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    Awarded Grants
    E2F Transcription Factors in Mammary Gland Development and Tumorigenesis

    Scientific Abstract:
    E2F Transcription Factors in Mammary Gland Development and Tumorigenesis Eran R. Andrechek Background: The expression pattern of E2F family members in various stages of mammary gland development and lactation suggests that these genes play an integral role in the control of the mammary gland. However, the mammary glands in the various E2F null mice have not been examined for developmental defects. Additionally, recent data has illustrated that Cyclin D1, which can activate the E2F transcription factors, is a critical component of tumor formation mediated by ErbB2 and Myc. Indeed, mice with a null mutation in cyclin D1 do not develop ErbB2 mediated tumors, suggesting that Cyclin D1 and the genes downstream of it are involved in ErbB2 mediated mammary tumors. Objective / Hypothesis: The hypothesis that will be tested is that E2Fs play distinct and critical roles in normal mammary gland development and function and are also integral components in mammary tumorigenesis mediated by ErbB2 and Myc. Specific Aims: (1) To examine how the targeted deletion of E2F transcription factors affects mouse mammary gland development and function, singly and in combination with multiple E2F null mutations. (2) To determine the role of the the E2F transcription factors in ErbB2 mediated mammary tumorigenesis through both in vitro and in vivo studies using the E2F null mice and MEF cell lines derived from these mice. (3) To test the in vivo role of the E2Fs in Myc mediated mammary tumorigenesis and compare this to ErbB2 mediated tumor model. Study Design: The Nevins lab has generated or has access to a number of genetically modified mice that lack the various E2F alleles. These mice will be examined individually, and in various combinations, to determine the role of the various E2F allele on mammary gland development and function. Given the E2F3 / E2F4 switch during the transition from lactation to regression, it will be particularly interesting to examine mice lacking these genes. To assess the role of the E2Fs in mammary carcinogenesis, the E2F null mice will be interbred with mice overexpressing both ErbB2 and Myc in the mammary gland. In addition to a detailed examination of the resulting tumors, Affymetrix gene expression profiles will be generated for each set and will be compared. Potential targets for therapy or further investigation will then be explored. Potential Outcomes and Benefits: The E2F family of transcription factors is a critical portion of the cellular mechanism involved in controlling both proliferation and apoptotsis. Clearly these types of cell fate decisions are important for normal development and are often disrupted during tumorigenesis. Understanding the role of these transcription factors in the normal mammary gland will aid in understanding how alteration of their activity may result in alteration of tumor properties. In addition to being involved in the normal mammary gland, there is evidence to suggest that these genes are involved in breast cancer. Given that ErbB2 mediated mammary tumorigenesis is dependent on Cyclin D1, which has been shown to activate the E2Fs, it is likely that the various E2F alleles will influence the properties of the ErbB2 mediated tumors. This research will allow us to elucidate the importance of the E2Fs in both ErbB2 and Myc mediated mammary tumorigenesis.

    Lay Abstract:
    E2F Transcription Factors in Mammary Gland Development and Tumorigenesis Eran R. Andrechek The E2F class of transcription factors is a group of 6 distinct genes that share structural similarity but have a variety of functions. These genes can either promote cell growth or death dependent on the nature of their activation. When cell growth is induced by stimulation of growth factors, a cascade of events occurs that results in the activation of specific members of the E2F family. For example, when a mouse is engineered to overexpress ErbB2 in the mammary gland, a series of signaling molecules are activated which eventually culminates in the formation of a mammary carcinoma. One of the genes that is activated in this process is cyclin D1, which in turn is able to activate various members of the E2F family. Interestingly, when mice lacking cyclin D1 are interbred with mice overexpressing ErbB2 in the mammary gland, mammary tumorigenesis is blocked. It is currently not known which of these E2F genes are important in ErbB2 mediated tumorigenesis. Clearly, elucidation of this pathway may lead to clinical applications that could benefit the 25% of women afflicted with breast cancer that overexpress ErbB2. The goals of this proposal are to determine how the E2F genes contribute to both normal development and function of the mammary gland and to define how they function in mammary tumorigenesis. Mice lacking the various E2F genes have been created and will be examined for defects in mammary gland development. Further, since there is a switch in which E2F genes are active during the transition from lactation to regression of the mammary gland, mice lacking these genes will be closely examined during this period for structural changes. However, since they are numerous E2F genes, it is possible that mice lacking a single E2F gene will not exhibit any changes. Accordingly, mice lacking multiple E2F genes will also be examined. To determine the role of the E2F genes in tumor formation, mice lacking various E2F alleles will be interbred with mice that have been engineered to develop mammary carcinomas. Specifically, mouse models overexpressing ErbB2 or Myc in the mammary gland will be interbred with the E2F null mice. Any tumors that may develop in these combinatorial crosses will be closely examined for both physical and genetic changes. The experiments outlined in this proposal will be relevant towards generating a better understanding of the mechanisms governing cellular growth or regulated cell death. Since these processes are often disrupted during the progression of mammary tumors, it is critical to understand the role of the E2F genes in both the normal mammary gland and tumor formation. Prior to the development of specific clinical applications, it is crucial to understand how these genes are regulated in both the normal and tumorigenic state. The goals that I have outlined in this proposal will address the role of the E2Fs in mammary development and tumorigenesis, areas that have not been previously explored. These experiments will explore the suitability of these genes as targets for eventual therapies, but will also highlight any problems in normal development if these genes are targeted for elimination from the mammary gland. While there are no immediate clinical applications, this basic research will generate a better understanding of the mechanism of mammary tumorigenesis.