| Breast cancer is the most common malignancy diagnosed among women in the United States. Despite recent advances in targeted therapy and early diagnosis breast cancer remains one of the leading causes of cancer deaths with about 40,000 fatalities each year. The initiation and progression of breast cancer is a multi-step process that involves genetic and epigenetic changes in tumor suppressor genes and oncogenes. Two important oncogenes, ErbB2 and Cyclin D1, are overexpressed in 25% and 40% of breast cancer cases, respectively. As a cell cycle regulator, Cyclin D1 is suggested to mediate excessive cell proliferation in response to increased signaling through the ErbB2 receptor tyrosine kinase, and it is therefore a candidate molecular target for the treatment of ErbB2-positive breast cancers. However, it has never been shown that the specific ablation of Cyclin D1 within mammary cancer causes growth arrest. In this dissertation I describe the generation and analysis of a novel breast cancer model in which Cyclin D1 can be ablated prior to or after neoplastic transformation to assess whether this cell cycle regulator is indispensable for mammary tumor initiation and progression. Collectively, my studies show that deficiency in Cyclin D1 delays but does not prevent ErbB2-induced mammary cancer initiation. Deficiency in Cyclin D1 leads to a compensatory upregulation of Cyclin D3, which explains why the targeted downregulation of Cyclin D1 in established mammary tumors has no effect on cancer cell proliferation. The reciprocal upregulation of Cyclin D3 is a compensatory mechanism by which cancer cells sustain normal proliferation in the absence of Cyclin D1. Similar to our cancer model, both Cyclins are overexpressed in human breast cancer cell lines and primary breast tumors, and Cyclin D3 frequently exceeds the expression of Cyclin D1 in ErbB2-positive cases The simultaneous downregulation of Cyclin D1 and D3 reduced the proliferation of cancer cells and decreased the tumor burden. My studies provide experimental evidence that only the combined inhibition of Cyclin D1 and D3 might be suitable therapeutic strategy to treat ErbB2-associated breast cancer. |
