Abstract
Peroxisome proliferator-activated receptor gamma agonists have been proposed as breast cancer preventives. Individuals who carry a mutated copy of BRCA1, DNA repair-associated gene, are at increased risk for development of breast cancer. Published data in the field suggest there could be interactions between peroxisome proliferator-activated receptor gamma and BRCA1 that could influence the activity of peroxisome proliferator-activated receptor gamma agonists for prevention. This review explores these possible interactions between peroxisome proliferator-activated receptor gamma, peroxisome proliferator-activated receptor gamma agonists and BRCA1 and discusses feasible experimental directions to provide more definitive information on the potential connections.
Interactions between PPARG and BRCA1
BRCA1, DNA repair-associated gene (BRCA1), is one of the most highly associated cancer susceptibility genes, principally with breast and ovarian cancer (Turnbull et al. 2018). Currently recommended preventive strategies are primarily surgical (Ludwig et al. 2016, Andrews & Mutch 2017) with evaluation of the relative effectiveness of the lifestyle-driven (Lammert et al. 2018) and hormonal approaches used, more generally, for reduction of breast cancer risk (Pujol et al. 2012, Phillips et al. 2013, Dabydeen et al. 2015, Alothman et al. 2017) considered more investigational.
Molecular studies have identified dysregulation of TNF receptor superfamily member 11a (RANK)/TNF superfamily member 11 (RANKL) and nuclear factor NF-kappa-B p105 subunit (NFKB1) as possible intersecting pathways with BRCA1 mutation-related breast cancer pathophysiology that may be approachable with pharmacologic chemoprevention (Sigl et al. 2016, Kotsopoulos et al. 2017, Nolan et al. 2017).
Questions arise as to other possible interacting signaling pathways in cancer prevention. Peroxisome proliferator-activated receptor gamma (PPARG), a member of the PPAR family of nuclear hormone transactivators, functions as a heterodimer with retinoid X receptor in normal physiology and development (Derosa et al. 2018). It has been characterized as a potential therapeutic target for cancer therapy and prevention (Yun et al. 2018).
PPARG ligands have been variously considered as potential chemopreventives as well as cancer therapeutics (Peters et al. 2012). This class of drugs is also considered for treatment of diabetes and cardiovascular disease. Considerations of relative efficacy vs potential side- and off-target effects have not only tempered enthusiasm for the drug class but also stimulated the synthesis and investigation of new generation PPARG therapeutic ligands and inhibitors (Ahmed et al. 2007, Rubenstrunk et al. 2007, Youssef & Badr 2013, Chandra et al. 2017). Phase 1 studies of efatutazone, a more recently developed and highly selective peroxisome proliferator-activated receptor gamma (PPARγ) agonist that can be delivered orally, demonstrated an acceptable safety profile for cancer therapy, alone and in combination with other drugs (Pishvaian et al. 2012, Esteva et al. 2013, Smallridge et al. 2013, Komatsu et al. 2014, Murakami et al. 2014). Rosiglitazone was investigated in a pilot study in breast cancer where safety and systemic biological activity were documented, but there was no significant evidence of efficacy (Yee et al. 2007).
Experimental animal in vivo studies have yielded mixed results on efficacy for cancer chemoprevention with a PPARG agonist. It is challenging to derive a clear answer from these investigations as studies have been performed in a diverse range of rodent cancer models, employed different PPARG agonists, utilized a variety of dosing schedules and were not always investigated as single agents. In addition, pharmacological intervention is initiated at different time points relative to cancer initiation and study durations are mixed. Positive impacts provide support for the principle of PPARG agonist chemoprevention (Kocdor et al. 2009, Li & Brown 2009, McCormick et al. 2015, Ory et al. 2018) but when significant effects are limited to hyperplasia and/or preneoplasia, alterations in cancer histology and/or mean tumor volume, there is less enthusiasm (Borbath et al. 2007, Wu et al. 2008, Skelhorne-Gross et al. 2012, Nakles et al. 2013, Bojková et al. 2016, Alothman et al. 2018). Occasional published studies report no effect at all (Yee et al. 2005).
In breast cancer prevention research one of the most highly targeted groups for development of new therapeutic approaches is women carrying a BRCA1 mutation. In vitro and in vivo molecular and genetic research provide potential intersecting points for BRCA1 and PPARG pathways, raising the possibility that BRCA1 status could influence response to therapy. Some (Pignatelli et al. 2003, Subbaramaiah et al. 2012, Apostoli et al. 2015), but not all (Rogue et al. 2010), published data indicates that BRCA1 expression can be increased by PPARG agonist therapy. Loss of PPARG in mammary adipocytes is reported to reduce Brca1 expression (Skelhorne-Gross et al. 2012). It has been suggested that PPARG agonists could reduce mammary cancer development through inhibition of aromatase expression that would be, at least in part, mediated through PPARG agonist driven Brca1 upregulation (Margalit et al. 2012).
