10.6084/m9.figshare.5759613.v1
Jia S.
Jia
S.
Miedel M.T.
Miedel
M.T.
Ngo M.
Ngo
M.
Hessenius R.
Hessenius
R.
Chen N.
Chen
N.
Wang P.
Wang
P.
Bahreini A.
Bahreini
A.
Li Z.
Li
Z.
Ding Z.
Ding
Z.
Shun T.Y.
Shun
T.Y.
Zuckerman D.M.
Zuckerman
D.M.
Taylor D.L.
Taylor
D.L.
Puhalla S.L.
Puhalla
S.L.
Lee A.V.
Lee
A.V.
Oesterreich S.
Oesterreich
S.
Stern A.M.
Stern
A.M.
Supplementary Material for: Clinically Observed Estrogen Receptor Alpha Mutations within the Ligand-Binding Domain Confer Distinguishable Phenotypes
Karger Publishers
2018
Estrogen receptor
Estrogen dependence
Metastatic breast cancer
Ligand-binding domain mutations
2018-01-05 10:46:14
Dataset
https://karger.figshare.com/articles/dataset/Supplementary_Material_for_Clinically_Observed_Estrogen_Receptor_Alpha_Mutations_within_the_Ligand-Binding_Domain_Confer_Distinguishable_Phenotypes/5759613
<p><b><i>Objective:</i></b> Twenty to fifty percent of estrogen
receptor-positive (ER+) metastatic breast cancers express mutations
within the ER ligand-binding domain. While most studies focused on the
constitutive ER signaling activity commonly engendered by these
mutations selected during estrogen deprivation therapy, our study was
aimed at investigating distinctive phenotypes conferred by different
mutations within this class. <b><i>Methods:</i></b> We examined the two
most prevalent mutations, D538G and Y537S, employing corroborative
genome-edited and lentiviral-transduced ER+ T47D cell models. We used a
luciferase-based reporter and endogenous phospho-ER immunoblot analysis
to characterize the estrogen response of ER mutants and determined their
resistance to known ER antagonists.<b><i> Results:</i></b> Consistent
with their selection during estrogen deprivation therapy, these mutants
conferred constitutive ER activity. While Y537S mutants showed no
estrogen dependence, D538G mutants demonstrated an enhanced
estrogen-dependent response. Both mutations conferred resistance to ER
antagonists that was overcome at higher doses acting specifically
through their ER target. <b><i>Conclusions:</i></b> These observations
provide a tenable hypothesis for how D538G ESR1-expressing clones can
contribute to shorter progression-free survival observed in the
exemestane arm of the BOLERO-2 study. Thus, in those patients with
dominant D538G-expressing clones, longitudinal analysis for this
mutation in circulating free DNA may prove beneficial for informing more
optimal therapeutic regimens.</p>