PPARα, the first PPAR identified, is recognized as an orphan receptor activated by a variety of peroxisome proliferators. The PPARα was originally discovered in rodents and was named for its role in peroxisome proliferation [4]. On the other hand, PPARβ/δ and PPARγ were subsequently discovered and identified as cognate receptors that are activated by distinct peroxisome proliferators [24,52]. However, subsequent research proved that all PPARs fail to play a role in human peroxisome proliferation. PPARα is mainly expressed in metabolically vigorous cells with active fatty acid oxidation capacity, for example in skeletal muscle, brown fat, the liver, heart, and intestinal mucosal tissues [89]. PPARα is of considerable importance to glucose and lipid metabolism and the balance of transport in mammals. Its main function of maintaining lipid homeostasis is realized by increasing cell mobilization, promoting cell uptake, activation, oxidation, and decomposition of fatty acids, and generating ketone bodies for energy production [90]. The ligand-activated PPARα could also catalyze the hydroxylation of fatty acids. Hence, PPARα is the target of fibrates and hypolipidemic drugs for the treatment of abnormal lipid metabolism. The transcription of PPARα is up-regulated by fibrates, which enhance the lipolysis mediated by lipoprotein lipase, promote the oxidative decomposition of fatty acids, and achieve the curative effect of reducing total cholesterol and total triglycerides [91]. Fibrates are effective in increasing insulin sensitivity and protecting the cardiovascular system, so they are also widely used in the clinical treatment of diabetes and cardiovascular diseases [92].

In addition to regulating glucose and lipid metabolism, PPARα plays a role in various cancers. Long-term administration of PPARα agonists was reported as early as 1980 to cause liver cancer in rodents [93]. This effect of agonists was dependent on the receptor PPARα, as they (Wy-14,643 or bezafibrate) did not induce liver cancer in PPARα-null mice [94,95]. The pro-hepatocarcinogenesis effect of PPARα agonists was not evident in humans [96]. The species-specific mechanism of promoting hepatocarcinogenesis is that mouse-derived PPARα rather than human-derived PPARα down-regulated let-7C miRNA to increase the stability of its target gene MYC, an oncogenic factor. The increased expression of MYC promoted hepatocyte mitosis until carcinogenesis [97,98,99]. Some studies have shown increased expression of PPARα in endometrial cancer. Fenofibrate treatment significantly prevented the proliferation of endometrial cancer cells and promoted cell apoptosis [100]. However, other studies have also shown that PPARα knockdown inhibited the proliferation of endometrial cancer cells, promoted cell apoptosis, and reduced the secretion of the angiogenesis-related factor VEGF, while fenofibrate treatment also reduced the secretion of VEGF [101]. Since this contradictory phenomenon is not caused by nonspecificity to PPARα and cytotoxicity at the dose of fenofibrate [102], a possible explanation might be the biphasic response of PPARα activity, i.e., PPARα with very low activity and expression and PPARα with very high activity and expression producing the same effect, known as a U-shaped dose-response curve. PPARα was also aberrantly expressed in melanoma. Fenofibrate treatment inhibited the clone formation and migration abilities of melanoma cells and rendered them highly sensitive to staurosporine (a protein kinase C inhibitor with strong pro-apoptotic activity) [103].

