Metabolic deregulation is one ofthe frst tumor-specific alterations during cancer progression and is recognized as the seventh hallmark of cancer. Increased aerobic glycolysis provides cancer cells various sun/ival and growth advantages. The 14-3-3 proteins are involved in many important cellular processes. We discovered that 14-3-3^ is overexpressed in >40% of breast cancers. 14-3-3^ overexpression is significantly associated with increased disease recurrence and metastatic death of patients. In human breast cancer cells, overexpression of exogenous 14-3-3^ led to increased transformation, reduced apoptosis, whereas blocking 14-3-3^ expression by siRNA increased apoptosis and inhibited tumor growth. Excitingly, we recently found that 14-3-3^ overexpression in both MCFIOA mammary epithelial cells (MECs) and breast cancer cells led to increased glycolysis, whereas inhibiting 14-3-3^ expression decreased glycolysis. Moreover, 14-3-3^ conventional knockout mice had reduced uptake of 2-NBDG (a fluorescent derivative of D-glucose) in their livers and brains. Activation of HI F1 a is known as one ofthe principal mechanisms underlying metabolic reprogramming and 14-3-3^ overexpression also led to upregulation of HlF1a. Based on these, we hypothesize that 1) 14-3-3^ modulates mammary tumor progression/metastasis and 2) 14-3- 3t,-mediated metabolic deregulation may play a critical role in mammary tumor progression. To test the hypothesis, we will establish inducible, mammary gland-specific 14-3-3^ transgenic and knockout mouse models that allow us to explore in well-defined in vivo systems the complex roles of 14-3-3? in mammary tumorigenesis/metastasis and metabolic deregulation (Aims 1 &2). We will establish MECs and mammary tumor cell strains from 14-3-3? transgenic and knockout mice and use them to investigate whether 14-3-3?- mediated metabolic deregulation plays a role in transformation and tumor progression, determine the mechanisms of HIFia upregulation by 14-3-3? and its contribution to metabolic deregulation and transformation (Aim3). These comprehensive approaches will determine the functions of 14-3-3? in mammary gland development, transformation, tumor progression/metastasis, and the contribution of 14-3- 3?-mediated metabolic deregulation in these processes.

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Currently, nothing is known on how 14-3-3? contributes to mammary gland development, transformation, tumorigenesis, metastasis and their relationship with metabolic alterations in vivo. This study will provide the initial answers to these important questions. Understanding the intrinsic link between 14-3-3?-mediated tumor progression/metastasis and cancer cell metabolic deregulation will also identify therapeutic targets for effective intervention and treatment ofthe highly aggressive, 14-3-3? overexpressing breast cancers.

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