Development of the female murine breast, which begins during embryogenesis and terminates during adulthood, proceeds in five ordered and distinct stages: the embryonic stage, the adolescent stage, pregnancy, lactation, and involution. In normal breast development, oncogenes and growth suppressor genes affect the cellular differentiation and growth rate and in tumorigenic state, they dictate metastatic pattern and response to treatment. The myb gene family currently consists of three members, named A, B and c-myb all of which code for nuclear proteins which bind DNA in a sequence-specific manner and function as regulators of transcription. Two lines of evidence implicate a role for myb gene family in breast development and cancer; (1) c-myb and A-myb genes are highly expressed in many breast tumors; and (2) their studies with A-myb null mutant mice revealed a dramatic abnormality in mammary function, where the loss of A-myb expression seems to result in a loss or diminution of progesterone-induced proliferative events associated with the pregnancy-induced morphogenesis of breast tissue. Based on this data, it is their hypothesis that c-myb and A-myb play a pivotal role in the proliferation of breast epithelial cells in adult mice. It is their hypothesis that proliferative events that occur during adolescent stage require c-myb while proliferative events that occur following pregnancy require the combined action of c-myb and A-myb. Events that lead to deregulation of expression of c-myb and A-myb might represent a point at which the onset of neoplasia, which in combination with other mutations and deletions in oncogenes and growth suppressor genes, results in a metastatic disease.
The specific aims of the proposal are: 1. To study the effects of breast-specific c-myb gene deletion on breast development using the Cre-lox system. 2. To study the effects of loss of c-myb and A-myb on breast development by mating A-myb and c-myb null mutant mice. 3. To study the effects of oncogenic activation of A-myb and c-myb genes on breast tumor formation. 4. To study the role of c-myb and A-myb in breast tumor development by mating A-myb and C-myb mutant mice with transgenic mouse lines that spontaneously develop breast tumors to determine the effect of loss of A-myb and c-myb expression on the spontaneous development of breast tumors in these compound mice.
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