Chang et al. found that, compared to adjacent normal tissues, PPARα and its natural ligand, arachidonic acid (AA), were significantly overexpressed in the tissues of breast cancer. The growth of three breast cancer cells, MDA-MB-231 (ER-), MCF7 (ER++++), and BT-474 (ER++), were stimulated by AA, with the most pronounced pro-proliferative effect on MCF7 cells, revealing a positive correlation between PPARα and the proliferation of ER+ breast cancer cells [104]. Human cytochrome P450 1B1 (CYP1B1)-mediated biotransformation of endogenous estrogens and environmental carcinogens promotes the progression of multiple hormone-dependent tumors, including breast cancer [105]. Hwang et al. found that Wy-14,643 increased CYP1B1 mRNA and protein levels in MCF7 cells and activated PPARα enhanced CYP1B1 promoter activity through directly binding to its PPRE elements [106]. In addition, Castelli et al. found that treatment of breast cancer stem cells with the specific PPARα antagonist GW6471 reduced cell proliferation, viability, and spheroid formation, resulting in metabolic dysfunction and apoptosis [107]. The above experiments in vitro all suggest that PPARα functions in promoting the development of breast cancer. However, Pighetti et al. found that treatment with Wy-14,643 inhibited the ability of DMBA to induce breast tumor formation in rats and induced tumor volume regression [108]. Chandran et al. showed that clofibrate treatment activated the PPARα transcriptional activity and exerted an anti-proliferative effect on breast cancer cells by regulating the levels of tumor suppressors, cell cycle inhibitors, and cell to cycle checkpoint kinases, causing cells to arrest in the G0/G1 phase and significantly inhibiting cell growth. In addition, activated PPARα reduced the expression of inflammatory pathway-related enzymes and their receptors, reduced the protein levels of lipogenic enzymes, regulated the fatty acid oxidation associated gene expression, and affected various lipid metabolism pathways [109]. Yin et al. found that Runt-related transcription factor 2 (RUNX2), with high expression in breast cancer, recruited metastasis-associated 1 (MTA1)/NuRD and the Cullin 4B (CUL4B)-Ring E3 ligase (CRL4B) complex to form a ternary complex. This complex catalyzed histone deacetylation and ubiquitination, inhibited the transcriptional activity of target genes, including PPARα, and promoted the proliferation and invasion of breast cancer cells in vitro. These physiological processes finally led to breast cancer occurrence, bone metastasis, and tumor stemness in vivo (Table 2) [110]. The above findings indicate that PPARα plays a role as a tumor suppressor in breast cancer.

PPARα was generally highly expressed in human primary inflammatory breast cancer cells SUM149PT (3.9-fold higher than primary human breast epithelial cells HMEC) and highly invasive breast cancer cells SUM1315MO2 (3.7-fold higher than HMEC cells) and in human breast tumor tissue (2–6-fold higher than adjacent normal tissues) [109]. The correlation between PPARα and breast cancer is worth further investigation.

Among the three subtypes of PPARs, PPARβ/δ exhibits higher evolutionary efficiency [4]. In addition, uncoordinated PPARβ/δ also showed more potent transcriptional repression activity. Compared with uncoordinated PPARβ/δ, unligated PPARα and PPARγ do not inhibit PPRE-mediated transcription, which is possibly due to their inability to bind to the nuclear receptor corepressors such as SMRT and NCoR [111]. This relatively rapid rate of evolution and more potent transcriptional repression activity underscore the importance of investigating PPARβ/δ function. The PPARβ/δ are referred to as HUC-1 in humans [112], fatty acid-activated receptors (FAAR) in mice [113], and PPARδ in rats [114]. The PPARβ/δ are widely expressed in most tissues, and their expression level is often higher than that of PPARα and PPARγ. This widespread expression proves its importance in systemic activities and basic cell functions [52,115]. The high baseline expression of PPARγ, especially in the gastrointestinal tract and skeletal muscle, reveals the critical role of PPARβ/δ in fatty acid oxidation and obesity prevention [116]. PPARβ/δ is specific and diversified in cell fate. It can activate housekeeping genes and regulate energy metabolism. In addition, the endogenous natural ligands of PPARβ/δ are very broad and non-specific. The ability of these ligands to activate PPARβ/δ is relatively weak. Therefore, the physiological function of PPARβ/δ is difficult to simplify. Without ligand binding, PPARβ/δ degrades fast, while ligand binding inhibits ubiquitin-proteasome activity, thereby extending its half-life [117,118]. This phenomenon may also be attributed to ligand-induced PPARβ/δ expression [119]. Ligand-activated PPARβ/δ could increase the levels of serum high-density lipoprotein cholesterol, decrease the levels of serum triglycerides in mice [60], non-human primates [62], and humans [120], and improve the metabolic syndrome such as obesity and insulin resistance induced by a high-fat diet or genetic predisposition [116,121]. Inhibition of insulin resistance by activated PPARβ/δ might also improve progressive neurodegeneration and its associated learning and memory deficits and prevent Alzheimer’s disease [122,123]. In addition, PPARβ/δ also have considerable preventive or therapeutic capacity against genetic [124], diet [125], or chemically induced [126] liver inflammation.

