br Experimental Procedures br Acknowledgments br Introductio
Introduction Bisphenol A (BPA), 2,2-bis (4-hydroxyphenyl) propane, is widely used to manufacture consumer products including food and beverage containers (Vandenberg et al., 2007). It can be accumulated in human body via leaching from the polymers into food and water, particularly when BPA was exposed to elevated temperatures such as boiling and heating (Le et al., 2008). Therefore, BPA can be detected in human tissues such as urine, blood, fetal tissues, and amniotic fluid collected from all over the world (Geens et al., 2012, Vandenberg et al., 2007). Fox example, BPA has been detected in 100% of urine samples from Chinese children (Li et al., 2013) and in 96% of urine samples from American (Carwile et al., 2009). Due to the similar structure to estradiol (E2), BPA can influence multiple endocrine-related pathways and then cause various diseases such as obesity, sexual behavior, thyroid function, cancer, and neurological effects (Rubin, 2011). As a potential endocrine disrupting chemical (EDC), BPA has been considered as a weak environmental estrogen because the binding affinity of BPA for the classical nuclear receptors ER alpha and ER beta was estimated to be over 1000–10,000 fold lower than that of estradiol (Kuiper et al., 1998, Vandenberg et al., 2009). While recent studies indicated that BPA can stimulate some cellular responses at very low concentrations (Chen et al., 2014, Ge et al., 2014a, Ge et al., 2014b), these studies indicated that BPA has the equivalent potency to estradiol (Hugo et al., 2008, Zsarnovszky et al., 2005). This might be due to that BPA has great bind affinity to non-classical membrane estrogen receptors such as G-protein coupled receptor 30 (GPR30) (Thomas and Dong, 2006) and estrogen related receptor (ERR) (Okada et al., 2008) and then act through non-genomic pathways. ERR gamma (ERRγ) has been found to strongly bind BPA with a binding affinity constant (KD) of 5.5–5.7nM (Okada et al., 2008). Several studies have indicated that ERRγ is responsible for the effects of BPA in the developing 17 aag and neonate and other biological processes (Arase et al., 2011, Takeda et al., 2009). Breast cancer is the second-most common cause of cancer-related death in women (Desantis et al., 2014). The activity of estrogen signals as a growth factor is essential for the proliferation of a large subset of breast tumors (Deblois and Giguere, 2013). ERRγ shares 90% sequence identity with the DNA-binding domain of ERRα (Riggins et al., 2010) and is implicated in metabolism and cancer (Ariazi and Jordan, 2006, Giguere, 2008). It has reported that the expression of ERRα and ERRγ are associated with an unfavorable and favorable prognosis of breast cancer, respectively (Ariazi et al., 2002). The nuclear immunoreactivity of ERRγ was detected in 79% breast cancer patients and tended to correlate with the lymph node status (Ijichi et al., 2011) while exogenously transfected ERRγ increased MCF-7 cell proliferation (Ijichi et al., 2011). These results suggested that ERRγ plays an important role as a modulator of estrogen signaling in breast cancer cells. Considering that over expression of ERRγ can increase the risks of breast cancer (Dairkee et al., 2008) and BPA has great binding affinity with ERRγ (Okada et al., 2008), therefore we hypothesized that BPA can stimulate the proliferation of breast cancer cells. In the present study, we revealed that nanomolar BPA can significantly increase the proliferation of both ER positive and negative breast cancer cells, and ERRγ mediated this stimulation effect of BPA.
Materials and methods
Discussion More and more studies indicated that BPA can modulate the tumorigenesis and development of cancer cells, particularly for estrogenic related cancers (Ptak et al., 2014, Rezg et al., 2014). Estrogen signals have been proven to trigger the tumorigenesis and development of breast cancer (Schiff et al., 2003). The present study revealed that BPA can promote the cell proliferation of both ER positive and negative breast cancer cells. ER and GPER signals were not involved during this process, while ERRγ mediated this effect. The silence of ERRγ significantly abolished the BPA induced cell proliferation. Further, BPA can up regulate the mRNA and protein expression of ERRγ via ERK1/2. ERK1/2/ERRγ signals mediated the BPA induced proliferation of breast cancer cells. Our study further confirmed the involvement of ERRγ in BPA induced tumorigenesis (Babu et al., 2012, Matsushima et al., 2007).