From the other side, PPARG expression is reported upregulated specifically in BRCA1 mutant breast cancers (Heublein et al. 2017). When qualitatively assessed by immunohistochemistry at the protein level, PPARgamma remains detectable at the protein level in normal-appearing mammary epithelial cells with Brca1 exon 11 deletion in combination with Trp53 germ-line haploinsufficiency, with a relative increase and more uniform expression in adenocarcinomas (Nakles et al. 2013). One Phase 1 study showed that higher levels of PPARG correlate with an enhanced therapeutic response to the PPARG agonist efatutazone (Pishvaian et al. 2012) although this observation was not replicated in a second study (Komatsu et al. 2014). Interestingly, at the RNA level, loss of full-length Brca1 exon 11 in non-cancer cells is correlated with significantly decreased Pparg expression in cardiac muscle and whole mammary gland (Singh et al. 2013, Dabydeen et al. 2015).
Conclusions
In summary, it is not yet clear whether or not interactions between PPARG and BRCA1 modify the impact of a PPARgamma agonist used as a breast cancer chemopreventive. The PPARg agonist efatutazone is effective in significantly reducing mammary hyperplasia in mice with targeted deletion of Brca1 exon 11 in mammary epithelial cells, but there is no profound effect on invasive cancer incidence (Nakles et al. 2013, Alothman et al. 2018). However, preservation of one intact Brca1 allele is sufficient to significantly improve the preventive response. More uniformly positive effects from PPARG agonist exposure are reported in in vivo models of mammary cancer with two intact Brca1 genes (Kocdor et al. 2009, Ory et al. 2018). This could be an indication that initial levels of endogenous BRCA1 impact therapeutic response; however, this question still needs to be directly and specifically investigated in order to make a definitive statement (Fig. 1A). For example, therapeutic preventive response could be evaluated in a series of mouse models that develop mammary preneoplasia and cancer in the presence of two intact Brca1 genes as well as with one and two Brca1 alleles, perhaps in both the presence and absence of p53 heterozygosity, to evaluate the impact of specific genetic gain/loss determinants on response to efatutazone. Mammary-targeted Esr1 and CYP19A1 overexpression models are possible human pathophysiologically paralleled experimental directions to build Brca1 deletion models on to explore this question (Jones et al. 2008, Alamri et al. 2016). Polyoma middle T (PyMT), Wnt, HER2/Neu and simian virus 40 T antigen (TAg) overexpression models are opportunities to pursue studies of metastatic disease and interactions with other cancer-linked signaling pathways (Tilli et al. 2003, Fantozzi & Christofori 2006). The same ductal carcinoma in situ human xenograft model used to demonstrate efatutazone efficacy (Ory et al. 2018) could be re-tested with cells engineered to interrupt Brca1 expression or introduce specific clinically relevant mutations.
Questions to address for a more comprehensive understanding of peroxisome proliferator-activated receptor gamma and BRCA1 interactions. (A) Schematic illustrating the possibility that reduced levels of BRCA1 indicated by the vertical gradient of white to blue might influence the response to a PPARG agonist as indicated by the corresponding vertical gradient of white to orange labeled. (B) Schematic illustrating how the impact of a possible increase in BRCA1 expression levels indicated by the horizontal white to blue gradient mediated by exposure to a PPARG agonist could be determined to be related or unrelated to downstream PPARG agonist activity by experimentally blocking the BRCA1 increase. (C) Schematic illustrating the possibility that reduced BRCA1 levels indicated by the horizontal blue to white gradient could correspond to reduced PPARG levels indicated by the horizontal green to white gradient resulted in a reduced response to a PPARG agonist indicated by the horizontal orange to white gradient.
