1) Identification of gene signatures and biomarkers in breast cancer, such as the Notch pathway, may help develop targeted therapies for different subtypes. 2) The Notch pathway promotes breast cancer stem cell growth and inhibiting it with gamma secretase inhibitors reduces cancer cell proliferation and invasion. 3) PARP inhibitors show promise as a targeted treatment for triple negative breast cancer associated with BRCA mutations by exploiting "synthetic lethality" - inhibiting both BRCA and PARP pathways kills cancer cells. Large-scale identification of PARP substrates may help identify predictive markers for effective PARP inhibitor therapy.

1. DRUG TARGETS
Nic Russell
Identification of a Notch-Driven Breast Cancer Stem Cell Gene Signature for Anti-Notch
Therapy in an ER-Positive Presurgical Window Model.
Large-Scale Identification of Cell-specific PARP Substrates

2. Identification of gene signatures may aid in the development of
targeted therapies for various subtypes of Breast Cancers.
Breast cancer is the most common cancer in women, accounting for 18.2% of all
cancer deaths worldwide. It develops from breast cells and usually starts off in the1
inner lining of milk ducts or the lobules that supply them with milk.
The Anatomy of the breast:
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1. Chest wall. 2. Pectoralis muscles. 3. Lobules (glands that make milk). 4. Nipple surface. 5. Areola. 6.
Lactiferous duct tube that carries milk to the nipple. 7. Fatty tissue. 8. Skin.
The breast, like any other part of the body, consists of billions of microscopic cells. In
normal cell function, cells multiply in an orderly fashion, with new cells being made
to replace ones that have died. However, cancer arises when these orderly processes
go awry. As a result, the cells multiply uncontrollably, fail to die when they should,
and accumulate, forming a tumour in the breast or other organs.
These changes in cell behavior are predominantly the result of changes in the genetic
material of the cell. Researchers have also discovered stem cells located within breast
http://www.medicalnewstoday.com/articles/37136.php. Accessed on 12/12/141

3. cancer tumours, known as cancer stem cells (CSC). The cancer stem cells contribute
to tumour growth by self-renewing and driving progression of the disease.
Cancer Stem Cell:
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In addition to the discovery of cancer stem cells within breast cancer tumours,
researchers have been focusing on identifying an individual’s own unique biomarkers,
enabling personalized targeted therapies to treat their breast cancer. Analysing the
origin of breast cancer at the molecular level facilitates the identification of a drug
target, so the drug gets delivered to where it needs to go. These discoveries have had
important implications for breast cancer therapy, as historically, breast cancer
treatments have only been able to kill the surface cells in a breast tumour, along with
other healthy cells, but new targeted therapies maybe able to destroy cancer cells at
their root cause.
One of these examples of analysis at the molecular level in identifying biomarkers in
breast cancer was discussed at the world leading San Antonio Breast Cancer
Symposium in December 2014.

4. The whole of a person’s DNA is known as their genome (a blueprint and code for
cells). This code tells the cells which proteins it needs to produce to control critical
cell functions, such as cell multiplication and survival. When a mutation occurs or
there is damage to the DNA, the code is altered and this can result in cell
proliferation, which can lead to the development of cancer. Gene identification
(biomarkers) provides information on how to target these mutations to switch off/
inhibit the cellular signaling pathways. Dr Carlos Arteaga, co-chair of the SABCS and
president of AACR said, “I think personalization of therapy based on the molecular
analysis of cancers is revolutionizing the field of breast cancer.”
One such pathway is the well known Notch gene signature, a well-preserved cell
signaling system identified as aiding in breast cancer stem cell (CSC) survival and
intensifying during endocrine therapy treatment.
In 2011, Dr Hamed Al-Hussein and a team of researchers from the University of
Toronto noted that the Notch pathway was implicated in both the development and
progression of breast cancer, and as a result, the notch pathway emerged as a possible
target of therapy.
Clinical trials were undertaken to investigate the effectiveness of Gamma Secretase
inhibitors on mitigating the proliferation of breast cancer stem cells as a result of the
overactive Notch pathway. “There is preclinical and early clinical evidence that GSI’s
are most advanced in targeting the Notch pathway. Further clinical trials will
hopefully confirm the efficacy of Notch pathway inhibition either as a single agent or
in combination with endocrine therapy, targeted therapies, chemotherapy, or possibly
even radiation therapy as novel approaches, ultimately leading to improved patient
outcomes overall,” said Dr Al-Hussein.2
Mol Cancer Ther; 10(1); 9–15. ©2010 AACR. http://mct.aacrjournals.org/content/10/1/9.full.2
Accessed on 12/12/14

