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s1 {font-kerning: none}span.s2 {font: 7.3px ‘Trebuchet MS’; font-kerning: none}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.
