Growth factor-induced resistance to tamoxifen is associated with a mutation of estrogen receptor alpha and its phosphorylation at serine 305.
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.
Giordano
Cinzia
C
Department of Pharmaco-Biology, University of Calabria, Rende, Italy.
Cui
Yukun
Y
Barone
Ines
I
Ando
Sebastiano
S
Mancini
Michael A
MA
Berno
Valeria
V
Fuqua
Suzanne A W
SA
D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D047628:Estrogen Receptor alpha / Q000737:chemistry* / Q000235:genetics*; D006367:HeLa Cells; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D008239:Lysine / Q000737:chemistry; D009154:Mutation; D020890:Neuregulin-1 / Q000378:metabolism; D010766:Phosphorylation; D012694:Serine / Q000737:chemistry*; D015398:Signal Transduction; D013629:Tamoxifen / Q000494:pharmacology*; D013997:Time Factors
D047628:Estrogen Receptor alpha; D036341:Intercellular Signaling Peptides and Proteins; D020890:Neuregulin-1; D013629:Tamoxifen; D012694:Serine; D008239:Lysine