–124
Kelly DL, Rizzino A . 2000 Mol. Reprod. Dev. 56: 113–123
Koga M, Tanaka H, Yomogida K, Tsuchida J, Uchida K, Kitamura M, Sakoda S, Matsumiya K, Okuyama A, Nishimune Y . 1998 Biol. Reprod. 58: 261–265
Liu JJ, Chao JR, Jiang MC, Ng SY, Yen JJ, Yang-Yen HF . 1995 Mol. Cell. Biol. 15: 3654–3663
Lubet RA, Steele VE, Casebolt TL, Eto I, Kelloff GJ, Grubbs CJ . 1994 Carcinogenesis 15: 2775–2780
Lubet RA, Steele VE, DeCoster R, Bowden C, You M, Juliana MM, Eto I, Kelloff GJ, Grubbs CJ . 1998 Carcinogenesis 19: 1345–1351
Maass N, Hojo T, Zhang M, Sager R, Jonat W, Nagasaki K . 2000 Maspin. Acta. Oncol. 39: 931–934
Martikainen H, Koistinen R, Seppala M . 1992 Fertility Sterility 58: 543–546
Martin KJ, Kritzman BM, Price LM, Koh B, Kwan CP, Zhang X, Mackay A, O'Hare MJ, Kaelin CM, Mutter GL, Pardee AB, Sager R . 2000 Cancer Res. 60: 2232–2238
Matsushime, H, Roussel MF, Ashmun RA, Sherr CJ . 1991 Cell. 65: 701–713
Nacht M, Ferguson AT, Zhang W, Petroziello JM, Cook BP, Gao YH, Maguire S, Riley D, Coppola G, Landes GM, Madden SL, Sukumar S . 1999 Cancer Res. 9: 5464–5470
Popovici RM, Kao LC, Giudice LC . 2000 Endocrinology 141: 3510–3513
Ramachandra S, Machin L, Ashley S, Monaghan P, Gusterson BA . 1990 J. Pathol. 161: 7–14
Russo J, Russo IH . 1996 Breast Cancer Res. Treat. 39: 7–20
Russo J, Russo IH . 2000 J. Mammary Gland Biol. Neoplasia 5: 187–200
Sager R, Sheng S, Anisowicz A, Sotiropoulou G, Zou Z, Stenman G, Swisshelm K, Chen Z, Hendrix MJ, Pemberton P . 1994 Cold Spring Harb. Symp. Quant. Biol. 59: 537–546
Sager R . 1997 Proc. Natl. Acad. Sci. USA 94: 952–955
Sager R, Sheng S, Pemberton P, Hendrix MJ . 1996 Curr. Top. Microbiol. Immunol. 213: 51–64
Sallinen SL, Sallinen PK, Haapasalo HK, Helin HJ, Helen PT, Schraml P, Kallioniemi OP, Kononen J . 2000 Cancer Res. 60: 6617–6622
Schedin P, Mitrenga T, Kaeck M . 2000 J. Mammary Gland Biol. Neoplasia 5: 211–225
Schultz LB, Weber BL . 1999 Curr. Opin. Oncol. 11: 429–434
Slamon DJ, Godolphin W, Jones LA, Holt JA, Wong SG, Keith DE, Levin WJ, Stuart SG, Udove J, Ullrich A . 1989 Science 244: 707–712
Steele VE, Moon RC, Lubet RA, Grubbs CJ, Reddy BS, Wargovich M, McCormick DL, Pereira MA, Crowell JA, Bagheri D . 1994 J. Cell. Biochem. 20: 32–54
Suikkari AM, Tiitinen A, Stenman UH, Seppala M, Laatikainen T . 1991 Fertility Sterility 55: 895–899
Thompson HJ, Singh M, McGinley J . 2000 J. Mammary Gland Biol. Neoplasia 5: 201–210
Van de Vijver MJ, Nusse R . 1991 Biochim. Biophys. Acta 1072: 33–50
Wang TC, Cardiff RD, Zukerberg L, Lees E, Arnold A, Schmidt EV . 1994 Nature 369: 669–671
Wasylyk B, Hagman J, Gutierrez-Hartmann A . 1998 Trends Biochem. Sci. 23: 213–216
Wouters W, De Coster R, van Dun J, Krekels MD, Dillen A, Raeymaekers A, Freyne E, Van Gelder J, Sanz G, Venet M, Jansson M . 1990 J. Steroid Biochem. Mol Biol. 37: 1049–1054
Yamashita H, Kobayashi S, Iwase H, Itoh Y, Kuzushima T, Iwata H, Itoh K, Naito A, Yamashita T, Masaoka A . 1993 Jpn. J. Cancer Res. 84: 871–878
Acknowledgements
We are grateful to G Stoner for critical reading of this manuscript and helpful discussions. We thank Rita Purnell for secretarial assistance. This work was supported by NIH grants CN05113, CA58554, CA78797 and CA16058.
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Wang, Y., Hu, L., Yao, R. et al. Altered gene expression profile in chemically induced rat mammary adenocarcinomas and its modulation by an aromatase inhibitor. Oncogene 20, 7710–7721 (2001). https://doi.org/10.1038/sj.onc.1204941
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DOI: https://doi.org/10.1038/sj.onc.1204941
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