Growth inhibition of breast cancer cells by Grb2 downregulation is correlated with inactivation of mitogen-activated protein kinase in EGFR, but not in ErbB2, cells

Increased breast cancer growth has been associated with increased expressio n of epidermal growth factor receptor (EGFR) and ErbB2 receptor tyrosine ki nases (RTKs), Upon activation, RTKs may transmit their oncogenic signals by binding to the growth factor receptor bound protein-2 (Grb2), which in tur n binds to SOS and activates the Ras/Raf/MEK/mitogen-activated protein (MAP ) kinase pathway. Grb2 is important for the transformation of fibroblasts b y EGFR and ErbB2; however, whether Grb2 is also important for the prolifera tion of breast cancer cells expressing these RTKs is unclear. We have used liposomes to deliver nuclease-resistant antisense oligodeoxynucleotides (ol igos) specific for the GRB2 mRNA to breast cancer cells. Grb2 protein downr egulation could inhibit breast cancer cell growth; the degree of growth inh ibition was dependent upon the activation and/or endogenous levels of the R TKs. Grb2 inhibition led to MAP kinase inactivation in EGFR, but not in Erb B2, breast cancer cells, suggesting that different pathways might be used b y EGFR and ErbB2 to regulate breast cancer growth.