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The Role of TRAP220 in Estrogen Receptor-Dependent Function and in Mammary Gland Development and Neoplasia
Background: Estrogen plays its key regulatory role in mammary gland development and various human disease states, including breast cancer, through estrogen receptor (ER) a. Recent studies have demonstrated that TRAP/Mediator complex, via the ERa-interacting TRAP220 subunit, mediates ERa function both in cell-free transcription assays and in cultured cells. These in vitro data clearly indicate the potential of TRAP220, through the associated Mediator complex, to mediate the function of ERa on at least some target genes in vivo.
Objective: The main objective of this project is to utilize tissue-specific gene knockout techniques to elucidate physiological roles of the TRAP/Mediator complex, especially the TRAP220 subunit, in mammary gland development and breast cancer.
Specific Aims: The specific aims are (1) to generate mammary gland-specific TRAP220 knockout mice, (2) to utilize these mice to investigate the role of TRAP220, and its underlying molecular mechanism, in mammary gland development and (3) to investigate the role of TRAP220 in breast tumorgenesis through studies of the effects of mammary gland-specific conditional deletion of TRAP220.
Study Design: We propose here to determine the physiological roles of TRAP220 in vivo, especially in mammary gland development and tumorgenesis, by using a combination of cellular and mouse genetic methods. We will generate TRAP220 conditional mice by using a Cre-loxp based system. We will then determine the roles of TRAP220 in the development and homeostasis of mammary gland and its underlying mechanisms. Finally, we will determine whether TRAP220 plays a role in breast tumorgenesis by using mutagens and/or by crossing the TRAP220 conditional knockout mice with existing transgenic breast cancer mouse models.
Potential outcomes and Benefits of the Research: ERa is the key mediator of estrogen function, which plays major physiological roles in the development of mammary gland and breast cancer. Importantly, TRAP220, the ER interacting subunit of the TRAP/Mediator complex, was recently found overexpressed and amplified in a proportion of primary breast cancer and breast cancer cell lines. Completion of this study will help us better understand the mechanisms of mammary gland development and likely provide new insight into breast cancer detection, prevention and treatment.
The hormone estrogen plays important roles in mammary gland development and breast tumorgenesis. The biological effect of estrogen is mediated through its interacting protein, estrogen receptor (ER) a, that binds to target gene to activate their expression. Recently, a large 25-component protein complex (TRAP/Mediator) has been found to bind to ERa through a specific component (TRAP220) and to enhance ERa function. Importantly, the TRAP220 gene has been found to be amplified and overexpressed in human breast cancers.
In this study, we will use genetic methods to determine the role of TRAP220 in mammary gland development and breast tumorgenesis, as well as biochemical mechanisms that may help design strategies for attenuating TRAP220 function. The specific aims are (1) to generate mammary gland-specific TRAP220 knockout mice, (2) to utilize these mice to investigate the role of TRAP220, and its underlying molecular mechanism, in mammary gland development and (3) to investigate the role of TRAP220 in breast tumorgenesis through studies of the effects of mammary gland-specific conditional deletion of TRAP220.
This study will likely provide important new insights to the molecular mechanism of mammary gland development and breast tumorgenesis and allow the development of new tools for breast cancer detection, prevention and treatment.