To date attention has been directed towards new
To date, attention has been directed towards new molecular targets in luminal phenotype (ER-positive), such as CDK4/6 and, to a lesser extent, androgen receptor (AR) pathways . While the role of CDK4/6 has been elucidated and their inhibitors have shown a benefit in luminal BC, the role of AR in BC has not yet been fully clarified .
AR signaling has been extensively studied in prostate cancer (PC), where it plays a crucial role in the pathogenesis and natural history of both androgen-sensitive and androgen-resistant PC .
Similarly, recent studies have shown that this pathway also plays an important role in BC, particularly in the metastatic setting. AR is reported to be expressed in more than 60% of BC and up to 90% of ER-positive tumors, suggesting a potential androgen responsiveness . Although there has been much controversy in defining the prognostic role of AR in BC, most data suggest a substantial difference between subtypes (i.e., ER-negative BC and ER-positive BC). For instance, in ER-negative AR-positive cell lines, AR binds to a ligand in the nucleus allowing cell proliferation. On the contrary, an emerging set of data has shown that AR 4E1RCat is associated with anti-proliferative activity among patients with ER-positive BC and with a better outcome compared to ER-negative tumors, where the role of AR expression remains controversial , .
Therefore, the biological role of AR in the development and growth of BC is an active area of investigation. Of note, AR seems to be involved in resistance development in luminal BC treated with AIs or tamoxifen. As a consequence, the use of AR inhibitors is a promising strategy to overcome resistance to endocrine treatment. Also, AR-targeted therapy is well tolerated and its use in combination with other agents seems feasible. 
The present review focuses on both preclinical and clinical evidence analyzing the role of AR in ER-positive BC, particularly with respect to endocrine treatment resistance .
The biological role of AR in BC Steroid hormones, androgens and estrogen, are involved in the development and differentiation of normal breast tissue. Their activity and concentration depend on both circulating levels and conversion at the local level . Androgens are synthesized from cholesterol, and, in women, they are physiologically produced by adrenal glands and ovaries. AndrogensbindtoAR, a member of the nuclear hormone receptor transcription factor superfamily, modulating gene transcription and eliciting their effects. Particularly, testosterone and dihydrotestosterone(DHT) bind to AR with greater affinity than the other intermediates of biosynthesis. Testosterone can directly bind to AR, be converted to DHT via 5 alfa-reductase, or be converted to estradiol via the aromatase enzyme which is found in numerous tissues including the breast .
Preclinical evidence Preclinical studies provide variable data on the role of androgens in BC growth. The potential anti-proliferative effect of androgens on BC has been known since the 1950s, when Huggins and colleagues pointed out the influence of sex hormones on mammary tumors in rats . The following data confirmed the inhibitory effect of androgen administration on the growth of different human BC cell lines. The treatment of the ZR-75-1 ER-positive cell lines with DHT resulted in a significant inhibition of both the estradiol-dependent and estradiol-independent cell growth. Its effect was then reversed using the anti-androgen hydroxyflutamide, indicating a possible AR-mediated underlying mechanism . The DHT inhibitory effect on ZR-75-1 cells was also associated with a marked down-regulation of the Bcl-2 proto-oncogene expression . Likewise, DHT and mibolerone, a synthetic androgen, were able to inhibit MCF-7 and T47-D ER-positive BC cell line proliferation in vitro , . The inhibitory effect of DHT was further confirmed in vivo on the growth of human ZR-75-1 BC in athymic mice .