estrogen signaling pathway, breast cancer
Estrogen
Estrogen receptor and signaling pathway
Introduction of cancer and gene involvement
Causes of breast cancer
Type of breast cancer
Different approaches to treat breast cancer
Estrogen receptor antagonism
2. CONTENTS
1. Estrogen
2. Estrogen receptor and signaling pathway
3. Introduction of cancer and gene involvement
4. Causes of breast cancer
5. Type of breast cancer
6. Different approaches to treat breast cancer
7. Estrogen receptor antagonism
3. ESTROGEN
The primary female sex hormones, estrogens, are responsible for the
control of functions of the female reproductive system, as well as the
development of secondary sexual characteristics that appear during
puberty and sexual maturity.
Estrogens are primarily synthesized in the ovaries, but also in the
adrenal glands and adipose tissue.
Estradiol, the predominant circulating estrogen in humans, it is
mainly secreted by the granulosa cells of the ovarian follicles, and the
corpora lutea.
These include estrone, estradiol, estriol, and estretrol
They consist of one benzene ring, a phenolic hydroxyl group, and a
ketone group (estrone), or one (17β-estradiol), two (estriol), or three
5. ESTROGEN RECEPTOR
Two type of estrogen receptor are there ERα Erβ
ER-α is expressed in the mammary gland, uterus, ovary, bone, male
reproductive organs (testis, prostate), liver and adipose tissue while ER-β is
mainly expressed in the prostate gland, bladder, ovary, colon, adipose tissue
and immune system
ER-α is also responsible for the maintenance of the female phenotype of the
somatic cells of the ovary by inhibiting the development of male phenotype
interstitial cells (sex steroid-producing) and hence protecting the integrity of
female sex differentiation
ER-β generally counteracts the ER-α promoted cell hyperproliferation in
tissues such as breast and uterus . Therefore, the estrogen signalling is a
balance between the mechanism and efect of these two distinct receptors
which leads to the activation of numerous genes that are responsible for a
wide variety of developmental and organizational changes in females
6. SIGNALING PATHWAY OF ESTROGEN RECEPTOR
GPER1 signaling pathway occurs
through various second
messengers. Phospholipase C Beta
(PLCβ), inositol triphosphate (IP3),
nuclear factor of activated T-cells
(NFAT), calcium/calmodulin-
dependent protein kinase (CamK),
cAMP response element-binding
protein (CREB), adenylate cyclase
(AC), protein kinase A (PKA),
phosphoinositide 3-kinase (PI3K),
protein kinase B (Akt), IκB kinase
(IKK), nuclear factor kappa-light-
chain-enhancer of activated B cells
(NF-κB), endothelial nitric oxide
synthase (eNOS), non-receptor
tyrosine kinase (SRC), matrix
metallopeptidases (MMPs), heparin-
binding EGF-like growth factor (HB-
EGF), son of sevenless (SOS), Src
homology 2 domain-containing
transforming protein (SHC), growth
factor receptor-bound protein 2
(GRB2), RAS protein (RAS), RAF
kinase (RAF), mitogen-activated
protein kinase kinase (MEK),
7. INTRODUCTION OF CANCER AND THEIR GENE INVOLVEMENT
A normal cell undergoes
regulated division ,
differentiation and apoptosis.
When normal cell have lost
the usual control over their
division ,differentiation and
apoptosis, they become
tumor cell.
8. CANCER RELATED GENES
PROTO-ONCOGENES GENES TUMOR SUPPRESOR GENES
SIS – synthesis of platelet derived
growth factor
BRCA1 and BRCA2 – transcription
factor,
DNA repair
ERBB- synthesis of epidermal
growth factor receptor
NF1 – GTPase
SRC- synthesis of tyrosine kinase TP53- transcription factor
FOS – synthesis of transcription
fator
RB1- cell cycle checkpoint
BRCA1 BRCA2 breast cancer
susceptibility gene are tumor
suppressor gene encoding
proteins involved in the
maintenance of genome
stability through repair of DNA,
cell growth regulation and
control of regulation.
