Growth factor receptors-mediated signal pathways, such as those activated by EGFR and ErbB-2, play an active role in breast cancer cell growth, survival, cell cycle deregulation, tumor initiation, and tumor progression/metastasis. Additionally, there is accumulated evidence demonstrating a close relationship between cancer progression and energy metabolism. Metabolic deregulation has even lately been considered as the seventh hallmark of cancers in addition to the well-established six hallmarks. The development and the utilization of novel molecular therapies requires an understanding of both signal aberrations and metabolic regulation, and of how they relate to each other. This renewal program project grant (PPG) aims at understanding signaling pathways of a few key molecules that play critical roles in breast tumor progression and metabolic regulation. The immediate goals of this PPG are to understand the EGFR family-mediated signaling pathways and metabolic regulation in the initiation and progression of breast cancer. This PPG consists of four interactive projects supported by one administrative core. Each of the four projects has its own unique set of specific aims that target at the common theme and are interdependent on components of other projects in the PPG. Project 1 will evaluate pathways of kinase-dependent and -independent of EGFR that link to cancer and metabolic regulation. Project 2 plans to exploit role of EGFR family in mammary tumorigenesis and metastasis in transgenic mice models. Project 3 will examine the role of Rab 25 in breast cancer bioenergetics and autophagy. Project 4 will investigate metabolic deregulation by 14-3-3^ and mammary tumor progression/metastasis. The long-term goals of this PPG are to understand how grovirth factor receptorsmediated pathways may contribute to breast cancer progression. In addition to traditional signal pathways, this renewal PPG also addresses how metabolic regulation may be regulated by growth factor receptors and involved in breast cancer progression. The outcome of this PPG will advance our understanding of the effect of growth factor receptor-mediated signaling on metabolic regulation and breast cancer progression and may shed light on new directions for breast cancer therapy.
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