5. Expanding upon the previous findings on the Notch genetic signaling pathway in
breast cancer, Dr Kathy Albain and a team of researchers from the Loyola University
Chicago Cardinal Bernardin Cancer Centre, Baylor College of Medicine Duncan
Cancer Centre and Louisiana State University Cancer Centre also identified the over-
expression of the Notch gene signature in ER positive Breast Cancer patients who had
become resistant to endocrine therapy (ET). They proposed the Gamma Secretase
Inhibitor maybe an effective targeted therapy for such patients in the neo-adjuvant
setting.
In concordance with the previous findings of Dr Hamed Al-Hussein, Dr Albain’s
research also identified that the Notch signaling pathway regulated 18 genes that
promoted breast cancer stem cell growth. When targeted by Gamma Secretase
Inhibitors (GSI), the overexpression of the Notch pathway was inhibited, reducing
cancer stem cell proliferation, invasion and estrogen signaling. In addition, tumours
were suppressed and cell apoptosis increased. The implications of these findings are
that this biomarker maybe used to identify ER positive women who are resistant to
ET, and who could benefit from a targeted GSI therapy.
In other subtypes of breast cancer, including BRCA1/2 mutations, which are
associated with triple negative breast cancer (TNBC), treatment options have been
limited. Normal BRCA1 function is involved in tumour suppression, while normal
BRCA2 function is involved in DNA repair. In the case of BRCA1/2 gene mutations,
the tumour cell loses the ability to repair damaged DNA, and must fall back on other
ways of repairing its DNA. Recent research identified PARP enzymes as playing a
key role in DNA repair by binding to DNA breaks and attracting DNA repair proteins
to the damaged site.3
Targeting PARPs with Novel Drugs: Back to the Laboratory? Exploiting synthetic lethality for cancer
3
therapy. Patricia Fitzpatrick Dimand, 2014: http://www.genengnews.com/insight-and-intelligence/
targeting-parps-with-novel-drugs-back-to-the-laboratory/77900337/ . Accessed on
12/12/14

6. The BRCA mutations often lead to TNBC, where there is a lack of three receptors
known to fuel most breast cancers: estrogen receptors, progesterone receptors and
human epidermal growth factor receptor 2 (HER2). The most successful treatments
for breast cancer target these receptors.
Unfortunately, none of these receptors are found in TNBCs. In other words, a triple
negative breast cancer diagnosis means that the offending tumor is estrogen receptor-
negative; progesterone receptor-negative and HER2-negative, thus giving rise to the
name "triple negative breast cancer." This type of breast cancer is typically responsive
to chemotherapy. Because of its triple negative status however, triple negative tumors
generally do not respond to receptor-targeted treatments. Depending on the stage of
its diagnosis, TNBC can be particularly aggressive, and more likely to recur than
other subtypes of breast cancer. The discovery of PARP1 enzymes in DNA repair held
promise as a targeted treatment for TNBC.
PARP1 interacts with BRCA1 in the following way: occurring in the cell nucleus,
PARP1 is active in repairing breaks in DNA – while mutated BRCA1 genes cause
such breaks to occur, PARP1 does some repair work that allows these cells to survive
and form tumours. Researchers found that PARP1 inhibitors stopped the repair and
allowed these damaged cells to die rather than continuing to proliferate. Fast growing
tumours are low in oxygen and can be sensitive to PARP inhibitors.4
If both BRCA and PARP mechanisms are dysfunctional, the cell dies. Therefore,
investigators reasoned, tumors of patients carrying BRCA mutations could potentially
be eliminated with chemical PARP inhibitors.
PARP inhibitors have been shown to be very specific - there are at least 7 different
sub-types of TNBC and one inhibitor may work against only one of the sub-types.
This has been a major challenge for researchers and is where a lot of new work is
focused.
Yidup Hu, S,A. Petit, S,B. Ficarro, K,J. Toomire, A, Xie, A, E, Lim, S,A. Cao, E, Park, M,J. Eck, R,4
Scully, M, Brown, J,A, Marto, D,M. Livingston. PARP1-Driven Poly-ADP-Ribosylation Regualtes
BRCA1 Function in Homologuous Recombination-Mediated DNA Repair (2014). cancer
dISCOVERY, 1431-1447.

7. To address this challenge, Yonghao Yu from the Department pf Biochemistry, UT
Southwestern Medical Centre, Dallas undertook a large-scale identification of cell-
specific PARP substrates. A substrate binds to another molecule, and if identified, can
enable screening of a number of candidate molecules to identify those that bind to
PARP in cells. This is one step in trying to interfere with PARP's role in DNA repair
in tumours. Previous research into the use of PARP inhibitors, such as Iniparib, held
promise as a targeted drug therapy for TNBC. Unfortunately, the clinical trials did not
meet their endpoints, however, the basic science provides insights for continued
investigation.
In relation to the effectiveness of a PARP inhibitor as a targeted therapy, Dr Daniel
Silver, of Dana-Farber's Breast Oncology Center, was cited as saying “This could be a
very elegant way to utilize a defect in DNA repair without inflicting the same amount
of damage to normal cells, because normal cells aren't defective in this compensating
repair pathway.”5
Cell Mutation:
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http://www.genengnews.com/insight-and-intelligence/targeting-parps-with-novel-drugs-back-to-the-5
laboratory/77900337/ Accessed on 14/12/12

8. A mutation in a cancer cell creates opportunities to selectively kill tumor cells by mimicking
the effect of a second genetic mutation with targeted therapy, such as PARP inhibitors.
Yonghao Yu’s study identified 340 PARP proteins involved in a wide array of nuclear
functions, including the activation of estrogen receptor target genes, and further
identified many PARP downstream targets. The implications of these findings are that
individual screening could identify predictive markers for effective targeted therapy
from a PARP inhibitor, such as Iniparib.
Submitted by: Nic Russell
Kenzie’s Gift
Breast Cancer Aotearoa Coalition
Auckland | New Zealand
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