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Cyclin E Mediates Response To Chemotherapeutic Agents In Breast Cancer
Background: Chemotherapy in the adjuvant or neoadjuvant setting has been shown to benefit approximately one-third of breast cancer patients. The ability to determine which patients will respond to treatment, and those that will not, remains a challenge. Traditional prognostic factors fail to adequately stratify the patients, leading to either over or under treatment. Predictive markers assessed in the primary tumor, such as estrogen receptor and HER-2/neu, identify patients who would benefit from anti-estrogen therapy or HER-2-targeted therapy but do not predict response to chemotherapy. Currently, patients with invasive breast cancer over 1 cm in size are felt to be candidates for systemic polychemotherapy. Clearly not all of these patients will benefit from the treatment and therefore additional markers are needed for identifying appropriate patients for these interventions. Cyclin E has been shown to be a prognostic marker for poor outcome in breast cancer patients. The role of cyclin E in response to therapy however, has not been fully explored. Objective/Hypothesis: We hypothesize that cyclin E modulates response to chemotherapy and therefore, is predictive of response to chemotherapeutic agents. To test this hypothesis, we propose the following specific aims: (1) To determine the role of cyclin E in response to chemotherapeutic agents in vitro, (2) To establish cyclin E as a predictor of response to chemotherapeutic agents in breast cancer patients, and (3) To assess cyclin E expression in the process of tumor progression and metastasis. Study design: We have generated breast cancer cell lines that express full-length cyclin E or the low molecular weight (LMW) isoforms of cyclin E under an inducible promoter. In addition, cell lines that endogenously express cyclin E (with or without the LMW isoforms), in which we can down regulate cyclin E expression, will be employed to determine the function of cyclin E in sensitivity to chemotherapy in vitro. A xenograft model will be utilized to assess the response of human breast cancer to chemotherapy in vivo. Breast cancer tumor samples will be obtained from patients participating in an established clinical protocol to determine the in vivo role of cyclin E in tumor progression, and to determine whether cyclin E can predict clinical and pathologic response to chemotherapy. Potential outcomes and benefits: This proposal will advance our ability to deliver the appropriate therapeutic agents currently available and to understand the mechanisms of cancer progression to establish targets for design of future therapeutic agents.
Chemotherapy is beneficial to many women with breast cancer, however there are still many who do not respond to chemotherapy. Because of the toxic side-effects of chemotherapy, it would be beneficial to be able to determine which patients will respond to chemotherapy and which will not, sparing those who will not benefit the side-effects. Cyclin E is a protein that is involved in regulation of the proliferation of cells and is often aberrant in cancer cells. High levels of cyclin E or expression of smaller forms of cyclin E, called low molecular weight (LMW) isoforms of cyclin E are associated with poor outcome in breast cancer patients. Therefore, we hypothesize that cyclin E expression may play a role in how patients respond to chemotherapy and may help to delineate which patients will benefit from treatment with chemotherapy. To study this, we will treat cells that have different levels and different forms of cyclin E expression with chemotherapy to determine the effects of cyclin E on the sensitivity or resistance to each chemotherapeutic agent. We will also treat mice that have tumors with different forms of cyclin E with the chemotherapeutic agents to assess whether the tumors regress or not in terms of their cyclin E expression. We will use slides that are already being collected from patient samples, before and after chemotherapy, to see whether their cyclin E expression correlates with their response to chemotherapy. The role of cyclin E in metastasis has never been explored. Because the goal of chemotherapy is to get rid of metastases, we will determine whether cyclin E is involved in metastasis. Therefore, to better understand the deregulation of cyclin E in cancer patients, we will use the slides from patient samples to follow the cyclin E expression through the course of their disease. These experiments will help us understand the mechanisms of breast cancer progression and help us deliver treatment more appropriately. Cyclin E is aberrantly expressed in many cancer, therefore this research could also be applied to many cancer types in the future