This document discusses potential molecular targets for breast cancer treatment. It begins with an introduction to breast cancer and anatomy. It then discusses several potential targets including receptors like HER2, VEGF, estrogen and progesterone receptors. It also discusses signaling pathways and proteins involved in cancer growth like mTOR, PI3K, PARP, CDK4/6 and EZH2. Finally, it discusses tumor microenvironment factors like tumor associated macrophages. In summary, the document provides an overview of many molecular-level targets that could be exploited for more targeted breast cancer therapies.
4. WHAT IS BREAST CANCER ?
• Cancer that forms in the cells of the breasts is
called as breast cancer. Breast cancer starts
when cells in the breast begin to grow
uncontrollably.
• These cells usually form a tumor that can often
be seen on x-ray or felt as a lump.
• Most breast cancers begin in the breast tissue
made up of glands for milk production, called
lobules to the nipple.
6. • The breast is a modified skin appendages
which functions in the females during
lactation.
• Female hormones such as oestrogen and
progesterone are important in promoting
growth and changes that occur in the breast,
especially during pregnancy and the menstrual
cycle.
7. • The mammary gland is made up of lobules -
glandular structures that produce milk in females
when stimulated to do so.
• The lobules drain into a system of ducts,
connecting channels that transport the milk to
the nipple.
• Between the glandular tissue and ducts,
the breast contains fat tissue and connective
tissue.
• There are two types of tissue components:
Epithelial and Stromal
CONT…
8.
9. Types of breast cancer
• Non-invasive Carcinoma
- Intraductal carcinoma
- Lobular carcinoma
11. Breast cancer epidemiology
• After lung cancer, breast cancer second leading
cause of cancer-related death in women
worldwide, with an evaluated 1.7 million new
cases and 521,900 deaths in 2012
• The cases are expected to increase by 26% by
2020
• In India, premenopausal patients are about
50% of all patients of breast cancer.
12. • Breast cancer has ranked 1st cancer among
Indian women with an age-adjusted rate as
high as 25.8 per 100,000 women and mortality
12.7 per 100,000 women.
• Earlier cervical cancer was most common
cancer in Indian woman but now the incidence
of breast cancer has surpassed cervical cancer
and is the leading cause of death.
CONT…
13. • In the United States of America, more than 3.5
million women with a family history of breast
cancer were alive on January 1, 2016.
15. Targets of breast cancer
• Drugs or other substances that block the
growth and spread of cancer by interfering
with specific molecules involved in tumor
growth & progression are the agents which act
upon targets.
• Most researchers consider the new approach of
treating breast cancer that targets the cell
signaling pathways of cancer cells.
16. • Blocking of signals help to stop cancer
progression and may induce cancer cell death
through apoptosis.
• The development of targeted therapies requires
the identification of good targets.
CONT…
21. HER/ERBB/EGFR
• HER-1 (ERRB-1), HER-2, HER-3, and HER-4
are nearly related members of the EGFR
family which are expressed to a different
extent in most epithelial tumors.
• The prototype of receptor tyrosine kinase that
is EGRF is a crucial target in cancer therapy.
22. • The epidermal growth factor receptor (EGFR)
family serves as a magnificent example of
therapeutic targets based on tumor formation,
which is defined by aberrant cell proliferation.
• In breast cancer cells, HER-2 neu (erbB-2) has
been shown to accord notably to the malignant
phenotype in many cases.
CONT…
23. • Overexpression HER2 found in breast cancer
(approximately 25–30%) cells which has also
been associated with resistance to
chemotherapy and hormone therapy.
• HER2 target is present in a very high
proportion of tumor cells.
CONT…
24. • HER1, HER3, HER4 all of these three play a
crucial role in signal transduction for normal
cell growth and cell division and are linked to
the tumorigenesis and progression of breast
cancer
• HER2 inhibitors such as trastuzumab,
lapatinib, pertuzumab, and trastuzumab
emtansine target HER2 in breast cancer.
CONT…
25. • The first monoclonal antibody to restructure
the treatment strategy for early as well as for
advanced breast cancer was trastuzumab,
which is a humanized monoclonal antibody of
immunoglobulin G1.