Individual carrying germline
pathogenic mutation in BRCA1
and BRCA2 are at highly
elevated risk of developing
9.
10.
11. BREAST CANCER TYPE
Hormone Receptor-Positive Breast
Cancer
About 80% of all breast cancers are “ER-
positive.” That means the cancer cells grow
in response to the hormone estrogen. About
65% of these are also “PR-positive.” They
grow in response to another hormone,
progesterone.
The medication
tamoxifen helps stop cancer from coming
back by blocking hormone receptors,
preventing hormones from binding to them
aromatase inhibitors actually stops
estrogen production. These
include anastrozole (Arimidex), exemestan
e (Aromasin), and letrozole (Femara).
They’re only used in women who’ve
already gone through menopause.
CDK 4/6
inhibitors abemaciclib (Verzenio), palbocic
lib (Ibrance) and ribociclib (Kisqali) are
sometimes used with aromatase inhibitors
or the hormone
therapy fulvestrant (Faslodex).
HER2-Positive Breast Cancer
In about 20% of breast cancers, the cells
make too much of a protein known as
HER2. These cancers tend to be
aggressive and fast-growing.
There are several other targeted therapies
sometimes used in the treatment of
HER2-positive breast cancer. These
include:
Abemaciclib (Verzenio)
Lapatinib (Tykerb)
Margetuximab (Margenza)
Neratinib (Nerlynx)
Pertuzumab (Perjeta)
Tucatinib (Tukysa)
Triple-Negative Breast Cancer
Some breast cancers -- between
10% and 20% -- are known as
“triple negative” because they
don’t have estrogen and
progesterone receptors and don’t
overexpress the HER2 protein.
Many breast cancers associated
with the gene BRCA1 are triple
negative. They are often treated
with surgery, chemotherapy, and
radiation.
talazoparib (Talzenna)
Atezolizumab (Tecentriq) is an
immunotherapy drug used in
combination with the
chemotherapy nab-
paclitaxel (Abraxane) to block a
protein called PD-L1 in certain
breast cancers that are triple
negative.
12. DIFFERENT APPROACHES TO
TREAT BREAST CANCER
(MOLECULAR TARGETS)
cyclin-dependent kinase CDK4 and CDK6 INHIBITION
Antagonise directly estrogen receptor
Prevention of dimerization
Deficiency of coregulatory like SRC1 (proto onco gene)
Increased apoptosis
Inhibition of tyrosine kinase pathway etc.
13. REFERENCES
Kumar N, Gulati H K, Sharma A, “Most recent strategies targeting estrogen receptor
alpha for the treatment of breast cancer” 2020, Molecular Diversity
https://doi.org/10.1007/s11030-020-10133-y
Christy W. S. Tong , Mingxia Wu , William C. S. Cho and Kenneth K. W. To, “Recent
Advances in the Treatment of Breast Cancer” 2018, Front. Oncol.
https://doi.org/10.3389/fonc.2018.00227
Christian J. Gruber, Doris M. Gruber, Isabel M.L. Gruber, Fritz Wieser and Johannes
C. Huber, “Anatomy of the estrogen response element” 2004, TRENDS in
Endocrinology and Metabolism Vol.15 No.2 Elsevier, 73-8.
doi: 10.1016/j.tem.2004.01.008
Chelsea DeLeon , David Q.-H. Wang and Christopher K. Arnatt, “G Protein-Coupled
Estrogen Receptor, GPER1, Offers a Novel Target for the Treatment of Digestive
Diseases” 2020, Front. Endocrinol. https://doi.org/10.3389/fendo.2020.578536
Rainer G , Günter E and Carsten G, “ Estrogen Signaling in ERα-Negative Breast
Cancer: ERβ and GPER” 2019, Front. Endocrinol
https://doi.org/10.3389/fendo.2018.00781