Studies have recently raised concerns about the
Studies have recently raised concerns about the potential role of parabens in breast cancer, as these chemicals are commonly detectable in human breast cancer tissues. An analysis of 160 breast tissue samples collected from 40 mastectomies for primary breast cancer in England showed that at least one intact paraben ester was detectable in virtually all of the samples (99%), and that all five paraben esters investigated were detectable in 60% of the samples, with a total median value of 85.5 (range 0–5134.5) ng/g of tissue for all five parabens (Barr et al., 2012). Another study also showed detectable intact parabens in 20 human breast cancer tissue samples collected in Scotland at an average of 20.6±4.2ng/g of tissue (Darbre et al., 2004). Parabens are also commonly detectable in general populations. A recent analysis of urine samples from the US general SGI-1027 showed that MP, PP and BuP were measurable in 99.9%, 98.3% and 73.6% of women and 99.3%, 90.2% and 35.9% of men, respectively (Smith et al., 2012). Studies have similarly shown the presence of parabens in 98% of urine samples from Danish men (Frederiksen et al., 2011) and in 100% of urine samples from pregnant women and children in Spain (Casas et al., 2011). The toxicology of parabens and their role as endocrine-disrupting chemicals have been documented in recent years. The antiandrogenic properties and spermatotoxic effects of PP and BuP were reported by Satoh et al. (2005) and Oishi, 2001, Oishi, 2002a, Oishi, 2002b, respectively. The oestrogenic properties of parabens have aroused high concern since 1998, generating debate over the role of parabens in the increased incidence of breast cancer (Darbre and Harvey, 2008, Routledge et al., 1998, Soni et al., 2005). In vitro and in vivo assays have since shown that all of the widely used parabens possess oestrogenic properties (Darbre and Harvey, 2008). Because oestrogen is known to play a central role in the development, growth and progression of breast cancer (Miller, 1996), some researchers argue that parabens are involved in its increased incidence. Others, however, maintain that the oestrogenic activities of parabens are too weak to have a significant effect, with the most potent (BuP) being 10,000 times less potent than 17β-estradiol (E2) (Golden and Gandy, 2004, Golden et al., 2005, Routledge et al., 1998). Using expression microarrays, studies have shown some similarities in the global gene expression patterns of parabens and E2 in MCF-7 human breast cancer cells (Pugazhendhi et al., 2007, Terasaka et al., 2006). However, it has also been noted that the majority of genes, whether up- or down-regulated, do not follow the same pattern of regulation under parabens and E2 treatments (Pugazhendhi et al., 2007). This raises the question of whether parabens use other pathways in the regulation of gene expression. Darbre and Harvey (2008) reviewed more than 150 studies on paraben toxicology and observed that ‘whether the parabens can also bind to the oestrogen-related receptors (ERRs) will be important in the light of the recent description of the binding of bisphenol A (BPA) to human oestrogen-related receptor-γ (ERRγ)’. ERRs are a subfamily of orphan nuclear receptors most closely related to oestrogen receptors (ERs), with which they share target genes, coregulatory proteins, ligands and sites of action (Giguere, 2002). Oestrogen-related receptor-γ (ERRγ) is a member of the ERR subfamily. A recent study reported that ERRγ could be detected in 79% of human invasive breast cancer cases, and that it may play an important role as a modulator of oestrogen signalling in breast cancer cells (Ijichi et al., 2011). Some earlier studies indicated that ERRγ may be a biomarker of the development of hormone-sensitive breast cancer and a breast cancer treatment target for tamoxifen (Ariazi et al., 2002, Coward et al., 2001). In a recent study on uterine endometrial cancer, Yamamoto et al. (2012) showed that a selective ERRγ agonist, DY131, inhibited the growth of ERα-positive cancer cells but promoted that of ERα-negative cancer cells. Therefore, clarification of the binding activities of parabens on ERRγ is necessary to better understand their role in breast cancer.