Relevance and Specific Aims Relevance: There is a critical need to understand the pathogenesis of breast cancer, in particular in minority and underserved populations who have poor survival. The purpose of this project is to develop a comprehensive breast cancer research project that provides the opportunity to identify novel biological targets for diagnosis and to follow progression of cancer in response to therapy in Minority and Underserved populations. We will accomplish our goal with the following specific aims:
Specific Aim 1 : Associate levels of CCN proteins and downstream targets in breast cancers with clinical parameters of the patients (Year 1). Breast cancer tissue arrays will be stained for CCN proteins and results will be correlated with ethnic grouping, especially African American and Hispanic populations, as well as their clinical information. This activity will be performed at CDU. Also, we have breast cancer cell line data that shows that CCN proteins bind to integrins and activate the (3-catenin/TCF and PI3K/AKT/mTOR/4EBP1/ SK6 pathways. Replicate breast cancer arrays will be stained to determine if these downstream proteins are activated in patient samples. We will use large tissue arrays from National Cancer Institute;validation will take advantage of large and well-characterized breast cancer paraffin blocks from Charities Drew University/ Martin Luther King Junior-MuIti Service Ambulatory Care Center (formerly known as the King-Drew Medical Center).
This aim will demonstrate if there are biological differences between African American, Latina, and Caucasian breast cancer patients. To date, no one has associated level of expression of CCN proteins and ethnic group or other clinical characteristics of breast cancer. Our prior studies at the RNA level lead us to hypothesize that we will show by immunohistochemistry that levels of CCN proteins will be independent prognostic markers that foreshadow the aggressiveness of the disease. If we are correct, a simple immunohistochemical test for expression of CCN proteins can be performed at diagnosis to provide an indicator of prognosis and help direct the aggressiveness of therapy.
Specific Aim 2 : Study the effects of selective overexpression of CCN proteins in breast tissue of transgenic mice (Years 2-3). Transgenic mice that selectively overexpress CCN1 will be created to study the in vivo development of breast cancer. If cancers do not develop, these mice will be mated with mice that overexpress ErbB-2 (Her-2/neu). These mice should develop breast cancer at an earlier age than either transgenic alone. These mice can be used to test various chemopreventive, chemotherapeutic or other novel therapeutic strategies.
Specific Aim 3 : Identify domains of CCN1 and CCN2 necessary to enhance transformation of breast cancer cells (Years 1-2). Understanding the critical CCN motifs that enhance breast cancer growth will provide future targets for inhibiting breast cancer growth.
Specific Aim 4 (Year 2-3): Explore the therapeutic implications of overexpression of CCN proteins in breast cancer. Taking advantage of the knowledge garnered in the preceding Specific Aims knowing that overexpression of CCN proteins make the breast cancer cells resistant to chemotherapy, we will try various therapeutic measures to block the CCN stimulatory pathways.
Specific Aim 4 A: Investigate the range, magnitude, and cause of chemo-resistance in CCN overexpressing breast cancer cells.
Specific Aim 4 8: Inhibit the growth stimulating pathways in CCN expressing breast cancers. These approaches will include developing monoclonal antibodies that target CCN proteins and/or dominant negative proteins that block integrins (receptors of CCN proteins) or block the downstream pathways that are aberrantly stimulated by the CCN proteins. Taken together, the proposed studies will provide unique insights into the pivotal role that CCN proteins play in breast cancer especially in our minority served African American and Hispanic patients. These insights should lead to novel prognostic indicators of clinical outcome, as well as provide new therapeutic approaches to this devastating disease. The project offers outstanding opportunities for the CDU researchers to learn state of the art science and techniques in genomics in general, and specifically in the creation of transgenic animals. This project is run concurrently at CDU and Cedars/UCLA.
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