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Review
. 2022 Dec 28;12(1):130.
doi: 10.3390/cells12010130.

The Role of PPARs in Breast Cancer

Binggong Zhao  1 , Zhiqiang Xin  2 , Ping Ren  2 , Huijian Wu  1
Affiliations
Review

The Role of PPARs in Breast Cancer

Binggong Zhao et al. Cells. .

Abstract

Breast cancer is a malignant tumor with high morbidity and lethality. Its pathogenesis is related to the abnormal expression of many genes. The peroxisome proliferator-activated receptors (PPARs) are a class of ligand-dependent transcription factors in the nuclear receptor superfamily. They can regulate the transcription of a large number of target genes, which are involved in life activities such as cell proliferation, differentiation, metabolism, and apoptosis, and regulate physiological processes such as glucose metabolism, lipid metabolism, inflammation, and wound healing. Further, the changes in its expression are associated with various diseases, including breast cancer. The experimental reports related to "PPAR" and "breast cancer" were retrieved from PubMed since the discovery of PPARs and summarized in this paper. This review (1) analyzed the roles and potential molecular mechanisms of non-coordinated and ligand-activated subtypes of PPARs in breast cancer progression; (2) discussed the correlations between PPARs and estrogen receptors (ERs) as the nuclear receptor superfamily; and (3) investigated the interaction between PPARs and key regulators in several signaling pathways. As a result, this paper identifies PPARs as targets for breast cancer prevention and treatment in order to provide more evidence for the synthesis of new drugs targeting PPARs or the search for new drug combination treatments.

Keywords: ERs; PPARs; breast cancer; ligands.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Schematic representation of the principal domains of PPARs. PPARα, PPARβ, and PPARγ all have a modular structure that contains four domains: A/B domain, C domain, D domain, and E/F domain. The A/B domain contains an AF-1 region involved in the regulation of PPARs phosphorylation. The C domain is the DNA binding domain. The D domain is a hinge domain. The E/F domain contains an AF-2 region and is the RXR, ligand, and cofactor binding site.
Figure 2
Figure 2
PPARs-mediated gene regulation. PPAR forms a heterodimer with RXR and binds to the PPRE element of the target gene promoter. In the absence of ligand binding, the heterodimer recruits transcriptional corepressors such as NCoR and SMRT, as well as HDACs, to repress target gene transcription (A). Upon ligand binding, PPAR changes conformation, releases transcriptional repressor complexes, and recruits transcriptional coactivators such as RNAPII and HATs to promote target gene transcription (B). A/B, C, D, E/F: PPAR domains; PPRE: peroxisome proliferator response element; RXR: retinoid X receptor; NCoR: nuclear receptor corepressor 1; SMRT: nuclear receptor corepressor 2; HDACs: histone deacetylases; HATs: histone acetyltransferases; RNAPII: RNA polymerase II.
Figure 3
Figure 3
Agonist (A) and antagonist (B) secondary structures of PPARα.
Figure 4
Figure 4
Agonist (A) and antagonist (B) secondary structures of PPARβ/δ.
Figure 5
Figure 5
Agonist (A) and antagonist (B) secondary structures of PPARγ.
Figure 6
Figure 6
Schematic illustration of ligand-activated or ligand-independent PPARs affecting breast cancer progression. PPRE: peroxisome proliferator response element; Cyp1b1: cytochrome P450 1B1; RUNX2: Runt-related transcription factor 2; MTA1: metastasis-associated 1; CRL4B: Cullin 4B-Ring E3 ligase; PDK1: 3-phosphoinositide-dependent protein kinase 1; PTEN: phosphatase and tensin homolog; AKT: AKT serine/threonine kinase 1; GSK3β: glycogen synthase kinase 3β; mTOR: mechanistic target of rapamycin kinase; PI3K: phosphatidylinositol-4,5-bisphosphate 3-kinase; ERK: mitogen-activated protein kinase 1; DMBA: 7,12 dimethylbenzene(a)anthracene.
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This work was supported by grants (81872263) from the National Natural Science Foundation of China for Huijian Wu.
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