Estrogens play a crucial role in
breast tumor growth, which is the rationale for the use of
antiestrogens, such as
tamoxifen, in women with
estrogen receptor (ER)-alpha-positive
breast cancer. However,
hormone resistance is a major clinical problem. Altered
growth factor signaling to the
ERalpha pathway has been shown to be associated with the development of clinical resistance. We previously have identified a mutation that replaces
arginine for
lysine at residue 303 (K303R) of
ERalpha, which confers hypersensitive growth in low levels of
estrogen. To determine if the K303R mutation could participate in the evolution of
hormone resistance, we generated MCF-7
breast cancer cells stably transfected with either wild-type (WT) or K303R
ERalpha. We found that the mutation confers decreased sensitivity to
tamoxifen in the presence of the
growth factor heregulin, using anchorage-independent growth assays. K303R
ERalpha-expressing cells were hypersensitive to
growth factor signals. Our data suggest that phosphorylation of
serine 305 within the hinge domain of
ERalpha might play a key role in increasing
ligand-independent activity of the mutant receptor. We hypothesize that the mutation adapts the receptor for enhanced bidirectional cross-talk with the HER2
growth factor receptor pathway, which then impacts on responsiveness to
tamoxifen.