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    Research Grants Awarded

    BRCA1 Regulates AKT1 Activity in Breast Cancer

    Study Section:
    Tumor Cell Biology V

    Scientific Abstract:
    Background: The breast cancer susceptibility gene 1 (Brca1) plays a key role in both hereditary and sporadic mammary tumorigenesis. Intensive research has shown that the BRCA1 protein is involved in a multitude of pivotal cellular processes, including the regulation of the cell-cycle and maintenance of genomic stability. It is believed that failure of cell-cycle regulation leads to genomic instability and eventually tumorigenesis. However, why dysfunctional BRCA1 strongly predisposes to breast cancers remains an unsolved mystery. The extent to which BRCA1-activated molecular pathways contribute to its tumor suppressor activity also remains unclear. Activation of AKT1 kinase is one of the most common molecular alterations associated with human tumors. Increased AKT1 kinase activity is reported in about 40-50% of breast cancers. Objective/Hypothesis: Based on our preliminary data that BRCA1 directly binds to AKT1 kinase and down-regulates its activation through the ubiquitination pathway, we hypothesize that the activation of AKT1 is involved in BRCA1-deficiency mediated tumorigenesis. The objective of this project is to establish the role of this novel BRCA1-AKT1 pathway in mammary tumorigenesis. Specific Aims: 1. Determine whether BRCA1 regulates activation of AKT1 through a direct interaction. 2. Identify the role of BRCA1-AKT1 pathway in mammary tumorigenesis. 3. Establish the AKT1 pathway as a novel therapeutic target for BRCA1-deficent cancers. Study Design: 1. We will generate the AKT1 mutant vectors that lose the binding ability to BRCA1, and express them to determine the direct effect of BRCA1 on AKT1 in following functional studies, concerning the regulation of the cell-cycle and maintenance of genomic stability. We will further determine how BRCA1 directly ubiquitinates AKT1 for its degradation. 2. We will determine whether cell proliferation is enhanced through activation of the BRCA1-AKT1 pathway. We will generate double mutant mice with truncated Brca1 and Akt1-/- and determine whether the deficiency of Akt1 is sufficient to suppress tumor development in mice carrying a truncated Brca1 mutation. Immunohistochemical analysis will be performed to test whether defective BRCA1 expression correlates with activation of AKT1 using a panel of breast cancer specimens. 3. We will target mTOR, a key kinase of AKT1 pathway, as a novel therapeutic target for BRCA1-deficent cancers. Potential Outcomes and Benefits of the Research: The role of the BRCA1-AKT1 interaction in tumorigenesis is entirely novel. Establishment of this novel BRCA1-AKT1 pathway in tumorigenesis and elucidation of its precise molecular functions are expected to improve our understanding of hereditary as well as sporadic mammary tumorigenesis. Studies of the BRCA1-AKT1 pathway in breast cancers will benefit the development of diagnostic biomarkers and novel molecular therapies.

    Lay Abstract:
    Germline mutations of the breast cancer susceptibility gene 1 (Brca1) account for 50% of hereditary breast cancers and 85% of the families whose members have a high incidence of breast cancers. Although BRCA1 gene mutations are rare in sporadic breast cancers, BRCA1 protein expression is frequently reduced or absent in sporadic cases, suggesting a much wider role of BRCA1 in both hereditary and sporadic mammary tumorigenesis. However, why dysfunctional BRCA1 strongly predisposes to breast cancers remains an unsolved mystery. Activation of AKT1 kinase is one of the most common molecular alterations associated with human malignancy. Increased AKT1 kinase activity is reported in about 40-50% of breast cancers. Our preliminary data indicate that down-regulation of BRCA1 expression or mutations of the Brca1 gene activate the AKT1 oncogenic pathway. Moreover, BRCA1 directly binds to AKT1 kinase and down-regulates its activation through the degradation of the phosphorylated AKT1 protein. In this project, we plan to establish the role of this novel BRCA1-AKT1 pathway in mammary tumorigenesis. We will determine the mechanisms by which BRCA1 directly regulates AKT1 activity in tumorigenesis. The functional consequence of activation of AKT1 by BRCA1 deficiency will be investigated. Furthermore, the role of BRCA1-AKT1 pathway in mammary tumor formation will be identified. We will determine whether cell proliferation is enhanced through the activation of the BRCA1-AKT1 pathway. We will generate double mutant mice with defective Brca1 and Akt1 genes, thereby determining if the inactivation of Akt1 prevents tumor formation that is generated by Brca1-deficiency. We will determine whether defective BRCA1 expression correlates with activation of AKT1 using a panel of human breast cancer specimens. Finally, we will develop a novel therapeutic target on AKT1 pathway for BRCA1 deficient breast cancers. Establishment of this novel BRCA1-AKT1 pathway and elucidation of its precise molecular function are expected to improve our understanding hereditary as well as sporadic breast cancers development. Such understanding will make significant contributions to the field of cell signaling pathway and tumor formation. The proposed studies will provide new insights into the mechanisms underlying breast cancer development. Our studies will also lead to the development of diagnostic biomarkers and novel molecular therapies and/or therapies that can be combined with conventional modalities.