In previous studies we have identified and characterized the Notch related Int-3 gene and another gene designated Int6 which are frequently rearranged by MMTV in mouse mammary tumors. More recently we have found in a tumor arising from a MMTV induced mammary hyperplastic outgrowth line that the Int3 gene was rearranged by the integration of a intracisternal A particle (IAP) retroviral-like transposable element. The consequences of this mutational event was similar to that found in tumors where MMTV has integrated within the Int3 gene, in that we could detect the activation of expression of the portion of the gene encoding the intracellular domain of the gene product. In the case of Notch over expression of a truncated gene product corresponding to the intracellular portion of the protein represents a gain of function mutation which affects cell fate determination. We have found in the FVB3 transgenic mouse strain that expression of truncated gene product of the MMTV-Int3 transgene in mammary epithelial cells limits their capacity to perform the cell fate decisions required for morphogenesis and functional differentiation. The Int6 has been shown to be located on mouse chromosome 15. Five Int6 pseudogenes were shown to be located on chromosomes 6, 11, 14, 17, and 18. The human and Drosophila homologs of Int6 have been cloned and their nucleotide sequence determined. The deduced amino acid sequence of the human and mouse Int6 proteins are identical whereas the sequence of the Drosophila protein is 60% identical to the mouse protein. In our continuing effort to clarify the cellular basis of premalignant growth and progression in mammary tumorigenesis, we have made the following observations. TGFbeta1 expression targeted to the developing mammary secretory epithelium leads to premature senescence and programmed cell death. Conversely, TGFalpha promotes secretory epithelial cell growth and survival in postlactational females leading subsequently to mammary tumorigenesis upon successive pregnancies. Transplantation studies demonstrate the existence of mammary epithelial progenitor cells committed exclusively to the development of the lobular or ductal phenotype. These cells are targets for specific and distinct carcinogenic events.