The above evidence supports the development of PPARβ/δ specific agonists acting as clinical drugs for the treatment of diseases such as obesity, diabetes, metabolic syndrome, and liver inflammation. However, the synthesis of PPARβ/δ-targeted drugs has encountered significant obstacles related to clinical safety due to substantial controversy regarding the reports on the role of PPARβ/δ in cancer [127,128]. Ligand-activated PPARβ/δ could promote terminal differentiation of keratinocytes [129], enhance lipid deposition [130], inhibit cell proliferation [131], and inhibit the progression of skin cancers such as psoriasis. However, it has also been shown that transgenic mice that induced activation of PPARβ/δ in the epidermis developed an inflammatory skin disease strikingly similar to psoriasis. These mice were characterized by hyperproliferation of keratinocytes, aggregation of dendritic cells, and endothelial cell activation. The gene dysregulation and activation of key transcriptional programs and Th17 subsets of T cells in transgenic mice were also highly similar to psoriasis [132]. In addition, PPARβ/δ activated by UV stimulation directly promoted the expression of oncogene Src and upregulated its kinase activity, enhanced the EGFR/ERK1/2 signaling pathway, and promoted epithelial-mesenchymal transition (EMT), which promotes keratinocyte differentiation and proliferation [133]. This result also reveals the cancer-promoting effect of PPARβ/δ on skin cancer. A possible and one-sided explanation for this contradiction was that activation of PPARβ/δ existed both in keratinocytes and adjacent fibroblasts. The PPARβ/δ in fibroblasts inhibited IL-1 signaling by directly upregulating the expression of secreted interleukin-1 receptor antagonist (sIL-1ra), thereby regulating keratinocyte proliferation [134]. In addition to skin cancer, the PPARβ/δ also have a controversial role in colorectal cancer [40,135,136].

Human genome PPARβ/δ is located at 6p21.2, an increased site for ER- and high-risk breast cancer [137], which reveals the correlation between PPARβ/δ and breast cancer. PPARβ/δ was highly expressed in the nucleus in human normal breast epithelial cells and weakly expressed or even absent in 92% of human breast lobular and ductal cancer cells [138,139,140]. The expression of PPARβ/δ in mouse malignant breast cancer cells C20 was also significantly lower than that in mouse keratinocytes (nearly 4-fold) and human normal mammary epithelial cells MCF10A (more than 2-fold) [141]. The patients’ survival rate with breast cancer and the expression of PPARβ/δ have a negative correlation [142]. In 2004, Stephen et al. reported for the first time that PPARβ/δ activated by specific ligand compound F or GW501,516 could promote the proliferation of ER+ breast cancer cells MCF7 and T47D. It could also promote in T47D cells vascular endothelial growth factor α (VEGFα) and its receptor FLT-1 and encourage the proliferation of human umbilical vein endothelial cells (HUVEG) in vitro. However, activated PPARβ/δ did not exert similar effects on ER- breast cancer cells MDA-MB-231 and BT-20, revealing that the pro-proliferative and pro-angiogenic effects of PPARβ/δ on breast cancer are dependent on ER [143]. Conversely, in 2008, Girroir et al. reported that PPARβ/δ was activated by specific ligands (GW0742 or GW501,516) and inhibited the growth of MCF7 cells [144]. In 2010, Foreman et al. reported that PPARβ/δ activated by the above two ligands also inhibited proliferation and clone formation and promoted apoptosis in mouse C20 cells [141]. Additionally, in 2014, Yao et al. reported that the overexpression of PPARβ/δ prevented the proliferation of breast cancer cells, MDA-MB-231 and MCF7, while the treatment of the agonist GW0742 further inhibited the proliferation of MCF7 cells without any effect on the MDA-MB-231 cells. The overexpression of PPARβ/δ inhibited the clone formation of these two cell lines, while further treatment with GW0742 inhibited the clone formation of MDA-MB-231 cells significantly more than that of MCF7 cells. However, the overexpression or ligand-activated of PPARβ/δ did not affect apoptosis in either of the two breast cancer cell lines. Further, the overexpression of PPARβ/δ could inhibit the growth of xenograft tumor in MDA-MB-231 cells better than in MCF7 cells, and treatment with GW0742 further inhibited the volume of mouse xenografts [145]. These findings, although inconsistent with Stephen’s report [143], also confirm that the effects of PPARβ/δ on ER+ and ER- breast cancer cells were different. However, by real-time analysis of cell doubling time, Palkar et al. found that neither GW0742-activated nor highly specific irreversible antagonist GSK3787 inhibited PPARβ/δ had effects on the proliferation of MCF7 cells, despite the fact that both of them had the converse effect on the mRNA level of PPARβ/δ target gene Angptl4 in vitro and in vivo [30]. Additionally, although these disparate results may be attributed to the concentration of ligands used, cell treatment time, cell proliferation assessment methods, etc., the exact function of PPARβ/δ on breast cancer cell apoptosis and proliferation remains unclarified so far. Several experiments are required to reach consensus.

