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    The Cul3 Ubiquitin Ligase Is A Potential Marker for Breast Epithelial Tumorigenesis

    Scientific Abstract:
    Cyclin E is required for cells to progress from G1 to S-phase, a necessary commitment step for cell growth and proliferation. Regulation of cyclin E is achieved by periodic synthesis and degradation such that cyclin E is maximally expressed at the G1-to-S phase transition and degraded upon entry into S-phase. In some breast cancer cell lines it has been shown that cyclin E levels are increased without an increase in mRNA abundance which strongly suggests that there is a post-transcriptional mechanism responsible for upregulating cyclin E levels. In addition elevated levels of cyclin E in primary tumors has been shown to be statistically correlated with poor prognosis. Proteolysis is a major mechanism used in cells to control protein levels. Ubiquitin mediated proteolysis has been shown to regulate many important cellular processes such as cell cycle, signaling and DNA synthesis. We have identified a component of the ubiquitin proteolytic machinery, an E3 ligase called Cul3, as a regulator of cyclin E degradation in mammalian cells. We have also shown that in primary tumors elevated levels of cyclin E are statistically correlated with decreased levels of Cul3. We hypothesize that the observed elevated levels of cyclin E in breast tumors is the result of reduced degradation caused by mutations in the machinery responsible for degrading cyclin E, specifically mutations in Cul3. To address our hypothesis we propose two experimental approaches: Specific Aim 1: To restore Cul3 function to tumor cell lines to determine if Cul3 loss of function contributes to the proliferative defects. Specific Aim 2: To see if Cul3 acts as a tumor suppressor in an animal model by comparing the frequency and spectrum of tumors in breast epithelium in the presence and absence of Cul3. These questions will be answered in two ways. One approach will involve using breast tumor lines to determine if modulation of Cul3 levels and or function can increase or decrease the tumorigenic state of those cells. The second approach we will use is to develop an animal model in which Cul3 function is either reduced or eliminated to determine if loss of Cul3 could be an early step in the evolution of breast cancer. Due to the association of cyclin E and development of tumors in the breast epithelium of both humans and mice, elucidating the role of Cul3 in tumor development in breast tissue will uncover new therapeutic targets for treatment.

    Lay Abstract:
    Inappropriate growth and loss of normal controls is a hallmark of cancer. Early events in the steps that ultimately lead to a cell having those characteristics are hard to detect. For the most part the controls that affected are those that determine when a cell should divide or not and these are referred to as cell cycle controls. The most important players in cell cycle control are the cyclins and the proteins they activate, the cyclin dependent kinases (CDKs). Inappropriate production of these proteins has been shown in many cases to lead to cancer. In fact these proteins are regulated in two ways: their production (synthesis) and their destruction (proteolysis). Many cancers that appear to occur as the result of over expression of proteins have been shown to have normal synthesis rates but are defective in proteolysis. Recently, the major destruction pathway in cells, the ubiquitin-mediated pathway, has been the focus of attention in this process because the machinery that specifically recognizes these proteins for degradation is beginning to be understood in great detail. Since this pathway seems to be a major potential contributor to cancer, we propose to look specifically at how it regulates a cyclin called cyclin E. Cyclin E has been shown by many investigators to be a potential causative agent in breast cancer. We hypothesize that breast cancer inducing-proteins like cyclins are over expressed because they are degraded incorrectly and thus there is an error in proteolysis. We also propose that the errors lie in the regulation of the E3/Ubiquitin ligases, which are the proteins in the pathway that recognize substrates. In particular we have identified an E3 called Cul3 that is involved in cyclin E degradation and have shown it is incorrectly regulated in breast tumors. We propose to test this hypothesis using the following approaches: Specific Aim 1: To restore Cul3 to tumor cell lines to determine if the proliferative defects are due to Cul3 loss of function. Specific Aim 2: To see if Cul3 acts as a tumor suppressor in an animal model by comparing the frequency and spectrum of tumors in breast epithelium in the presence and absence of Cul3. Since cyclin E levels have been associated with the development of breast tumors in both humans and mice, elucidating the role of Cul3 in tumor development in breast tissue will uncover new therapeutic targets for treatment.