Type to 1.21). In regards to biological mechanisms,

Type 2
diabetes (T2D) has been making its negative impact on the human society
prevalently in recent years. The rising effect of T2D on populations around the
world can be statistically observed since 1950 in parallel with obesity1. Based on a 2015 report there were approximately
392 million people diagnosed with the disease compared to around 30 million in
19852-3. For diabetes4-6 and breast cancer7-8, obesity appears to predict a higher risk for Asian women than for
Caucasian women. Considerable evidence suggests an association between diabetes
and a higher breast cancer risk independent of obesity, but this question has
been investigated primarily in Caucasian populations and not in Qatar
population, as summarized in several meta-analyses9-11. Moreover, female population seem to be at a greater risk as do
certain ethnic groups12-13. Studies on the association between diabetes and breast cancer risk in
differing geographic locations are contradictory; whereas in 1 meta-analysis10, diabetes was associated with similar risk for
breast cancer in women with diabetes from Asia (RR 1.45; 95% CI, 1.07 to 1.97)
compared with reports from North America (RR 1.12; 95% CI 1.06 to 1.18) and
Europe (RR 1.19; 95% CI 1.08 to 1.31), a more recent meta-analysis11 showed a stronger association between diabetes and
breast cancer in studies from Europe (RR 1.88; 95% CI 1.56 to 2.25) as compared
to Asia (RR 1.01; 95% CI 0.84 to 1.21). In regards to biological mechanisms, it
has been hypothesized that ethnic differences in visceral fat and adipokines14-15 or the adverse metabolic consequences of obesity on glucose
control and chronic inflammation may be the reason to modify the relationship
between diabetes and breast cancer risk in ethnic populations. As we see,
association studies between diabetes and breast cancer have been performed on
regional populations. These studies are generating geographical-based data
which could be used for developing tailored therapies for patients suffering
from diabetes and who could be at the brisk of breast cancer or even death.
Furthermore, it has been proposed that diabetes increases the risk of breast
cancer based on the studies conducted on Latinas16. The study examined the impact of co-occurring
diabetes on patient outcomes in a sample of Latina breast cancer survivors
(BCS). The findings highlight the urgent need for additional inquiry examining
multiple chronic conditions, particularly in the face of cancer. Additionally,
it also points towards integrative and coordinated care to tackle multiple
chronic conditions, especially among elderly and ethnic minority patients.
Similar study on Qatar population could be useful to understand the effect of
the relation and association between these diseases. Furthermore, such
association studies will have impact on our understanding of relation between
diabetes and cardio-vascular diseases, since advance studies show that type 2
diabetes are at high risk for several cardiovascular disorders such as,
coronary heart disease, stroke, peripheral arterial disease, cardiomyopathy,
and congestive heart failure17. Pharmacogenomics approach to innovate tailored
therapies for this problem could be an answer to mediate a reasonable solution.
However, developing a platform to integrate the data for pharmacogenomics
studies of the number of diabetic patients suffering from breast cancer will be
a challenge.

 

In
our study we are aiming to study 5 significant genetic targets based on their therapeutic
significance and relevance of association with diabetes and breast cancer, namely,
protein-tyrosine phosphatase 1B (PTP1B), Cytochrome P450 2C9 (CYP2C9),
peroxisome proliferator-activated receptors (PPARs), angiotensin-converting
enzyme (ACE) and p62/sequestosome 1 (SQSTM1), which play vital role in the
mechanism of both diseases.

 

A
non-transmembrane protein tyrosine phosphatase, PTP1B, is studied as a negative
regulator of leptin and insulin signaling. Also, it has been considered as an
essential factor in tumorigenesis. PTP1B’s role in inhibiting leptin and
insulin receptors signaling18 makes it one of the vital targets of our
study. PTP1B dephosphorylates insulin receptors (IR) and its substrates (IRS)
in the insulin signaling, whereas in contrary, the tyrosine kinase JAK2 (Janus
Kinase 2) is the prime target of dephosphorylation in leptin signaling. Moreover,
with the recent finding where it was deciphered that dephosphorylation of the
inhibitory Y529 site in Src is operated by PTP1B, it has been speculated that PTP1B
might also play signaling role in cell proliferation19-22. Additionally, in two landmark papers PTP1B was shown to
play a positive role in a mouse model of ErbB2-induced breast cancer23-24, which signifies PTP1B as a signaling stimulant. Hence, considering
the involvement of PTP1B in insulin, leptin and ErbB2 signaling pathways
(Figure 1), it can be put among the potential drug targets in the association
study of diabetes and breast cancer. Its inhibition could bring significant
benefits in the study of ailments such as adult-onset diabetes and cancer.

 

Figure 1:
Representation of the receptor pathways PTP1B is involved in, confirming its
relevance as a potential target of study25.

Cytochrome P450 2C9, CYP2C9, is a member of the
cytochrome P450 superfamily of enzymes encoded by gene Cytochrome P450. These
monooxygenases are responsible for the catalysis of reactions entailed in drug
metabolism and synthesis of lipids, steroids, and cholesterol. It plays major
role in the oxidation of endogenous and xenobiotic compounds. CYP2C9 especially
metabolizes docosahexaenoic acid to epoxydocosapentaenoic acids (EDPs), and arachidonic
acid to the eicosatrienoic acid epoxide ( EETs), and eicosapentaenoic acid to
epoxyeicosatetraenoic acids (EEQs)26. Influence of certain EDPs and EEQs in cancer growth
has been indicated in In vitro and in vivo animal models; EPAs and EEQs
contribution in the inhibition of angiogenesis, endothelial cell-proliferation
and cell-migration, and breast metastasis and growth have also been stipulated
in various studies, whereas EETs in contrary have been stated to have
stimulatory effects in these systems27-30. Moreover, epoxyeicosatrienoic acids (EETs) can be
further hydrolyzed to less active diols by the enzyme soluble epoxide hydrolase
(sEH); increasing evidence suggests that inhibition of sEH increases levels of
EETs, which have beneficial effects in metabolic diseases such as diabetes28. Therefore, CYP2C9 may be a
potential therapeutic target to study these disorders.