Citation: Endocrine-Related Cancer 26, 2; 10.1530/ERC-18-0449
A second question is whether or not upregulation of normal full-length BRCA1 expression levels contribute to PPARG agonist efficacy (Fig. 1B). Before this question can be clearly answered, researchers, however, need to establish whether or not BRCA1 expression is, in fact, uniformly and reproducibly upregulated by PPARG agonists. A related issue is whether or not levels of normal BRCA1 expression are sufficiently upregulated when a second allele contains a BRCA1 mutation, as occurs in the clinical setting. At present BRCA1 expression levels have not been uniformly reported in published studies of PPARG agonist therapy; however, it is possible that potential publication bias against negative or less marked results could have influenced reporting (Diaz-Cruz et al. 2006, Mlinarić et al. 2017). Disparate results that may have been found could be due to differences between the pharmacology of specific PPARG agonists, dose and schedule, timing of measurement and even acquired differences between cell lines or incorrect cell line identification as authentication of cell lines has only more recently been recognized as an important component of experimental design (Almeida et al. 2016). Even after recognizing all these challenges, from an experimental point of view, it is still feasible to design a mechanistic experiment using a panel of relevant normal, premalignant and malignant mammary human epithelial cell lines and primary cells to compare reproducibility of BRCA1 upregulation in different experimental reagents, establish if there are dose–response relationships, and evaluate both short- and longer-term exposures. Once optimal clinically relevant conditions are established, one could then test if blocking BRCA1 upregulation would modify impact of PPARG agonist therapy. In cell lines and primary material theoretically this could be accomplished with either genetic deletion of BRCA1 or siRNA or related approaches with read-out of PPARG agonist activity centering on downstream genes and signaling pathways as well as cellular morphology and behavior.
A third question is whether or not loss of normal BRCA1 function and/or expression impact PPARG expression levels (Fig. 1C). Published data are insufficient to answer this question as seemingly conflicting initial studies reporting reduced expression in cardiomyocytes and mammary tissue (Singh et al. 2013, Dabydeen et al. 2015) with loss of full-length Brca1 and increased levels in human breast cancers carrying a BRCA1 mutation (Heublein et al. 2017) have not yet been rigorously reproduced. Theoretically both observations could be true as loss of full-length Brca1 is not the same as BRCA1 mutation, the former studies are in mouse tissues and the later in human tissue, and RNA was examined in the mice and protein in the humans but additional work examining both RNA and protein are needed to clarify the issues. BRCA1 can play a role in transcriptional regulation (Mullan et al. 2006). Understanding the biology could be significant as there have been some suggestions that higher levels of PPARG expression could serve as a biomarker predictive of a positive response to a PPARG agonist (Pishvaian et al. 2012). An interesting speculation is whether or not a PPARG-mediated increase in BRCA1 expression levels could secondarily be associated with increased PPARG expression levels that would then contribute to an enhanced response to a PPARG agonist. The impact of BRCA1 deletion on PPARG mRNA and protein expression could be approached utilizing a panel of mammary epithelial cell lines and primary cells representing human normal, premalignant and malignant cells to assess both if PPARG expression levels are altered by loss of mutation of BRCA1, and if this occurs reproducibly across different cell lines and stages of cancer development.
Appropriate experimentation in human tissues and in vitro and in vivo model systems is merited when the promise of current therapeutic PPARG agonists is sufficiently convincing (Ferrari et al. 2016, Wang et al. 2016, Vella et al. 2017). The impact of specific BRCA1 variants on PPARG expression levels, signaling and downstream gene regulatory networks could be assessed with specific mutation and variant targeting (Findlay et al. 2018). Experiments focusing on the impact of functional BRCA1 haploinsufficiency in the presence of different mutations could be performed (Sedic & Kuperwasser 2016). Biological effects of known PPARG functions related to cell growth and differentiation could be stringently examined in the presence and absence of BRCA1. Measurements of downstream gene regulatory networks that follow PPARG activation could be evaluated and compared to determine if there were significant differences correlated with Brca1 gene dosage in murine cancer prevention models (Savic et al. 2016, Alothman et al. 2017, 2018).
There are additional questions that could also be approached. For example, the majority of published data to date has focused on RNA expression differences but newly designed studies could examine whether or not PPARG agonists reproducibly increase BRCA1 protein expression, follow-up with assessment of the biological and/or pathogenic significance and explore protein-based and metabolic interactions. Studies in which BRCA1 expression levels are deliberately varied should be correlated with assessment of PPARG levels and intentional manipulation of PPARG levels performed to assess how combinations of changes in expression of BRCA1 and PPARG impact response to specific PPARG agonists. Dose–response experiments might elucidate whether or not response to a PPARG agonist is a threshold event at the cellular level, occurring at the same magnitude once that expression threshold has been reached, even with low versus high PPARG levels, or differentially regulated at different PPARG expression levels. Finally, targeted mechanistically based molecular studies examining PPARG agonists might also reveal possible opportunities for rational combination therapy for breast cancer prevention (Johnson & Brown 2010).
Declaration of interest
The author declares that there is no conflict of interest that could be perceived as prejudicing the impartiality of this review.
Funding
This work was supported by National Institutes of Health, National Cancer Institute RO1 CA112176 (P A F) and 5P30CA051008.
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