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The Role of E2F3 in Breast Cancer
The Role of E2F3 in Breast Cancer.
Background: The Rb/E2F pathway, which is regulated by cyclin D1 kinase activity, is an integral component of the regulatory network that controls the G1/S transition of the cell cycle. The critical role of cyclin D1 in ErBb2/Neu initiated, but not in Wnt or Myc-initiated, breast cancers was recently highlighted by the almost complete suppression of tumor onset in mice lacking the cyclin D1 gene. Similar studies in our laboratory using mice deleted for the E2F3 gene revealed that E2F3 is essential for the onset of ErBb2/Neu, but not for Wnt or Myc mediated cancers. These striking results demonstrates a critical role for E2F3 in breast carcinogenesis and begins to delineate a tumor specific pathway that links ErBb2/Neu to the regulation of cyclin D1 and E2F3 in the mammary gland. Objectives: I propose to take a genetic approach utilizing mouse tumor models to study the mechanism of E2F3 action in ErBb2/Neu initiated breast cancer.
Recent work from the Lees and Leone laboratories suggests that the E2F3 family member, one of eight E2F members, plays an essential role in the control of cellular proliferation by modulating the activities of p53. Thus in Specific Aim 1: I will use conditional knockout strategies in mice to determine whether the regulation of the p53 axis by E2F3 is an important mechanism for controlling breast cancer onset in ErBb2/Neu transgenic mice. The complexity of the E2F3 gene locus, which encodes two distinct gene products E2F3a and E2F3b, has made it difficult to determine whether E2F3a, E2F3b, or both protein products might be required to regulate the p53 pathway, cellular proliferation, and tumor onset. Thus in Specific Aim 2: I will use conditional alleles of E2F3a and E2F3b in mice to determine whether E2F3a, E2F3b or both are required for ErBb2/Neu induced mammary carcinogenesis. In Specific Aim 3: I plan to elucidate the mechanism of E2F3 action in the transformation of mammary epithelial cells and breast cancer onset. To this end, I will use a 3-dimensional mammary epithelial tissue culture system derived from mouse mammary glands that has recently been established in the Leone lab to genetically assess the role of E2F3 in the control of proliferation at the most early stages of ErBb2/Neu –mediated transformation. The proposed study will elucidate the mechanism of E2F3 action in breast cancer and will identify E2F3a, E2F3b or both as an important novel therapeutic target for cancer intervention.
The Role of E2F3 in Breast Cancer
Each year, approximately 180,000 new cases of breast cancer will be diagnosed in the United States and over 40,000 women will die from the disease, ranking breast cancer as the second leading cause of death in women. Approximately one third of breast cancer patients have amplification of the ErBb2/Neu gene. ErBb2/Neu activation leads to the induction of cyclin D1 and the stimulation of cell division. The critical role of cyclin D1 in breast cancer was recently highlighted by the suppression of tumor onset in mice lacking cyclin D1 activity. We have recently found that E2F3 also has a critical role in tumor onset since mice deleted for E2F3 in the mammary glands no longer are susceptible to ErBb2/Neu induced tumors, strongly suggesting that E2F3 is in the same genetic pathway as ErBb2/Neu and cyclin D1. Interestingly, a recent study shows cyclin D1 overexpression served as a biomarker to predict tamoxifen treatment resistance in breast cancer. Given that cyclin D1 protein is overexpressed in >50% of breast cancer, and active ErBb2/Neu is sufficient to upregulate the expression of cyclin D1 in cancer cells, suggests that blocking cyclin D1 and/or E2F3 should enhance tamoxifen treatment in hormone-receptor-positive breast cancers. While our data shows that E2F3 is critical for breast cancer onset, it is not clear whether the two isoforms of E2F3, E2F3a and E2F3b, play equal or different roles in regulating cell division and tumor onset. Obviously, understanding how E2F3 functions to promote tumorigenesis will be essential for the future development of effective breast cancer therapies. Thus I propose to use in vivo and in vitro models to elucidate how E2F3 functions to control cell division and tumor onset. In Aim1, I will use mouse models of cancer to define whether the ablation of E2F3 leads to the activation of p53 in ErBb2/Neu induced breast tumors. In Aim2, I will investigate whether E2F3a, E2F3b, or both play the critical role in breast cancer onset. In Aim3, I will use a 3-dimensional tissue culture technique recently developed in our lab to study how exactly E2F3 functions to regulate cell division in normal and tumor epithelial cells of the breast gland. The proposed study will elucidate the mechanism of E2F3 action in breast cancer and will identify E2F3a, E2F3b or both as important novel therapeutic targets for cancer intervention.