Correlative studies provide evidence for increased expression and/or activity of Akt/NF-kappaB/beta-catenin and cyclin D1 in both murine and human breast cancers. Recent studies have indicated dissociable events may govern the initiation vs the maintenance of mammary tumorigenesis. The current proposal uses tissue specific ponsterone-inducible mammary gland targeted transgenic and knockout mice generated during the last funding period to determine the role of an Akt/beta-catenin/cyclin D1 pathway in induction vs maintenance of mammary tumorigenesis. 1. Increased Akt1 activity correlates with increased Erb-B2 transformation. Mice deleted of the Akt1 gene were crossed with animals expressing MMTV-ErbB2 to determine the role of Akt1 in Erb-B2-induced mammary tumorigenssis in vivo. 2. We hypothesize that IkappaB (NF-kappaB),-beta-catenin and cyclin D1 signaling contributes to Erb-B2-mammary tumorigenesis. We generated ecdysone-inducible transgenic lines expressing dominant inhibitors or anti-sense cDNAs to block each component of this pathway (""""""""target lines""""""""). We have generated lines referred to as """"""""(Onco-blue)"""""""" in which four transgenes are homozygously cointegrated (MMTV-Erb-B2 oncogene, the ecdysone regulated transgenes (MMTV-VgEcr/RXRalpha) and a ponsterone- regulated beta-galactosidase reporter gene). The """"""""target lines"""""""" are crossed with the """"""""Oncoblue"""""""" mice. Temporal control of the """"""""target lines"""""""" will establish the requirement for this pathway in the induction vs maintenance of Erb-B2-mediated mammary tumorigenesis. 3. We have characterized an activating estrogen receptor alpha (ERalphaK303R) mutant, seen frequently in human breast cancer (greater than 60 percent) and premalignant lesions (greater than 30 percent). The ERalphaK303R conveys a growth advantage to breast cancer cells in culture, induces cyclin D1, and induces aberrant mammary gland development when driven constitutively. Transgenic mice were generated expressing the ERalphaK303R under control of the ecdysone enhancer. These transgenic lines will be characterized to determine if induction of ERalphaK303R in the adult mammary gland is sufficient for mammary tumorigenesis. Through temporal and spatial control these murine models allow the dissection of events at distinct time points during the pathogenesis of mammary tumorigenesis.
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