Retinoic acid (RA) as a tumor suppressor exhibits potent anticancer activity mediated by the nuclear retinoic acid receptor (RAR). The intracellular lipid-binding protein cellular retinoic acid-binding protein II (CRABP-II) targets RA to the RAR, while another lipid-binding protein, fatty acid binding protein 5 (FABP5), could deliver it to the non-canonical RA receptor PPARβ /δ. The FABP5/CRABP-II ratio determines the partition of RA between the two receptors. Noy’s team constructed two breast cancer MMTV-neu transgenic mouse models expressing different FABP5/CRABP-II ratios in breast tissue. It was observed that transgenic mice with a high FABP5/CRABP-II ratio produced larger breast tumors. On the contrary, the reduction of this ratio resulted in the suppression of breast tumor growth and gene expression, including PDK1 and cell proliferation-related genes, through the transfer of RA signaling from PPARβ/δ to RAR. This study proposes a new mechanism by which PPARβ/δ promote breast cancer [152]. Additionally, the epidermal growth factor receptor (EGFR) as a tumor-promoting factor can promote breast cancer cell proliferation and induce breast tumorigenesis. Noy’s team also found that treatment of MCF7 cells with the EGFR ligand heregulin-β1 could directly upregulate the expression of FABP5 and PDK1. The results indicated that FABP5 and PPARβ/δ were the key mediators of EGFR’s ability to enhance cell proliferation, further confirming that PPARβ/δ acted as a tumor-promoting factor playing a role in breast cancer [153]. However, studies on human keratinocyte HaCaT found that FABP5 neither delivered RA to PPARβ/δ nor promoted anti-apoptotic activity by upregulating PDK1 levels. This phenomenon was also identified in HaCaT cells that stably overexpress PPARβ/δ [154]. The above results suggest that the cancer-promoting effect of RA-mediated PPARβ/δ may be specific to breast cancer [155]. Wang et al. found that PPARβ/δ could promote the survival of MCF7 cells under rough microenvironmental conditions by reducing oxidative stress and promoting AKT-mediated survival signaling [156]. The correlation between PPARβ/δ and PDK1 is currently controversial. Although the above studies have found that the expression levels of the two are correlated, there are also studies showing that PDK1 is not a target gene of PPARβ/δ [136,155,157]. In addition to the research around the effect of PPARβ/δ on the proliferation and apoptosis of breast cancer cells, scholars have found that PPARβ/δ also has an effect on the invasion and metastasis of breast cancer cells. Adhikary found that PPARβ/δ, specifically antagonized by ST247 and DG172, inhibited serum and transforming growth factor β (TGFβ)-induced invasion of MDA-MB-231 cells [158]. However, Wang uncovered that the PPARβ/δ expression levels in more metastatic breast cancer basal cell lines were significantly higher than those in luminal cells. Additionally, after the inoculation with MCF7 cells overexpressing PPARβ/δ, the breast tumor volume and lung metastasis of mice increased significantly (Table 3) [156]. In conclusion, the exact role of PPARβ/δ on breast cancer still requires more experimental studies.

