Peroxisome clinically known to increase tumor cell invasiveness as

Peroxisome proliferator-activated receptors (PPARs)
are classified as orphan members of the nuclear receptor superfamily. To date,
three PPAR subtypes have been discovered and characterized (PPAR?, ?/?, ?). The
subtypes have been shown to play crucial roles in important diseases and
conditions such as obesity, diabetes, atherosclerosis, cancer, and fertility. The
most studied roles of PPARs is their involvement in inflammatory processes31. PPAR? and PPAR? are the most studied subtypes in
inflammatory processes whereas the role of PPAR? is yet to be elucidated. Loss-of-function
and gain-of-function mutations of PPAR? have been studied in a number of
disease processes, primarily type-2 diabetes mellitus, or insulin resistant
diabetes32. Thiazolidinedione (TZD) is one of the drugs whose
effect on PPARs has been well implicated, where it activates PPAR?, restoring
insulin sensitivity to tissue, upregulating free fatty acid uptake by
adipocytes, and altering expression of adipokines. However, it is pertinent
that the effect of other drugs on PPARs and their change in mechanism should be
dwelled into; especially because this subtype is involved in a number of other
disease conditions including breast cancer. In breast cancer, PPAR? ligands
inhibit proliferation and induce apoptosis both in vitro and in vivo. Moreover,
the mechanism of action of the thiazolidinediones in breast cancer cells is not
fully understood but involves interactions with other nuclear hormone
receptors, transcriptional co-activators and repressors as well as PPAR? -independent
effects. Additionally, it has been shown that PPAR? negatively regulates
several genes, including NFkB, a key transcriptional factor involved in
numerous disease processes, including inflammation by blocking gene
transcription machinery from binding the promoter site33. Since NFkB is clinically known to increase tumor
cell invasiveness as a result of increased uPA expression, the ability of PPAR?
to inhibit NFkB expression is important in breast cancer progression34. In addition to inhibiting NFkB expression, PPAR?
activation is also shown to downregulate transcription of the insulin receptor
(IR) by physically interacting with the transcription factors Sp1, C/EBP ?, and
AP1 in vitro, preventing IR transcription35. Furthermore, implications of insulin receptor
signalling has been shown in a number of neoplastic processes including
proliferation, invasion, and cell survival36. Adding to the evidences that insulin resistance is
associated with increased risk of breast cancer37 and poor patient prognosis38, elevated levels of insulin in newly diagnosed breast
cancer patients were shown to be related to an underlying insulin resistance39.These studies suggest that there is substantial
amount of data pertaining to association of diabetes with breast cancer40, however, there is no solid understanding of its
function. In our proposed project study, we strive to find relevant answers by
using our computational approach to analyse the significance of the drugs in
these aggressive diseases. It should be noted that where PPAR? is the most
studied subtype of PPARs with little evidences of PPAR? in inflammatory
processes, PPAR? has no such studies to report to. As a result, it becomes
imperative to perform a combined

study of these PPAR subtypes to understand their
complete mechanism of action in association between breast cancer and diabetes.

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