PPARG: A Promising Therapeutic Target in Breast Cancer and Regulation by Natural Drugs

Abstract

Breast cancer (BC) is the most common type of cancer among females. Peroxisome proliferator-activated receptor gamma (PPARG) can regulate the production of adipocyte-related genes and has anti-inflammatory and anti-tumor effects. Our aim was to investigate PPARG expression, its possible prognostic value, and its effect on immune cell infiltration in BC, and explore the regulatory effects of natural drugs on PPARG to find new ways to treat BC. Using different bioinformatics tools, we extracted and comprehensively analyzed the data from the Cancer Genome Atlas, Genotype-Tissue Expression, and BenCaoZuJian databases to study the potential anti-BC mechanism of PPARG and potential natural drugs targeting it. First, we found that PPARG was downregulated in BC and its expression level correlates with pathological tumor stage (pT-stage) and pathological tumor-node-metastasis stage (pTNM-stage) in BC. PPARG expression was higher in estrogen receptor-positive (ER+) BC than in estrogen receptor-negative (ER−) BC, which tends to indicate a better prognosis. Meanwhile, PPARG exhibited a significant positive correlation with the infiltration of immune cells and correlated with better cumulative survival in BC patients. In addition, PPARG levels were shown to be positively associated with the expression of immune-related genes and immune checkpoints, and ER+ patients had better responses to immune checkpoint blocking. Correlation pathway research revealed that PPARG is strongly associated with pathways, such as angiogenesis, apoptosis, fatty acid biosynthesis, and degradation in ER+ BC. We also found that quercetin is the most promising natural anti-BC drug among natural medicines that upregulate PPARG. Our research showed that PPARG may reduce BC development by regulating the immune microenvironment. Quercetin as PPARG ligands/agonists is a potential natural drug for BC treatment.

PPARG and the PTEN-PI3K/AKT Signaling Axis May Cofunction in Promoting Chemosensitivity in Hypopharyngeal Squamous Cell Carcinoma

“…PPARG also contributes to cell cycle dysregulation, related to chemosensitivity [ 34 , 35 ], and influences drug detoxification processes, affecting chemotherapy efficacy [ 36 , 37 ]. Moreover, PPARG's involvement in the inflammatory response is critical for determining chemosensitivity [ 38 , 39 ].…”

Oxidative Stress and the Nrf2/PPARγ Axis in the Endometrium: Insights into Female Fertility

“…Activation of STATs is mediated by Janus Kinases (JAKs) which are activated by IL-6 or leukemia inhibitory factor (LIF) binding to their receptors [139]. The activation of PPARγ has been shown to inhibit the transcription of STAT5 target genes, signifying a reciprocal negative regulation between PPAR and STAT pathways studied in breast cancer cells [140]. Therefore, PPARγ might inhibit P4 signalization during the secretory phase by trans-repression of STATs which results in the non-receptive endometrium or shift in WOI [137,139,140].…”

“…The activation of PPARγ has been shown to inhibit the transcription of STAT5 target genes, signifying a reciprocal negative regulation between PPAR and STAT pathways studied in breast cancer cells [140]. Therefore, PPARγ might inhibit P4 signalization during the secretory phase by trans-repression of STATs which results in the non-receptive endometrium or shift in WOI [137,139,140]. Additionally, PPARγ increases the expression of the suppressor of cytokine signaling (SOCS) protein which negatively regulates JAK/STAT signaling [141].…”

“…However, this mechanism remains to be fully confirmed by experimental data. In this context, the PPARγ/NLRP3 axis may indirectly inhibit EMT which is a necessary step in the implantation of blastocyst, in addition to already known inhibitory pathways of EMT by PPARγ [140,146].…”

Traditional Chinese Medicine for Breast Cancer: A Review

“…The Th1/Th2 ratio of tumor patients changes, which leads to inhibition of anti-tumor immune response, so that cancerous cells can survive and improve the appearance and progress of malignant tumors. Li and other researchers consider that the immune microenvironment has an essential part in the development and growth of BC, 104 closely associated with the PI3K/AKT and PD-1/PD-L1 signal transduction pathway and inhibits the progression of lymphoma. 96 They found that Xihuang pill can serially enhance IFN-γ and IL-2, inhibit IL-4 and IL-10, and modulate Th1/Th2 cell balance, improving the immune microenvironment.…”