PPARγ1 and PPARγ2 are two isoforms of PPARγ, that were found in mice. The PPARγ2 mRNA was the predominant PPAR isoform in mouse mammary tissues [159]. In humans and monkeys, in addition to PPARγ1 and PPARγ2, a third isoform of PPARγ4 was found. These isoforms are the transcripts of seven mRNA spliceosomes (PPARγ1, PPARγ2, PPARγ3, PPARγ4, PPARγ5, PPARγ6, and PPARγ7) from the different transcription start sites, which are transcribed through alternative splicing of exons in the 5’-terminal region (A1, A2, B, C, and D) [160]. The PPARγ1, PPARγ3, PPARγ5, and PPARγ7 mRNAs translate into the same protein, PPARγ1, while PPARγ2 mRNA translates into PPARγ2 protein, whereas PPARγ4 and PPARγ6 mRNAs translate into the same PPARγ4 protein. PPARγ1 is expressed in almost all tissues, with the highest level in white and brown adipose tissues. Under normal physiological conditions, the larger PPARγ2 isoform (with additional amino acids at the amino-terminal of PPARγ2, 30 in mice and 28 in humans) is only expressed in brown and white adipose tissue, whereas its expression in the liver and skeletal muscle is caused by excessive caloric intake or genetic obesity. PPARγ4 is under-researched and expressed in macrophages and adipose tissues [161,162,163]. PPARγ widely expressed in white and brown adipose tissues, the large intestine, and the spleen. However, PPARγ is also found in the liver, pancreas, and tissues of the immune system [164]. A considerable number of studies have confirmed that ligand-activated PPARγ could regulate fat distribution and glucose and lipid metabolism [165] and reduce the inflammatory response of cardiovascular cells, especially endothelial cells [166]. Its specific agonist is relatively effective in the treatment of hyperlipidemia, hyperglycemia, and cardiovascular disease [167]. The specific agonists of PPARγ, i.e., TZDs, are clinical drugs currently on the market as insulin sensitizers for the treatment of type 2 diabetes, targeting PPARγ to exert a hypoglycemic effect. The antidiabetic activity of TZDs was first discovered in the early 1980s [168,169,170,171]. PPARγ is also involved in neural differentiation during the formation of neural precursor cells [83]. Therefore, its specific agonists could also act as protective agents for neurons, inducing synaptic plasticity and neurite outgrowth, and improving the symptoms of some neurological diseases [172]. In addition to the above effects, a large number of reports also pointed out that ligand-activated PPARγ exerts anti-tumor effects by promoting cell apoptosis and preventing cell proliferation, regulating cell metastasis, and stimulating angiogenesis, thereby inhibiting the occurrence and development of tumors of the liver [173], bladder [174], lung [175,176], brain [177], thyroid [178], esophagus [179] and colorectum [180,181,182,183].

PPARγ also plays a role in breast cancer progression. In 1998, it was reported that TZD-activated PPARγ could induce terminal differentiation of malignant mammary epithelial cells in vitro [184]. However, in 1999, researchers found that ligand-activated PPARγ could prevent the development of experimental breast cancer in vivo. The report showed that GW7845 as an activator of PPARγ significantly inhibited nitrosomethylurea (NMU)-induced mammary tumor incidence, tumor number, and tumor weight in rats [79]. Subsequent reports of ligand-activated PPARγ inhibiting breast cancer development have experienced a rise. A 2001 study showed that TGZ inhibited DMBA-induced mammary tumor progression in rats, reduced malignancy incidence, and induced regression or stasis of total tumor volume [108]. A study in 2009 showed that the conjugated fatty acid α-eleostearic acid (α-ESA) could act as an agonist of PPARγ, upregulating the level of PPARγ mRNA in MCF7 cells, upregulating PPARγ’s DNA binding activity and transcriptional activity, and mediating PPARγ nuclear translocation, thereby reducing MCF7 cell viability and promoting tumor cell apoptosis. At the same time, α-ESA-induced high PPARγ expression was associated with an inhibitory effect on ERK1/2 MAPK phosphorylation activation. This suggests that pERK1/2 might play a negative regulatory role on PPARγ levels [185]. Bonofiglio’s team discovered an important pathway for PPARγ in human breast cancer cell growth, cycle arrest, and apoptosis. RGZ-activated PPARγ inhibits the PI3K/AKT pathway and induces the antiproliferative effect of MCF7 cells [186]. RGZ also increased the binding of PPARγ to the NF-κB sequence on the promoter sequence of p53, upregulated the expression level of p53 in MCF7, induced caspase 9 cleavage and DNA fragmentation, triggered the apoptotic pathway, stopped the growth, and promoted apoptosis of breast cancer cells [187]. Furthermore, in several breast cancer cell lines, RGZ activated the human Fas ligand (FasL) promoter in a PPARγ-dependent manner, increased the binding of PPARγ with Sp1 to the Sp1 sequence located within the FasL promoter, and positively regulated FasL expression [188]. FasL is a type II transmembrane protein expressed on the membrane surface of activated T lymphocytes and cancer cells. By binding to its receptor Fas [189,190], it activates the cascade of caspases and induces apoptosis [191]. These studies reveal a novel molecular mechanism by which PPARγ induces growth arrest and apoptosis in breast cancer cells. An in vivo study in 2011 showed that TZD-activated PPARγ inhibited MAPK/STAT3/AKT phosphorylation-mediated leptin signaling in MCF7 cells. On one hand, this effect led to the inhibition of MCF7 xenografts through the counteraction of the stimulatory effects of leptin on estrogen signaling. On the other hand, it inhibited leptin-induced cell-cell aggregation and tumor cell proliferation, exerting pro-apoptotic and anti-proliferative effects on breast cancer cell lines [192].

