SUPPRESSION OF MAMMARY EPITHELIAL-CELL DIFFERENTIATION BY THE HELIX-LOOP-HELIX PROTEIN ID-1

Cell proliferation and differentiation are precisely coordinated durin g the development and maturation of the mammary gland, and this balanc e invariably is disrupted during carcinogenesis, Little is known about the cell-specific transcription factors that regulate these processes in the mammary gland, The mouse mammary epithelial cell line SCp2 gro ws well under standard culture conditions but arrests growth, forms al veolus-like structures, and expresses beta-casein, a differentiation m arker, 4 to 5 days after exposure to basement membrane and lactogenic hormones (differentiation signals), We show that this differentiation entails a marked decline in the expression of Id-1, a helix-loop-helix (HLH) protein that inactivates basic HLH transcription factors in oth er cell types, SCp2 cells stably transfected with an Id-1 expression v ector grew more rapidly than control cells under standard conditions, but in response to differentiation signals, they arrested growth and f ormed three-dimensional structures similar to those of control cells, Id-l expressing cells did not, however, express beta-casein, Moreover, 8 to 10 days after receiving differentiation signals, they lost three dimensional organization, invaded the basement membrane, and then res umed growth, SCp2 cells expressing an Id-1 antisense vector grew more slowly than controls; in response to differentiation signals, they rem ained stably growth arrested and fully differentiated, as did control cells, We suggest that Id-1 renders cells refractory to differentiatio n signals and receptive to growth signals by inactivating one or more basic HLH proteins that coordinate growth and differentiation in the m ammary epithelium.