Abstract
Breast cancer is the most common cancer in women, but its pathogenesis is still unclear. Microsatellite instability (MSI) has been identified in breast cancer cells, suggesting an association with mismatch repair defects. To test this hypothesis, we investigated MSI, protein expression of hMSH2 and hMLH1, as well as genetic and epigenetic modifications of these two genes in 32 sporadic breast tumors. MSI was identified in 15 cases. Immunohistochemistry analysis revealed that all MSI cases but one had lower than normal expression of hMSH2 (nine cases), hMLH1 (12 cases), or both (seven cases). In tumors with MSI, both genetic and epigenetic modifications of these mismatch repair genes were also identified. Eight cases harbored mutations or polymorphisms in hMSH2 and hMLH1, and 10 exhibited hypermethylation in the promoter region of hMLH1. These results suggest that both genetic and epigenetic alterations of hMSH2 and especially of hMLH1 contribute to genomic instability and tumorigenesis in sporadic breast cancer.
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Aaltonen LA, Peltomäki P, Leach FS, Sistonen P, Pylkkänen L, Mecklin J-P, Järvinen H, Powell SM, Jen J, Hamilton SR, Petersen GM, Kinzler KW, Vogelstein B, de la Chapelle A . 1993 Science 260: 812–816
Aldaz CM, Chen T, Sahin A, Cunningham J, Bondy M . 1995 Cancer Res. 55: 3976–3981
Baylin SB, Herman JG . 2000 Trends Genet. 16: 168–174
Bevilacqua RAU, Simpson AJG . 2000 Int. J. Cancer 87: 200–203
Boland CR, Thibodeau SN, Hamilton SR, Sidransky D, Eshleman JR, Burt RW, Meltzer SJ, Rodriguez-Bigas MA, Fodde R, Ranzani GN, Srivastava S . 1998 Cancer Res. 58: 5248–5257
Contegiacomo A, Palmirotta R, De Marchis L, Pizzi C, Mastranzo P, Delrio P, Petrella G, Figliolini M, Bianco AR, Frati L, Cama A, Mariani-Costantini R . 1995 Int. J. Cancer 64: 264–268
Cui J, Shen F, Jiang F, Wang Y, Bian J, Shen Z . 1998 Chung Hua I Hsueh I Chuan Hsueh Tsa Chih 15: 348–350
Cunningham JM, Christensen ER, Tester DJ, Kim C-Y, Roche PC, Burgart LJ, Thibodeau SN . 1998 Cancer Res. 58: 3455–3460
de Marchis L, Contegiacomo A, D'Amico C, Palmirotta R, Pizzi C, Ottini L, Mastranzo P, Figliolini M, Petrella G, Amanti C, Battista P, Bianco AR, Frati L, Cama A, Mariani-Costantini R . 1997 Clin. Cancer Res. 3: 241–248
Deng G, Chen A, Hong J, Chae H-S, Kim YS . 1999 Cancer Res. 59: 2029–2033
Eshleman JR, Markowitz SD . 1995 Curr. Opin. Oncol. 7: 83–89
Esteller M, Catasus L, Matias-Guiu X, Mutter GL, Prat J, Baylin SB, Herman JG . 1999 Am. J. Pathol. 155: 1767–1772
Esteller M, Levine R, Baylin SB, Ellenson LH, Herman JG . 1998 Oncogene 17: 2413–2417
Fleisher AS, Esteller M, Wang S, Tamura G, Suzuki H, Yin J, Zou T-T, Abraham JM, Kong D, Smolinski KN, Shi Y-Q, Rhyu M-G, Powell MS, James SP, Wilson KT, Herman JG, Meltzer SJ . 1999 Cancer Res. 59: 1090–1095
Friedrich M, Villena-Heinsen C, Meyberg R, Woll-Hermann A, Reitnauer K, Schmidt W, Tilgen W, Reichrath J . 1999 Histochem J. 31: 717–722
Frommer M, McDonald LE, Millar DS, Collis CM, Watt F, Grigg GW, Molloy PL, Paul CL . 1992 Proc. Natl. Acad. Sci. USA 89: 1827–1831
Fujii S, Takeshima Y, Arihiro K, Kaneko M, Inai K . 1998 Hiroshima J. Med. Sci. 47: 89–97
Grady WM, Rajput A, Lutterbaugh JD, Markowitz SD . 2001 Cancer Res. 61: 900–902
Gurin CC, Federici MG, Kang L, Boyd J . 1999 Cancer Res. 59: 462–466
Hangaishi A, Ogawa S, Mitani K, Hosoya N, Chiba S, Yazaki Y, Hirai H . 1997 Blood 89: 1740–1747
Herman JG, Baylin SB . 2000 Curr. Top Microbiol. Immunol. 249: 35–54
Herman JG, Graff JR, Myohanen S, Nelkin BD, Baylin SB . 1996 Proc. Natl. Acad. Sci. USA 93: 9821–9826
Herman JG, Umar A, Polyak K, Graff JR, Ahuja N, Issa J-P, Markowitz S, Willson JK, Hamilton SR, Kinzler KW, Kane MF, Kolodner RD, Vogelstein B, Kunkel TA, Baylin SB . 1998 Proc. Natl. Acad. Sci. USA 95: 6870–6875
Hosoya N, Hangaishi A, Ogawa S, Miyagawa K, Mitani K, Yazaki Y, Hirai H . 1998 Jpn. J. Cancer Res. 89: 33–39
Jonsson M, Johannsson O, Borg A . 1995 Eur. J. Cancer 31A: 2330–2334
