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Alternative mammary oncogenic pathways are induced by D-type cyclins; MMTV-cyclin D3 transgenic mice develop squamous
Andreja Pirkmaier1, Renee Dow, Soula Ganiatsas
1Peter MacCallum Cancer Institute, Trescowthick Research Laboratories, St Andrew's Place, East Melbourne, Victoria 3002, Australia.
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.
Insights
Cyclin D3 overexpression in mouse mammary glands exclusively causes squamous cell carcinoma, unlike other D-type cyclins. This suggests cyclin D3 plays a specific role in squamous differentiation and distinct oncogenic pathways.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- D-type cyclins (cyclin D1, D2, D3) activate cyclin-dependent kinases 4 and 6 (cdk4/6).
- Previous studies show MMTV-cyclin D1 and D2 transgenic mice develop different mammary tumors.
- The specific role of cyclin D3 in mammary gland oncogenesis was previously unknown.
Purpose of the Study:
- To investigate the effect of cyclin D3 overexpression in mouse mammary glands.
- To determine the specific oncogenic pathway promoted by cyclin D3.
Main Methods:
- Generation of MMTV-cyclin D3 transgenic mice.
- Analysis of mammary gland development, proliferation, and tumor formation.
- Assessment of p16 and p27 expression during involution.
Main Results:
- MMTV-cyclin D3 transgenic mice exclusively developed squamous cell carcinoma.
- Cyclin D3 expression was detected early, but normal development occurred in virgin mice.
- Multiparous mice showed abnormal growth and squamous metaplasia, indicating a role in squamous differentiation.
- p16 expression was abolished, and p27 expression increased during involution.
Conclusions:
- Cyclin D3 plays a distinct role in promoting squamous cell carcinoma development.
- D-type cyclins, despite functional redundancy, drive unique oncogenic pathways.
- Cyclin D3 is implicated in squamous differentiation in the mammary gland.