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WAP-TAg transgenic mice and the study of dysregulated cell survival, proliferation, and mutation during breast
1The Institute of Human Virology, Division of Infectious Diseases, Department of Medicine, University of Maryland Medical School and the Baltimore Veterans Affairs Medical Center, Baltimore, Maryland, MD 21201, USA.
Abstract:
Understanding the process of carcinogenesis is key to developing therapies which might interrupt or reverse tumor onset and progression. Cell growth and death signals are dependent not only upon molecular mechanisms within a cell but also upon external stimuli such as hormones, cell - cell signaling, and extracellular matrix. Mouse models can be used to dissect these complex processes, to identify key signaling pathways operating at different stages of tumorigenesis, and to test the strength of specific interventions. In the WAP-TAg mouse model, carcinogenesis is initiated by expression of the Simian Virus 40 T antigen (TAg). TAg expression is triggered by hormonal stimulation, either during estrus or pregnancy. Breast adenocarcinomas (ranging from well to poorly differentiated) develop in 100% of the female mice by approximately 8 - 9 months of age. Three distinct stages of tumorigenesis are easily identified: an initial proliferation, hyperplasia, and adenocarcinoma. The mean time to first palpable tumor in mice which undergo at least one pregnancy is 6 months. The tumorigenic process is marked by a competition between proliferation and apoptosis and is characterized by cellular acquisition of genetic mutations and increased stromal fibrosis. Protein levels of cell cycle control genes cyclin D1, cdk2, and E2F-1 are increased in these adenocarcinomas. c-Fos protein levels are slightly increased in these cancers, while c-Jun levels do not change. Hormonal exposure alters progression. Estrogen plays a role during the early stages of oncogenesis although the growth of the resulting adenocarcinomas is estrogen-independent. Transient hormonal stimulation by glucocorticoids that temporarily increases the rate of cell proliferation results in tetraploidy, premature appearance of irreversible hyperplasia, and early tumor development. Tumor appearance also can be accelerated through over expression of the cell survival protein, Bcl-2. Bcl-2 over expression not only reduces apoptosis during the initial proliferative process but also decreases the total rate of cell proliferation. This block in cell proliferation is lost selectively as the cells transition to adenocarcinoma. The WAP-TAg model can be utilized to investigate how the basic processes of cell proliferation, apoptosis, DNA mutation, and DNA repair are modified by external and internal signals during mammary oncogenesis.
Insights
The WAP-TAg mouse model reveals how hormonal signals influence mammary oncogenesis, detailing stages from proliferation to adenocarcinoma. This model aids in understanding cell cycle control and apoptosis in cancer development.
Area of Science:
- Oncology and Molecular Biology
- Mammary gland carcinogenesis research
- Animal models for cancer studies
Background:
- Carcinogenesis involves complex molecular and external signaling pathways.
- Mouse models are crucial for dissecting tumorigenesis and testing interventions.
- Understanding cell growth and death signals is key to cancer therapy development.
Purpose of the Study:
- To investigate mammary oncogenesis using the WAP-TAg mouse model.
- To identify key signaling pathways and stages of tumor development.
- To explore the impact of hormonal stimulation on cancer progression.
Main Methods:
- Utilized the WAP-TAg mouse model where Simian Virus 40 T antigen (TAg) expression initiates carcinogenesis.
- Observed hormonal triggers (estrus, pregnancy) and their effect on tumor onset.
- Analyzed cellular and molecular changes including proliferation, apoptosis, genetic mutations, and protein levels (cyclin D1, cdk2, E2F-1, c-Fos, c-Jun, Bcl-2).
Main Results:
- 100% of female WAP-TAg mice developed breast adenocarcinomas by 8-9 months.
- Identified three distinct stages: proliferation, hyperplasia, and adenocarcinoma.
- Hormonal exposure, including glucocorticoids and estrogen, significantly altered progression; Bcl-2 overexpression accelerated tumor development.
Conclusions:
- The WAP-TAg model effectively recapitulates mammary oncogenesis stages.
- Demonstrates the critical role of hormonal signals and cell cycle regulators in tumor development.
- This model is valuable for studying the interplay of proliferation, apoptosis, and DNA repair in mammary cancer.