Role of Raf-1 Signaling in Breast Cancer - Progression to Estrogen Independent Growth.

摘要

Breast cancer progression may be characterized by a switch from hormone-dependent to hormone-independent growth that involves several cellular alterations and is a major problem in the treatment of breast cancer. Expression of a constitutively activated Raf in ER+ MCF-7 human breast cancer cells results in estrogen-independent growth, suggesting that activation of growth factor signaling pathways through Raf may confer a selective advantage for growth of breast cancer cells under estrogen-deprived conditions. In analyzing the mechanisms underlying this, it was discovered that the prolonged growth of these cells in the absence of estrogen also resulted in loss of ER expression. The work presented here has focused on determining the mechanisms underlying both the estrogen-independent growth and loss of ER expression. We have determined that constitutive MEK activity results in a similar phenotype. We have also determined that loss of ER expression is correlated with changes in transcription factor binding to the ER promoter, preferential ERK 2 activity, and extent of MAPK activity. We have also correlated our Raf results with the effects of EGFR or c-erbB-2 overexpression in MCF-7 cells. Finally, we have demonstrated that the abrogation of Raf signaling allows for re-expression of ER.