For example, ER mRNA and protein can be downregulated in MCF-7 cells by stably overexpressing EGFR or constitutively activating erbB-2, Raf, or MEK [52]; and in a number of ER- breast cancers, ER expression can be restored by inhibiting GFR through targeting of MAPK/ERK [48]. This evidence concerns the gene RAPGEF5 and breast cancer.