• It inhibits the downstream signal transduction
that participates in proliferation, motility, and
apoptosis in a normal cell by binding to the
extracellular domain IV of HER2.
CONT…
26.
27. Insulin like Growth Receptor (IGFR)
• Increased circulating levels of IGF-I are
associated with a greater risk of breast cancer
in premenopausal women, with an especially
high risk among those younger than 50 years.
• increased IGFs resists apoptosis in response to
chemotherapy and radiation.
• Docetaxel is an inhibitor.
28. Fibroblast Growth Factor
Receptor(FGF)
• The fibroblast growth factor (FGF) consist of
18 ligands.
• FGF1 & FGF23 signal through four high
affinity fibroblast growth factor receptor
(FGFR1 to FGFR4).
• Under physiological conditions, the highly
complex FGF signaling pathway is tightly
regulated.
29. • The deregulation of FGF signaling to
development of cancer, promoting cancer cell
proliferation, survival and migration.
• Brivanib, dovitinib, ponatinib are the
inhibitors.
Cont…
30. VEGF /VEGFR
• VEGF overexpression is common in breast
cancer
• Targeting VEGF and its receptors reflect its
central role in both physiologic and pathologic
angiogenesis.
• Angiogenesis is a composite process that leads
to the formation of new blood vessels from the
preexisting vascular network.
31. • Angiogenesis is a factor on which many
cancers depend for their growth, invasion, and
metastasis.
• Solid tumors are in need of the formation of
new blood vessels, so-called
neovascularization, to grow and develop
beyond a size of 1 mm3.
Cont…
32. • The VEGF protein family consists of six
members: VEGF, VEGF B–E and placenta
growth factor.
• Three endothelial receptors for VEGF have
been identified so far: VEGFR-1/Flt-1,
VEGFR-2/Flk1/KDR, and VEGFR-3/Flt-4.
Cont…
33. • VEGF RTKs are activated to transduce the
signal by binding of VEGF which induces
receptor dimerization and trans-
autophosphorylation of tyrosine residues in the
cytoplasmatic domain.
Cont…
34. • Bevacizumab is a humanized monoclonal
antibody that competitively binds to VEGF,
which regulates angiogenesis and tumor
survival.
• Lots of clinical trials targeting VEGF in breast
cancer are underway.
Cont…
35.
36.
37. Steroid Hormone receptor
• Steroid hormone receptors (SHRs) are ligand-
dependent intracellular transcription factors
• They have an impact on the development and
growth of countless human cancers.
• Steroid hormone like estrogen and
progesterone bind to SHRs and relay their
signals leading to downstream gene
expression.
38. Oestrogen receptor
• Oestrogen is a hormone of the female
reproductive system required for proliferation
and differentiation of healthy breast
epithelium. Oestrogen receptor also known as
ERα or ESR1.
• There is a strong evidence of estrogen playing
a key role in breast cancer development.
• ERα (ESR1) is a transcription factor (TF) that
plays a critical role in cell proliferation.
39.
40. Aromatase
• estrogens are no longer made in the ovaries
after menopause
• peripheral tissues produce sufficient
concentrations to stimulate tumor growth.
• As aromatase catalyzes the final and rate-
limiting step in the biosynthesis of estrogen,
inhibitors of this enzyme are effective targeted
therapy for breast cancer.
41.
42. Mammalian Target of Rapamycin
(mTOR)
• mTOR is a member of the cellular
mTOR/PI3K/Akt pathway. A high proportion
of breast tumors exhibit constitutive activation
of the mTOR pathway.
• Rapamycin is a macrolytic lactone produced
by Streptomyces hygroscopicus, which has
immunosuppressive, antimicrobial, and
antitumor properties. Rapamycin targets a
principal protein that was named mTOR.
43. • Two mTOR complexes have been identified:
mTORC1 and mTORC2 of cell growth and
proliferation, cell metabolism, angiogenesis,
and apoptosis.
• Sirolimus (Rapamycin) and Everolimus are
approved mTOR inhibitors.
CONT…
44.
45. Phosphoinositide 3-kinase (PI3K)
• Three classes of PI3K enzymes, designated I to
III, have been identified; members of PI3K
class I have been implicated in the mTOR
pathway
• PI3K can be key target that, if effectively
inhibited, could improve outcomes.
