Biomedical Engineering Reference
In-Depth Information
domain, binds to estrogen response elements (EREs) in DNA. The
D domain is a hinge region that connects the C and E domains. The
E domain contains the ligand binding cavity as well as binding
sites for coactivator and corepressor proteins. Upon binding of a
lipid-soluble hormone 17β-estradiol to the ligand-binding domain
(AF2) of the receptors, the hormone-bound receptor undergoes a
conformational change that allows dimerization and translocation
to the nucleus, and binds to EREs in the promoter regions of target
genes.
9
In particular, the transcriptional activity of ER is enhanced
by binding of coactivators such as SRC1, SRC2, and AIB1 to the
transcriptional complex. Examples of ER-regulated genes are PgR,
IGF-1 receptor (IGF1R), cyclin D1, antiapoptotic factor Bcl-2, and
vascular endothelial growth receptor.
Thus, transcriptional
activation of ER-responsive genes leads to the growth and survival
of normal as well as mammary tumor cells.
10-12
13,14
ERK
AKT
RSK
SIC
PKA
P
P
P
P
s118
s167
s305
S106/
y537
N
C
AF1
DNAbinding
AF2
1
180
203 302
552 595
Figure 5.1
The functional domains and phosphorylations sites of estrogen
receptor. ERK, extracellular signal-regulated kinases; PKA,
protein kinase A; RSK, ribosomal protein S6 kinase.
5.3
ER/PgR as Prognostic and Therapeutic
Biomarkers
In the era of personalized medicine, selection of patients who benefit
from a drug is of critical importance for treatment success. Perhaps
ER, the prototype of molecular target in cancer, is one of the best
characterized biomarkers in oncology. Prognostic biomarkers are
disease-specific markers and predict disease outcome in the absence
of therapeutic interventions. Predictive biomarkers are usually
treatment-specific and predict whether a patient will respond
to a specific therapy. ER and PgR have been established as both
prognostic biomarkers and, in particular, predictive biomarkers in
breast cancer, which are discussed in greater detail in the following
sections.
