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Role of the Breast Cancer Cell 2 (BRCC2) Tumor Suppressor Gene in Early-Onset Breast Cancer
Background: Breast cancer cell 2 (BRCC2) is an intronless gene localized on 11q24.1. LOH at 11q24.1q25 has been associated with early-onset breast cancer, and poor prognosis of breast and ovarian neoplasias. BRCC2 expression has a negative impact on cell survival and correlates with caspase activation, chromatin condensation and DNA fragmentation, hallmarks of apoptosis. Translocation of endogenous BRCC2 to the mitochondria is increased in response to doxorubicin and hydrogen peroxide, known cytotoxic agents.
Objective/Hypothesis: To investigate the hypothesis that BRCC2 is a new and important early-onset breast cancer tumor suppressor gene (TSG). Given BRCC2's abilities to regulate apoptosis, our study could significantly increase our understanding of the molecular regulation of apoptosis and survival in breast cancer cells.
Specific Aims: To test the hypothesis that BRCC2 is a putative early-onset breast cancer TSG located at 11q24.1, we will determine the frequency of BRCC2 gene inactivation pathways, i.e., mutational spectra and LOH in breast tumors of women with early-onset breast cancer and determine the correlation between loss of function of BRCC2 and overall survival (OS) (Aim 1), and we will develop and validate a FISH assay and an Immunohistochemistry (IHC) assay to evaluate the BRCC2 gene copy number changes and to examine the BRCC2 protein expression, respectively, in breast tissues (Aim 2).
Study Design: We will evaluate 80 patients with early-onset sporadic breast cancer (women under 40 years of age at diagnosis) compared to 80 patients with late-onset breast cancer (post-menopausal women over 55 years of age at diagnosis) matched for stage and ER/PR status, and with known clinical follow up/outcome data. In Aim 1: We will isolate tumor and normal tissues using Laser Capture Microdissection (LCM), and use the isolated DNA for sequencing and LOH studies; we will also study the correlation between loss of function of BRCC2 and overall survival (OS). In Aim 2: we will develop and test a FISH probe using BAC clones containing the BRCC2 gene (FISH studies) and IgG polyclonal antibody and a monoclonal antibody against the BRCC2-epitope (IHC studies).
Potential Outcomes and Benefits of the Research: This study will provide a better understanding of the role of BRCC2 as a TSG in early-onset breast cancer and will improve our understanding of the mechanisms of breast cancer formation.
Background: Breast cancer is the second leading cause of cancer death in women, and the most common malignancy diagnosed among women in the United States. Early-onset breast cancer in women under 40 exhibits a more aggressive clinical picture as compared to late-onset disease of the same size and nodal status. A recently discovered gene, called “the breast cancer cell 2” (BRCC2) plays an important role in the process of cell death, and therefore in preventing abnormal cells from developing into cancer. This gene is located on chromosome number 11, in a region of that chromosome which was reported in many previous studies to be commonly lost in early-onset breast cancer.
Objective/Hypothesis: Based on the above, we are proposing to investigate whether this new gene, the BRCC2, is indeed one of the important genes that are lost in early-onset breast cancer and whether its loss correlates with poor prognosis.
Specific Aims: We have only one focused objective, i.e. to test the hypothesis that BRCC2 is a putative early-onset breast cancer tumor suppressor gene. To achieve this objective, we will determine the frequency of BRCC2 gene inactivation pathways in breast tumors of women with early-onset breast cancer and determine the correlation between loss of function of BRCC2 and overall survival (Aim 1), and we will develop and validate molecular tests to evaluate breast tissues for possible loss of this gene (Aim 2).
Study Design: We will perform different molecular studies to establish the loss of function of this gene and we will also develop diagnostic reagents which will help us address this critical question. These reagents may also be clinically very relevant because they can be used to evaluate clinical specimens as well. All the assays that we are proposing to perform are well established in our laboratories and we have published several papers using similar assays.
Potential Outcomes and Benefits of the Research: We believe that our data will provide a better understanding of the role of BRCC2 as an important gene that suppresses the development of tumors in early-onset breast cancer and will improve our understanding of the mechanisms of breast cancer formation at a young age.