Epidemiologic and animal studies strongly suggest that the susceptibility of the mammary gland to carcinogenesis is a function of the gland's developmental state at the time of exposure to oncogenic stimuli. Specifically, reproductive endocrine events such as puberty, pregnancy, and parity have each been shown to markedly influence the susceptibility of the mammary gland to the subsequent development of cancer. At present, the cellular and molecular mechanisms by which normal developmental events modulate breast cancer risk are essentially unknown. Understanding these mechanisms is a central goal of our laboratory and will undoubtedly require a more complete understanding of the interaction between mammary development, reproductive history, and oncogenic pathways than currently exists. The central hypothesis of this proposal is that the susceptibility of the mammary gland to oncogene-induced carcinogenesis is a function of the specific developmental context in which oncogene activation occurs. Specifically, we hypothesize that normal developmental events such as puberty, pregnancy and parity modulate breast cancer susceptibility by modulating the effects of oncogenic stimuli on proliferation, differentiation, apoptosis, and global patterns of gene expression. In order to test this hypothesis, we have generated a novel doxycycline-dependent bitransgenic mouse model system that permits oncogenes to be inducibly expressed in the mammary epithelium for a defined period of time, at a desired level, and during any desired developmental stage. Iransgene expression in this system is mammary-specific, can be titrated over a wide range of expression levels, and is essentially undetectable in the uninduced state. Inducible expression of the c-MYC proto-oncogene using this system results in the formation of invasive mammary adenocarcinomas in a manner that is rapid, highly penetrant, mammary-specific, and absolutely dependent on transgene induction by doxycycline. These properties make this system ideally suited for expressing oncogenes in a spatially and temporally restricted manner during defined stages of development. In the present application we will use this inducible transgenic system to deliver distinct oncogenic stimuli during defined windows in development in order to test our hypothesis that normal developmental events modulate breast cancer susceptibility by modulating oncogene action. The experiments proposed will generate and validate four inducible transgenic mouse models for mammary tumorigenesis based on oncogenic pathways that are relevant to human breast cancer. These transgenic models will be used to determine the susceptibility of the mammary gland to oncogene-mediated carcinogenesis as a function of developmental stage, as well as to investigate the cellular mechanisms by which developmental events influence oncogene action. We anticipate that these studies will help to illuminate developmental mechanisms that contribute to the determination of breast cancer susceptibility.
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