Pirkmaier Andreja, Dow Renee, Ganiatsas Soula, Waring Paul, Warren Kerry, Thompson Anne, Hendley Joy, Germain Doris
Peter MacCallum Cancer Institute, Trescowthick Research Laboratories, St Andrew's Place, East Melbourne, Victoria 3002, Australia.
Oncogene. 2003 Jul 10;22(28):4425-33. doi: 10.1038/sj.onc.1206488.
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.
三种人类D型细胞周期蛋白，即细胞周期蛋白D1、D2和D3，都具有结合并激活细胞周期蛋白依赖性激酶4和6的能力。MMTV-细胞周期蛋白D1转基因小鼠主要发生腺癌，而MMTV-细胞周期蛋白D2小鼠在妊娠期间肺泡形成不足，仅以低频率发生癌。迄今为止，细胞周期蛋白D3在乳腺中过表达的影响尚不清楚。我们构建了MMTV-细胞周期蛋白D3转基因小鼠，并在此报告它们仅发生鳞状细胞癌。我们发现，虽然在青春期早期就检测到了细胞周期蛋白D3转基因表达，但未生育动物的出生后发育和乳腺增殖是正常的。相比之下，经产小鼠会出现多个异常生长灶，这些病灶对应于鳞状化生的不同阶段。因此，我们的结果支持细胞周期蛋白D3在鳞状分化中发挥作用。此外，我们发现，在退化过程中p16的表达被消除，而在MMTV-细胞周期蛋白D3小鼠中p27的表达增加，这两种改变在其他MMTV-D型细胞周期蛋白转基因模型中也有报道。我们的观察结果表明，尽管在体外和体内存在生化冗余，但D型细胞周期蛋白促进不同的致癌途径。
