The MMTV retrovirus is able to activate cellular oncogenes by insertion in the vicinity of these genes. This insertion is one of the key events leading to transformation of mammary epithelial cells. The mammary cell specificity of MMTV oncogenesis lies, in part, in tissue-specific expression of the MMTV promoter. Utilizing mouse and human mammary cell lines, two regulatory elements were discovered in the viral regulatory sequences that are responsible for cell-specific viral transcription, and presumably also for tissue-specific oncogene activation. One element is a positive enhancer and is located at the 5' end of the LTR. A second element, located internal to the LTR, acts as a negative transcription regulator. Both elements are restricted in their activity to mammary cells. Two factors (mp4 and mp5) that bind to the positive element have been characterized by EMSA analysis, DNA footprinting, and site-directed mutagenesis. Both factors are required for efficient mammary-specific expression. The mp4/mp5 element has been found to be active in in vitro transcription extracts, and this activity is limited to cells of mammary origin. The in vivo tissue specificity has thus been reconstructed in vitro.
