Resistance to endocrine therapy occurs in most patients with ER-positive
metastatic breast cancer (MBC) and is attributed to various mechanisms such as
loss of ER expression or altered activity of
co-regulators. To our knowledge, acquired mutations of the ER have not been described as mediating endocrine
resistance to endocrine treatment.
ER is a ligand-modulated transcription
factor that is a target for breast cancer therapy. Several available crystal
structures of ER with agonists (as estrogen)
and antagonists (as tamoxifen) demonstrate the effect of ligand binding on the
protein conformation, and as a result, its interactions with co-activator
(SRC-1) in order to bind the DNA.
In this study, a novel mutation (D538G) was identified in MBC patients. Experiments
in cell lines indicated constitutive ligand-independent transcriptional
activity of the mutated receptor. It may enhance
ligand-independent interaction with SRC-1. D538
is positioned within helix 12 of the ligand binding domain. Analysis of the wild
type ER crystal structure indicates the importance of helix 12 in mediating the
interaction of the receptor with co-activator SRC-1, and the effects of
estrogen and tamoxifen on helix 12 conformations. In order to study the
effects of D538G substitution, a structural model was generated. In silico
molecular docking of estrogen and tamoxifen were preformed on both WT and D538G
mutant.
The model suggests that D538G may cause a conformational change that mimics
the conformation of activated receptor and interferes with binding of either estrogen
or tamoxifen. This study may result in development of a new treatment against
endocrine resistance in MBC.
