The peroxisome proliferator-activated receptors (PPARs) are ligand activated transcription factors, belonging to the nuclear receptor superfamily, that control the expression of genes involved in organogenesis, inflammation, cell differentiation, proliferation, lipid, and carbohydrate metabolism [1
]. PPARs activated by their selected ligands, heterodimerizes and its receptor with the 9-cis-retinoic acid receptor, they then bind to peroxisome proliferator response elements (PPREs), specific sequences in their target genes. The consensus PPRE site consists of a direct repeat of the sequence AGGTCA separated by a single/double nucleotide, which is designated as DR-1 site/DR-2 site [3
] (). Each major isoforms of PPAR (PPARα
, and PPARγ
), encoded by a different gene, performs different functions and exhibit different tissue localizations in many parts of the human body [4
]. The peroxisome proliferator-activated receptor γ
) is the most extensively studied subtype of the PPARs [5
is expressed in adipose tissue, colon, immune system, hematopoietic cells, and retina involved in lipid anabolism, adipocyte differentiation, control of inflammation, macrophage maturation, embryo implantation, and molecular targets of antidiabetic thiazolidinediones [6
]. Its role in cancer development and potential as a target for cancer prevention and treatment strategies has been noted in recent years. Activation of PPARγ
could possibly be an approach to induce differentiation in cells thereby inhibiting proliferation of a variety of cancers. This antiproliferative effect has been reported in many different cancer cell lines including breast[7
], and non-small-cell lung cancer[10
]. In particular, breast tissue was found to express PPARγ
in amounts greater than those found in normal breast epithelium. Ligand activated PPARγ
is reported to inhibit invasion and metastasis of breast cancer cells and induce G1/S arrest by upregulation of p21WAF1
, and downregulation of cyclin D1 [11
]. Moreover, PPARγ
on activation by specific ligands exerts antitumor activity through growth inhibition and cellular differentiation [14
]. Imbalances in expression of target genes forms the core of metabolic syndrome and cancer regulation through atherogenic metabolic triad/lipid triad metabolism modulation by PPARs [18
]. Despite these promising results, the target genes involved in the anticancer activity of PPARγ
ligands and their pathways still remain elusive.
PPAR gamma activation mechanism. PPRE and PACM motifs are shown.
Breast cancer is the fifth most common cancer globally and accounts for the highest morbidity and mortality. It is the second highest occurring cancer in women and one of the leading causes of death[19
]. Although antiestrogens have provided an effective endocrine therapy, a significant proportion of patients have acquired resistance to these drugs, others are intrinsically resistant [20
]. Hence, there is a requirement for alternative therapeutics to treat breast cancer. Development of selective anticancer agents based on the biological differences between normal and cancer cells is essential to improve therapeutic selectivity, sensitivity, and specificity. A list of genes reported in the literature to be regulated by PPARγ
and involved in breast cancer is shown in .
PPAR gamma gene targets and their pathways.
Differences in energy metabolism between normal and cancer cells are reported andalterations in cellular bioenergetics are one of the hallmarks of cancer [21
]. The general principles of metabolic control analysis can be effective for cancer management as abnormal energy metabolism and biological disorder are characteristics of tumors [22
]. In line with this, increased aerobic glycolysis and elevated oxidative stress are two prominent biochemical features frequently observed in cancer cells, as shown by the Warburg hypothesis. This paper will discuss the function and role of PPARγ
in energy metabolism and cancer biology in general and its emergence as a promising therapeutic target in breast cancer.