In addition to its ligand-activated state, PPARγ also involves itself in the development of breast cancer in a non-ligand-independent manner. The PPARs and ERα are both members of the nuclear receptor superfamily. The ERα signaling pathway has a critical role in metabolism regulation and various physiological processes in the development of breast cancer [210,211]. Bonofiglio’s team found for the first time that ERα could bind to the PPRE element to inhibit its mediated transcriptional activity independently of PPARs. Interestingly, PPAR/RXR heterodimers could also bind to the ER response element (ERE) independently of ERs [212]. PPARγ physically interacted with ERα to form a ternary complex with a regulatory subunit of PI3K and p85. PPARγ and ERα played opposite roles in the regulation of PI3K/AKT signaling, which involves cell survival and proliferation [186]. The crosstalk between the PPARγ and ERα signaling pathways revealed the important role of PPARγ in the development of ER+ breast cancer. Since PPARγ-null mice are embryonic lethal, scientists have developed other ways to create transgenic animal models that silence PPARγ. Yin et al. investigated the susceptibility of PPARγ inactivation to MPA- and DMBA-induced breast cancer in mice by constructing an MMTV-Pax8PPARγ transgenic mouse model. In the absence of induction, the mammary glands of transgenic and wild-type mice did not differ in functional development or propensity for tumor formation, a finding consistent with Cui et al.’s [213]. However, after being induced by MPA and DMBA, transgenic mice developed higher tumor diversity than wild-type mice. These tumors were predominantly ER+ ductal breast cancers, further revealing the role of PPARγ in the development of ER+ breast cancer. The decrease in PTEN expression, the induction of pERK1 and pAKT levels, and decreasing pGSK3β level, Pax8PPARγ promotes Wnt signaling [214]. However, in constructing transgenic mice with constitutively active forms of MMTV-VpPPARγ, Saez et al. found that activation of PPARγ signaling did not affect mammary gland development in transgenic mice, which had no phenotypic difference with wild-type mice. On the other hand, when such transgenic mice were crossed with breast cancer-prone transgenic MMTV-PyV mice, the progeny biogenic mice developed tumors much faster and with a higher degree of malignancy and differentiation of the tumors. This molecular mechanism for promoting breast cancer development might also be attributed to the promotion of PPARγ on the Wnt signaling pathway [215]. Tian et al. conducted a parallel experiment on immunocompetent FVB mice, with one group of implanted tumor cells transduced with wild-type PPARγ, and the other with constitutively active PPARγCA. They found that the growth of mammary tumors in mice implanted with PPARγCA-transduced cells was enhanced, which was correlated with endothelial stem cells and angiogenesis increasing. PPARγCA induced ErbB2-transformed mammary epithelial cells to secrete Angptl4 protein, which enhanced angiogenesis in vivo and promoted tumor growth [216]. The above studies based on animal models reveal the contradictory roles (either inhibiting or promoting) of PPARγ in the occurrence and development of breast cancer. The potential reasons for this discrepancy remain to be investigated. The possible causes could be traced to the differences in the construction of animal models or the difference in the length of experimental periods. In addition, a 2019 study showed that PPARγ directly bound to the PPRE element of the protein tyrosine phosphatase receptor-type F (PTPRF) promoter and recruited RNA polymerase II and H3K4me3 to promote the transcription of PTPRF. These processes inhibited breast cancer cell proliferation and migration in vitro and inhibited breast tumor growth and distant metastasis in mice [217]. A 2020 experiment in vitro showed that PPARγ, which is commonly expressed in human primary and metastatic breast cancer [218], interacted with Nur77, recruited the ubiquitin E3 enzyme Trim13 to target the ubiquitin proteasomal degradation of Nur77, and promoted breast cancer progression. Nur77, a tumor suppressor, inhibits breast cancer cells from uptaking exogenous fatty acids and blocks the accumulation of fatty acids in the tumor metabolic microenvironment by inhibiting the transcription of the transmembrane protein CD36 and the cytoplasmic fatty acid-binding protein FABP4. Therefore, blocking the interaction between PPARγ and Nur77 can be used as a clinical approach for PPARγ ligand-independent treatment of breast cancer (Table 4) [219]. However, due to the relatively high concentrations of endogenous natural ligands in cells, it remains to be verified whether these conclusions are truly ligand-independent of PPARγ.