46. • PI3K inhibitors mainly include
- pan-PI3K inhibitors (buparlisib and
pictilisib)
- α specific inhibitors (alpelisib and taselisib).
47.
48. PARP
• PARP inhibitors have raised recent excitement
because of the activity reported in TNBC with
iniparib.
• DNA damage, double strand breaks are highly
toxic to cells
• Homologous recombination is DNA repair
mechanism.
• Homologous recombination is dependent on
functional BRCA1 and 2 pathways.
49. • Germline mutations in either the BRCA1 or
BRCA2 genes are associated with a high risk of
developing a number of breast cancers.
• When the BRCA-associated DNA repair pathway
(homologous recombination) is lost or
dysfunctional:
repair shifts toward alternate DNA repair
mechanisms dependent on a unique class of
enzymes, Poly-(adenosine diphosphate [ADP]-
ribose) polymerase (PARP).
CONT…
50.
51. Cyclin-dependent kinase 4/6(CDK4/6)
• Palbociclib, Ribociclib, Abemaciclib act
mainly by inhibiting the CDK4/cyclin D1
which is responsible for
- phosphorylation
- inhibition
of retinoblastoma (Rb) suppressor gene’s
product.
52. • When Rb is phosphorylated, the cell proceeds
from G1 to S phase of the cell cycle,
replicating DNA and preparing for DNA
synthesis
53.
54. EZH2 (enhancer of zeste homolog 2)
• EZH2 is the catalytic subunit of the Polycomb
Repressive Complex 2 (PRC2) for maintaining
transcriptional repression of target genes through
trimethylation of histone H3 on lysine 27
• Ezh2 is overexpressed in a number of human
malignancies, including breast cancer
• It’s overproduction leads to oncogenesis by
decreasing the expression of tumor suppressor
genes.
55. • Ezh2’s suppressor function occurs via the
addition of three methyl groups to Lysine 27 of
histone 3
• A modification leading to chromatin
condensationEzh2 is of interest as a
therapeutic target in TNBC, as TNBC has been
shown to overexpress this protein.
56.
57. TAMs (Tumor associated macrophages)
• TAMs play a key role in breast cancer
progression and invasiveness.
• Among cell types associated with tumor
microenvironment, tumor-associated
macrophages (TAMs) are the most influential
for tumor progression.
• Breast cancer is characterized by having a
large population of TAMs
58.
59.
60. Conclusion
• Targeted cancer therapies hold the promise of
being more selective, reducing side effects,
and improving quality of life.
• Targeted therapies may work best in
combination, either with other targeted
therapies or with more traditional therapies.
• We discussed potential breast cancer targets
that might be helpful in many ways for
aspirants seeking for knowledge.
61. Reference
• American Cancer Society. Breast Cancer Facts &
Figures 2017-2018. Atlanta: American Cancer Society,
Inc. 2017.
• Malvia S, Bagadi SA, Dubey US, Saxena S.
Epidemiology of breast cancer in Indian women.
Asia‐Pacific Journal of Clinical Oncology. 2017 Aug;
13(4):289-95.
• Kabel AM, Baali FH. Breast cancer: insights into risk
factors, pathogenesis, diagnosis and management. J
Cancer Res Treat. 2015; 3(2):28-33.
• Ju J, Zhu AJ, Yuan P. Progress in targeted therapy for
breast cancer. Chronic diseases and translational
medicine. 2018 Sep 1; 4(3):164-75.
62. • Paplomata E, O’Regan R. The PI3K/AKT/mTOR
pathway in breast cancer: targets, trials and
biomarkers. Therapeutic advances in medical
oncology. 2014 Jul; 6(4):154-66.
• Chumsri S, Howes T, Bao T, Sabnis G, Brodie A.
Aromatase, aromatase inhibitors, and breast
cancer. The Journal of steroid biochemistry and
molecular biology. 2011 May 1; 125(1-2):13-22.
• Hadinger KP, Marshalek JP, Sheeran PS, Dayton
PA, Matsunaga TO. Optimization of Phase-
Change Contrast Agents for Targeting MDA-MB-
231 Breast Cancer Cells. Ultrasound in medicine
& biology. 2018 Dec 1; 44(12):2728-38.