Metabolic Deregulation by 14-3-3 in Mammary Tumor Progression

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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.