In 2005, an immunohistochemical test of 170 patients with invasive breast cancer showed that the expression of PPARγ was negatively associated with histological grade (p = 0.019). PPARγ had a significantly favorable effect on recurrence-free survival in breast ductal carcinoma patients (p = 0.027) and was an independent prognostic factor in ductal carcinoma patients (p = 0.039) [220]. In 2008, a study presented that the nuclear expression of PPARγ had a preventive effect on the recurrence of female breast ductal carcinoma in situ. Its expression level was negatively correlated with tumor recurrence (p = 0.024) [221]. These clinical research studies and the above experimental results reveal the important function of PPARγ in the occurrence and development of breast cancer. The overexpression of PPARγ in breast tumors and the physiological effects of its ligands on breast cancer cells indicate that PPARγ will be a possible target in breast cancer clinical prevention and treatment.

TNBC, the most aggressive subtype of breast cancer, has no effect on hormone therapy or HER2-targeted therapy due to its lack of the three receptors. Surgery or chemotherapy, the only viable option, is a systemic therapy that causes not only physical distress but a poor prognosis for TNBC patients [222]. Therefore, it is very necessary to explore new treatment methods or target drugs to improve the prognosis of TNBC. Li et al. found that the PPARα-specific agonist fenofibrate had anti-proliferative effects on breast cancer cell lines, and the top 5 most sensitive cells are all TNBC cell lines [223]. Kwong found that fatty acid binding protein 7 (FABP7) failed to induce the efficient use of glucose to generate ATP in the TNBC cell line Hs578T during serum starvation, eventually leading to cell death. This metabolic effect of FABP7 on Hs578T cells was mediated by PPARα [224]. Studies by Stephen’s group showed that PPARβ/δ activated by GW501,516 could promote the proliferation of MCF7 and T47D cells, but it had no similar effect on the TNBC cell lines MDA-MB-231 and BT-20 [143]. The expression level of PPARβ/δ in highly aggressive basal cells was significantly higher than that in luminal cells [156]. In addition, Adhikary’s team found that ST247 and DG172 specifically antagonized PPARβ/δ strongly inhibited the invasion ability of MDA-MB-231 cells induced by serum and TGFβ [158]. Jiang’s team found that the expression of PPARγ in the breast tissues of TNBC patients was significantly lower than that of other subtype patients, and its expression in MDA-MB-231 cells was also significantly lower than that of other breast cancer cell lines. Previous studies have reported that the PPARγ-specific agonist RGZ had antitumor effects in breast cancer. However, it did not exert significant anti-proliferative effects on MDA-MB-231 cells. RGZ combined with the demethylation agent hydralazine significantly inhibited the proliferation of MDA-MB-231 cells and promoted cell apoptosis [200]. Apaya et al. showed that epoxy-eicosatrienoic acid (EET) induced the nuclear translocation of FABP4 and FABP5 in MDA-MB-231 cells, thereby promoting the nuclear accumulation of PPARγ and affecting cell proliferation and migration [225]. These results reveal the important roles of all three subtypes of PPARs and their ligands in TNBC and suggest that more attention should be directed to drug combination therapies against TNBC.