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  • br AR expression in breast tissue Although androgenic signal

    2022-11-18


    AR expression in breast tissue Although androgenic signalling is chiefly associated with the development and maintenance of primary and secondary male characteristics, especially during puberty when the testes are by far the major source of testosterone, the AR also plays important functions in females where the adrenal glands and ovaries form the main supply of androgens (Smith et al., 2013). Indeed, androgens are required for normal development and fertility of both sexes and studies using female AR knockout mice show that the receptor is vital for the development of ovarian follicles and ovulation (Walters et al., 2010). Visualisation of AR function in transgenic female mice shows robust activity in the mammary glands, ovaries, omentum tissue and uterus, and a strong correlation with AR expression in humans (Dart et al., 2013). Importantly, these studies confirm that androgens can act directly through AR in women rather than via androgen aromatisation to oestrogens which are the main drivers of female sexual development. The importance of androgens in women increases dramatically with age, especially after menopause when circulating levels of testosterone and oestradiol decrease by 1.5 and 10 fold respectively (Rothman et al., 2011) with androgens becoming the predominant sex hormone (Nicolas Diaz-Chico et al., 2007). The AR is expressed in glandular epithelial and stromal/fibroblast CID 2745687 in the breast (Hickey et al., 2012). Down-regulation of receptor mRNA has been reported in response to DHT in a number of breast cancer cell-lines (T-47D, MFM-2333, MDA-453) (Hall et al., 1992, Hackenberg et al., 1993, Yeap et al., 1999). Interestingly, in the latter cell model the response was at the level of stability of the receptor mRNA (Yeap et al., 1999). In our studies we also observed down-regulation of the AR mRNA in MCF-7 cells, but not in BT-474 cells (Fig. 3). These two cell lines represent different subtypes of breast cancer: luminal A and B respectively (Holliday and Speirs, 2011). The significance of this differential response is a topic of ongoing research. It has been understood for over a quarter of a century that the AR directly autoregulates its own gene (Table 1), with down-regulation observed in rat prostate, seminal vesicles, epididymis, kidney and brain, after castration (see Shan et al., 1990, Quarmby et al., 1990). Interestingly, this was not the case in the rat testes, suggesting tissue-selective regulation plays a role in the hormonal control of AR levels (Blok et al., 1992). Auto-repression of the AR mRNA has also been observed in a number of human cell-lines (Shan et al., 1990, Quarmby et al., 1990, Krongrad et al., 1991, Wolf et al., 1993); Fig. 3) and recent studies have focused on prostate epithelial cells (Cai et al., 2011, Hay et al., 2014). There are several confirmed AREs within the hAR gene that have been shown to alter expression (Fig. 2). The ARE closest to the main promoter and transcription start site lies +611 bp downstream within the 5′UTR (Hay et al., 2014). The sequence of this regulatory element, 5′-AGAACCctcTGTTTT-3′, differs from the consensus ARE, 5′- GGA/TACAnnnTGTTCT-3′, and is unique to primates. Binding of the AR to this element inhibits transcription of the gene and a reporter gene driven by the promoter and 5′UTR of the human AR gene was similarly down regulated by DHT in prostate (Hay et al., 2014) and MCF-7 cells (Hunter and McEwan unpublished observations) supporting the role of the identified receptor response element in negative auto-regulation. A second inhibitory ARE is situated in intron 2 over 100 kbp downstream of the main promoter (Cai et al., 2011) (Fig. 2). The mechanism of action has been elucidated, with the chromatin remodelling enzyme LSD1 being recruited by ARE-bound activated AR resulting in histone H3K4me1,2 demethylation and subsequent downregulation (Cai et al., 2014). A role for the pioneer transcription factor FOXA1, in this negative regulation, has also been identified (Jones et al., 2015).