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 if these cells in the absence of estrogen also resulted in loss of ER expression. The work presented here has focused on establishing whether his loss of ER expression was reversible, a very important question that has implications for ER-negative tumors, and on starting to the mechanisms underlying both the estrogen-independent growth and loss of expression. We have determined that constitutive Raf activity does not result in estrogen-independent activation of ER activity, by examining estrogen-induced genes and by transient transfection assays with an ERE-reporter construct. We have also determined that loss of ER expression is reversible if the Raf kinase activity is abrogated. Furthermore, ER expression only returns in cells that have significantly decreased Raf.