CONSTITUTIVE RAF-1 KINASE-ACTIVITY IN BREAST-CANCER CELLS INDUCES BOTH ESTROGEN-INDEPENDENT GROWTH AND APOPTOSIS

Overexpression of many growth factor receptors, as well as growth fact ors, has been shown to confer varying degrees of estrogen-independent growth on estrogen receptor (ER) positive breast cancer cells. The pro tooncogene Raf-1 is a key intermediate in the signal transduction path way of many of these growth factor receptors, and when constitutively activated in fibroblasts is transforming. To examine the effects of Ra f-1 kinase activity on the estrogen-dependent growth of human breast c ancer cells, ER+ MCF-7 breast cancer cells were stably transfected wit h an expression construct directing the expression of an amino-truncat ed protein having constitutive kinase activity. Expression of constitu tively activated Raf in MCF-7 cells is incompatible with growth in the presence of estrogen; that is, cells down-regulate expression of the transfected Raf. Constitutive Raf activity does allow for growth of th e cells in the absence of estrogen, suggesting that activation of grow th factor signaling pathways through Raf may confer a selective advant age for growth of breast cancer cells under estrogen-deprived conditio ns. In addition, the high levels of Raf activity induce apoptosis in c ells grown under either condition. This is a novel activity for Raf, a nd may occur because the levels of the constitutive Raf are extremely high in these cells.