Regulation of expression of mouse mammary tumor virus through sequences located in the hormone response element: involvement of cell-cell contact and a negative regulatory factor.

Mouse mammary tumor virus (MMTV) is a latently oncogenic retrovirus responsible for the neoplastic transformation of mammary epithelial cells. Its expression is regulated by steroids, polypeptide growth factors, and cell-type-specific factors. Using GR mouse mammary cells and NIH 3T3 fibroblasts stably transfected with chimeric constructs of the long terminal repeat region of MMTV, we have demonstrated a novel mechanism of cell-type-specific expression of this virus. In confluent monolayer cultures that permit cell-cell interaction, MMTV long terminal repeat expression is positively regulated by sequences within the hormone response element (HRE) that bind the transcription factors CTF/NFI and OTFI. Although these factors are present in NIH 3T3 cells, MMTV expression in these cells is not regulated by cell density. This is partially due to a negative regulatory factor that binds sequences between -164 and -151 in the HRE. Mutations that destroy the binding site for this factor restored in part the cell density-regulated expression of MMTV to NIH 3T3 fibroblasts. The HRE is thus a central coordinator of regulatory pathways that positively or negatively influence the expression of MMTV.