Kane MF, Loda M, Gaida GM, Lipman J, Mishra R, Goldman H, Hessup JM, Kolodner R . 1997 Cancer Res. 57: 808–811
Katabuchi H, van Rees B, Lambers AR, Ronnett BM, Blazes MS, Leach FS, Cho KR, Hedrick L . 1995 Cancer Res. 55: 5556–5560
Kinzler KW, Vogelstein B . 1996 Cell 87: 159–170
Kolodner RD . 1995 Trends Biochem. Sci. 20: 397–401
Kuismanen SA, Holmberg MT, Salovaara R, de la Chapelle A, Peltomäki P . 2000 Am. J. Pathol. 156: 1773–1779
Leung SY, Yuen ST, Chung LP, Chu KM, Chan ASY, Ho JCI . 1999 Cancer Res. 59: 159–164
Levati L, Marra G, Lettieri T, D'Atri S, Vernole P, Tentori L, Lacal PM, Pagani E, Bonmassar E, Jiricny J, Graziani G . 1998 Genes Chromosomes Cancer 23: 159–166
Li G-M, Modrich P . 1995 Proc. Natl. Acad. Sci. USA 92: 1950–1954
Li G-M, Wang H, Romano LJ . 1996 J. Biol. Chem. 271: 24084–24088
Liu B, Nicolaides NC, Markowitz S, Willson JKV, Parsons RE, Jen J, Papadopoulos N, Peltomäki P, de la Chapelle A, Hamilton SR, Kinzler KW, Vogelstein B . 1995 Nat. Genet. 9: 48–55
Lynch HT, de la Chapelle A . 1999 J. Med. Genet. 36: 801–818
Modrich P, Lahue R . 1996 Annu. Rev. Biochem. 65: 101–133
Parsons R, Li G-M, Longley MJ, Fang W-H, Papadopoulos N, Jen J, de la Chapelle A, Kinzler KW, Vogelstein B, Modrich P . 1993 Cell 75: 1227–1236
Paulson TG, Wright FA, Parker BA, Russack V, Wahl GM . 1996 Cancer Res. 56: 4021–4026
Rosenberg CL, Larson PS, Romo JD, De Las Morenas A, Faller DV . 1997 Hum. Pathol. 28: 214–219
Rush EB, Calvano JE, van Zee KJ, Zelenetz AD, Borgen PI . 1997 Ann. Surg. Oncol. 4: 310–315
Salvesen HB, MacDonald N, Ryan A, Iversen OE, Jacobs IJ, Akslen LA, Das S . 2000 Clin. Cancer Res. 6: 3607–3613
Scott RJ, McPhillips M, Meldrum CJ, Fitzgerald PE, Adams K, Spigelman AD, du Sart D, Tucker K, Kirk J . 2001 Am. J. Hum. Genet. 68: 118–127
Shaw JA, Walsh T, Chappell SA, Carey N, Johnson K, Walker RA . 1996 Br. J. Cancer 73: 1393–1397
Shen KL, Yang LS, Hsieh HF, Chen CJ, Yu JC, Tsai NM, Harn HJ . 2000 J. Surg. Oncol. 74: 100–107
Siah SP, Quinn DM, Bennett GD, Casey G, Flower RLP, Suthers G, Rudzki Z . 2000 Breast Cancer Res. Treat 60: 135–142
Strand M, Prolla TA, Liskay RM, Petes TD . 1993 Nature 365: 274–276
Thibodeau SN, Bren G, Schaid D . 1993 Science 260: 816–819
Thibodeau SN, French AJ, Cunningham JM, Tester D, Burgart LJ, Roche PC, McDonnell SK, Schaid DJ, Vockley CW, Michels VV, Farr Jr GH, O'Connell MJ . 1998 Cancer Res. 58: 1713–1718
Thibodeau SN, French AJ, Roche PC, Cunningham JM, Tester DJ, Lindor NM, Moslein G, Baker SM, Liskay RM, Burgart LJ, Honchel R, Halling KC . 1996 Cancer Res. 56: 4836–4840
Toyama T, Iwase H, Iwata H, Hara Y, Omoto Y, Suchi M, Kato T, Nakamura T, Kobayashi S . 1996a Cancer Lett. 108: 205–209
Toyama T, Iwase H, Yamashita H, Iwata H, Yamashita T, Ito K, Hara Y, Suchi M, Kato T, Nakamura T, Kobayashi S . 1996b Int. J. Cancer 68: 447–451
Vasen HF, Morreau H, Nortier JW . 2001 Am. J. Hum. Genet. 68: 1533–1535
Walsh T, Chappell SA, Shaw JA, Walker RA . 1998 J. Pathol. 185: 18–24
Weber TK, Conlon W, Petrelli NJ, Rodriguez-Bigas M, Keitz B, Pazik J, Farrell C, O'Malley L, Oshalim M, Abdo M, Anderson G, Stoler D, Yandell D . 1997 Cancer Res. 57: 3798–3803
Yee CJ, Roodi N, Verrier CS, Parl FF . 1994 Cancer Res. 54: 1641–1644
Zenklusen JC, Bieche I, Lidereau R, Conti CJ . 1994 Proc. Natl. Acad. Sci. USA 91: 12155–12158
Acknowledgements
We thank Dr Michael Cibull for providing specimens for this study. This work was supported partially by grant GMC-98538 from the American Cancer Society and grant DAMD17-99-1-9246 from the Department of Defense (to G-M Li).
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Murata, H., Khattar, N., Kang, Y. et al. Genetic and epigenetic modification of mismatch repair genes hMSH2 and hMLH1 in sporadic breast cancer with microsatellite instability. Oncogene 21, 5696–5703 (2002). https://doi.org/10.1038/sj.onc.1205683
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DOI: https://doi.org/10.1038/sj.onc.1205683
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