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  • Because R gene is positively regulated


    Because 5α-R2 gene is positively regulated by T and in the prostate gland (Torres Caspase-3/7 Inhibitor et al., 2003), and our BPA-treated rats showed decreased circulating T and probably intraprostatic androgen levels, it might be responsible for the decrease of 5α-R2 expression. However, in a previous work using castrated adult rats, we observed that BPA decreased transcription levels of 5α-R2independently of circulating T levels (Sánchez et al., 2013). It is also possible that BPA antagonizes androgen receptor (AR) signaling decreasing 5α-R2 mRNA levels accordingly. Nevertheless, Bernardo et al. (2015) recently reported that BPA administered to pregnant rats (25 μg/kg/day; GD10-to parturition) produced an increase in the prostate expression of AR at PND21. Therefore, a direct effect of BPA on 5α-R2 expression cannot be ruled out. Neither 5α-R1 nor 5α-R3 transcription was altered in the ventral prostate of juvenile BPA-treated rats in comparison with their respective controls. 5α-R1 is synthesized mainly in extraprostatic tissues such as skin and liver, but also contributes to a lesser extent than 5α-R2 to the synthesis of DHT in the prostate gland (Zhu and Imperato-McGinley, 2009). With regard to 5α-R3, its role in steroidogenesis remains controversial, although it has been proposed as a marker of carcinogenesis in various tissues (Godoy et al., 2011). In this paper, plasma E2 levels, as well as aromatase expression in prostate were significantly increased in BPA treated rat at dose of 10 μg/kg b.w./day leading to an increase in intraprostatic E2. In line with our results, fetal exposure to low-dose BPA increases Caspase-3/7 Inhibitor levels and aromatase activity in urogenital sinus, from which the prostate develops during embryogenesis (Arase et al., 2011). BPA has traditionally been considered a weak environmental estrogen. Thus, fetal exposure to low doses of estradiol or BPA lead to basal epithelial cell hyperplasia and to an increase in number and binding activity of prostate AR, resulting in an increase in prostate size in adulthood (Gupta, 2000; Nagel et al., 1997; Timms et al., 2005; Thayer et al., 2001; Vom Saal et al., 1997; Vom Saal, 2016). Exposure to low dose of estradiol or BPA during perinatal, as well as neonatal period, modulated the expression of several prostatic genes (Camacho et al., 2015) and altered the prostate epigenome leading to an increased susceptibility to carcinogenesis (Cheong et al., 2016; Ho et al., 2006; Prins et al., 2017, 2008, 2001; Putz et al., 2001; Richter et al., 2004; Stoker et al., 1999; Tang et al., 2012; Wong et al., 2015). In our previous study using adult rats (Castro et al., 2013b), the administration of BPA (25, 50, 300, or 600 μg/kg b.w./day) during four days produced effects on the expression of 5α-R1 and 5α-R3 which differs from our present results. Rodent studies often show contradictory results concerning BPA effects on prostate gland, including differences in direction of weight change, AR expression, and epithelium cell proliferation (Timms et al., 2005; Bernardo et al., 2015). Hence, we believe that: (i) both adult and the developing prostate are susceptible to BPA exposure; (ii) distinct responses could be expected to produce different prostate outcomes depending on the age at exposure and analysis. This last hypothesis needs to be interpreted with caution given diverse doses and regimes of administration have been used in the different studies.
    Conflicts of interests
    Acknowledgements This work was supported by a Spanish Ministry of Science and Innovation grant [BFU 2008-05340] and the Andalusian Regional Government [Endocrinology & Metabolism Group CTS-202].
    Breast cancer is affecting a growing number of patients all over the world. According to GLOBOCAN 2012, which was published by International Agency for Research on Cancer (AIRC), the type of cancer that affects the most number of women worldwide is breast cancer, both in terms of new cases (1.7million cases, 25.2% of the total number of cases) and deaths (522,000, 6.4%). Breast cancer is a highly estrogen-dependent tumour, and it has been reported that one-third of all breast cancer cases and two-thirds of all post-menopausal breast cancer cases are estrogen-dependent. In women, estrogen is secreted by the ovaries or synthesized from androgen by CYP19 (aromatase), which is a type of cytochrome P450. The route of estrogen secretion changes before and after menopause, i.e., while the former is the main route in pre-menopausal women, the latter is pre-dominant in post-menopausal women. Pharmaceutical treatment of breast cancer includes chemotherapy, Her2 antibody therapy and endocrine therapy. There are two types of endocrine therapies that can inhibit the action of estrogen: tamoxifen, which inhibits estrogen receptors, and aromatase inhibitors (AI), which inhibits the biosynthesis of estrogen. Of these two, endocrine therapy based on AI has witnessed spectacular advancements since the early 2000s, and in the last 15years, its recognition as a drug therapy for breast cancer has significantly increased. Meanwhile, many studies have compared the use of tamoxifen with that of AI in endocrine therapy,, , , , and a large number of those studies have confirmed that the third-generation AI, e.g., letrozole, are more effective than tamoxifen for pre- and post-operative administration to post-menopausal breast cancer patients. Although endocrine therapy has favoured the use of tamoxifen for post-menopausal breast cancer patients in the past, the use of AI is preferred nowadays. Moreover, the possibilities that AI present are expanding, and combining AI with gonadotropin-releasing hormone (GnRH) agonists has proven effective against pre-menopausal breast cancer. Additionally, it has been found that it is possible to use AI as a therapeutic agent against other highly estrogen-dependent disorders such as endometrial cancer, endometriosis, and uterine leiomyomas. AI has even proven to be effective against infertility as it promote the secretion of follicle-stimulating hormones. Therefore, there is an increasing demand for AI. However, only three types of AI are used currently: steroidal exemestane and the triazole derivatives anastrozole and letrozole. Finding AI that have different chemotypes is desirable from the viewpoint of drug tolerance and side-effect reduction; however, aromatase has a high substrate specificity, and most AI currently being developed are either steroidal or triazole derivatives. Since Chen, Leonetti et al. reported the inhibition of aromatase by coumarin derivatives and in 2004; attention has been focused on developing coumarin derivatives as a basis of breast cancer treatment drugs ().