Abstract
The three human D-type cyclins, cyclin D1, D2 and D3 share the ability to bind to and activate cdk4 and 6. MMTV-cyclin D1 transgenic mice develop mainly adenocarcinoma, while MMTV-cyclin D2 mice show a lack of alveologenesis during pregnancy and only develop carcinoma at low frequency. The effect of cyclin D3 overexpression in mammary glands remains hitherto unknown. We generated MMTV-cyclin D3 transgenic mice and report here that they develop exclusively squamous cell carcinoma. We show that although cyclin D3 transgene expression was detected early in puberty, postnatal development and mammary gland proliferation were normal in virgin animals. In contrast, multiparous mice develop multiple foci of abnormal growth that correspond to various stages of squamous metaplasia. Therefore, our results support a role for cyclin D3 in squamous differentiation. In addition, we found that p16 expression during involution is abolished, while p27 expression increased in MMTV-cyclin D3 mice, two modifications that have been reported in the other MMTV-D-type cyclin transgenic models. Our observations indicate that despite biochemical redundancy in vitro and in vivo, D-type cyclins promote distinct oncogenic pathways.
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Bartkova J, Lukas J, Strauss M and Bartek J . (1998). Oncogene, 17, 1027–1037.
Bartkova J, Zemanova M and Bartek J . (1996). Int. J. Cancer, 65, 323–327.
Bouchard C, Thieke K, Maier A, Saffrich R, Hanley-Hyde J, Ansorge W, Reed S, Sicinski P, Bartek J and Eilers M . (1999). EMBO J, 18, 5321–5333.
Ciemerych MA, Kenney AM, Sicinska E, Kalaszczynska I, Bronson RT, Rowitch DH, Gardner H and Sicinski P . (2002). Genes Dev., 16, 3277–3289.
Classon M and Harlow E . (2002). Nat. Rev. Cancer, 2, 910–917.
Evron E, Umbricht CB, Korz D, Raman V, Loeb DM, Niranjan B, Buluwela L, Weitzman SA, Marks J and Sukumar S . (2001). Cancer Res., 61, 2782–2787.
Fantl V, Edwards PA, Steel JH, Vonderhaar BK and Dickson C . (1999). Dev. Biol., 212, 1–11.
Gadd M, Pisc C, Branda J, lonescu-Tiba V, Nikolic Z, Yang C, Wang T, Shackleford GM, Cardiff RD and Schmidt EV . (2001). Cancer Res., 61, 8811–8819.
Geng Y, Whoriskey W, Park MY, Bronson RT, Medema RH, Li T, Weinberg RA and Sicinski P . (1999). Cell, 97, 767–777.
Geng Y, Yu Q, Sicinska E, Das M, Bronson RT and Sicinski P . (2001). Proc. Natl. Acad. Sci. USA, 98, 194–199.
Hauser PJ, Agrawal D, Flanagan M and Pledger WJ . (1997). Cell Growth Differ., 8, 203–211.
Huang AL, Ostrowski MC, Berard D and Hager GL . (1981). Cell, 27, 245–255.
Kong G, Chua SS, Yijun Y, Kittrell F, Moraes RC, Medina D and Said TK . (2002). Oncogene, 21, 7214–7225.
Miyoshi K, Rosner A, Nozawa M, Byrd C, Morgan F, Landesman-Bollag E, Xu X, Seldin DC, Schmidt EV, Taketo MM, Robinson GW, Cardiff RD and Hennighausen L . (2002a). Oncogene, 21, 5548–5556.
Miyoshi K, Shillingford JM, Le Provost F, Gounari F, Bronson R, von Boehmer H, Taketo MM, Cardiff RD, Hennighausen L and Khazaie K . (2002b). Proc. Natl. Acad. Sci. USA, 99, 219–224.
Muraoka RS, Lenferink AE, Simpson J, Brantley DM, Roebuck LR, Yakes PM and Arteaga CL . (2001). J. Cell. Biol., 153, 917–932.
Musgrove EA, Lee CSL, Buckley MF and Sutherland RL . (1994). Proc. Natl. Acad. Sci. USA, 91, 8022–8026.
Neuman E, Ladha MH, Lin N, Upton TM, Miller SJ, Direnzo J, Pestell RG, Hinds PW, Dowdy SF, Brown M and Ewen ME . (1997). Mol. Cell Biol., 17, 5338–5347.
Perez-Roger I, Kim SH, Griffiths B, Sewing A and Land H . (1999). EMBO J., 18, 5310–5320.
Serrano M, Hannon G and Beach D . (1993). Nature, 366, 704–707.
Sicinski P, Donaher JL, Geng Y, Parker SB, Gardner H, Park MY, Robker RL, Richards JS, McGinnis LK, Biggers JD, Eppig JJ, Bronson RT, Elledge SJ and Weinberg RA . (1996). Nature, 384, 470–474.
Sicinski P and Weinberg RA . (1997). J. Mammary Gland Biol. Neoplasia, 2, 335–342.
Signoretti S, Di Marcotullio L, Richardson A, Ramaswamy S, Isaac B, Rue M, Monti F, Loda M and Pagano M . (2002). J. Clin. Invest., 110, 633–641.
Tong W and Pollard JW . (2001). Mol. Cell. Biol., 21, 1319–1328.
Toyashima H and Hunter T . (1994). Cell, 78, 67–74.
Trimarchi JM and Lees JA . (2002). Nat. Rev. Mol. Cell. Biol., 3, 11–20.
Wang T, Cardiff RD, Zukerberg L, Lees E, Arnold A and Schmidt EV . (1994). Nature, 369, 669–671.
Wong SC, Chan JK, Lee KC and Hsiao WL . (2001). J. Pathol., 194, 35–42.
Yu Q, Geng Y and Sicinski P . (2001). Nature, 411, 1017–1021.
Zwijsen RML, Buckle RS, Hijmans EM, Loomans CJM and Bernards R . (1998). Genes Dev., 12, 3488–3498.
Zwijsen RML, Wientjens E, Klompmaker R, Van der Sman J, Bernards R and Michalides RAAM . (1997). Cell, 88, 405–415.
Acknowledgements
We are grateful to Drs Matthew O'Connell, Liliana Ossowski, Rafael Mira-Y-Lopez, George Acs and Samuel Waxman for critical reading of this manuscript. This grant was supported by an NHMRC grant to DG and by the Samuel Waxman Foundation.
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Pirkmaier, A., Dow, R., Ganiatsas, S. et al. Alternative mammary oncogenic pathways are induced by D-type cyclins; MMTV-cyclin D3 transgenic mice develop squamous cell carcinoma. Oncogene 22, 4425–4433 (2003). https://doi.org/10.1038/sj.onc.1206488
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DOI: https://doi.org/10.1038/sj.onc.1206488
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