Bleach Rachel, McIlroy Marie
Endocrine Oncology Research Group, Department of Surgery, Royal College of Surgeons in Ireland, Dublin, Ireland.
Front Endocrinol (Lausanne). 2018 Oct 26;9:594. doi: 10.3389/fendo.2018.00594. eCollection 2018.
Androgen receptor (AR) is the most widely expressed steroid receptor protein in normal breast tissue and is detectable in approximately 90% of primary breast cancers and 75% of metastatic lesions. However, the role of AR in breast cancer development and progression is mired in controversy with evidence suggesting it can either inhibit or promote breast tumorigenesis. Studies have shown it to antagonize estrogen receptor alpha (ERα) DNA binding, thereby preventing pro-proliferative gene transcription; whilst others have demonstrated AR to take on the mantle of a pseudo ERα particularly in the setting of triple negative breast cancer. Evidence for a potentiating role of AR in the development of endocrine resistant breast cancer has also been mounting with reports associating high AR expression with poor response to endocrine treatment. The resurgence of interest into the function of AR in breast cancer has resulted in various emergent clinical trials evaluating anti-AR therapy and selective androgen receptor modulators in the treatment of advanced breast cancer. Trials have reported varied response rates dependent upon subtype with overall clinical benefit rates of ~19-29% for anti-androgen monotherapy, suggesting that with enhanced patient stratification AR could prove efficacious as a breast cancer therapy. Androgens and AR have been reported to facilitate tumor stemness in some cancers; a process which may be mediated through genomic or non-genomic actions of the AR, with the latter mechanism being relatively unexplored in breast cancer. Steroidogenic ligands of the AR are produced in females by the gonads and as sex-steroid precursors secreted from the adrenal glands. These androgens provide an abundant reservoir from which all estrogens are subsequently synthesized and their levels are undiminished in the event of standard hormonal therapeutic intervention in breast cancer. Steroid levels are known to be altered by lifestyle factors such as diet and exercise; understanding their potential role in dictating the function of AR in breast cancer development could therefore have wide-ranging effects in prevention and treatment of this disease. This review will outline the endogenous biochemical drivers of both genomic and non-genomic AR activation and how these may be modulated by current hormonal therapies.
雄激素受体（AR）是正常乳腺组织中表达最广泛的类固醇受体蛋白，在约90%的原发性乳腺癌和75%的转移病灶中均可检测到。然而，AR在乳腺癌发生和发展中的作用存在争议，有证据表明它既可以抑制也可以促进乳腺肿瘤发生。研究表明，它可拮抗雌激素受体α（ERα）与DNA的结合，从而阻止促增殖基因转录；而其他研究则表明，AR尤其在三阴性乳腺癌中扮演假ERα的角色。AR在内分泌抵抗性乳腺癌发生中起增强作用的证据也在不断增加，有报道将高AR表达与内分泌治疗反应不佳相关联。对AR在乳腺癌中功能的兴趣再度兴起，导致各种新出现的临床试验评估抗AR疗法和选择性雄激素受体调节剂在晚期乳腺癌治疗中的作用。试验报告的反应率因亚型而异，抗雄激素单药治疗的总体临床获益率约为19%-29%，这表明通过加强患者分层，AR可能被证明是一种有效的乳腺癌治疗方法。雄激素和AR已被报道在某些癌症中促进肿瘤干性；这一过程可能通过AR的基因组或非基因组作用介导，而后者机制在乳腺癌中相对未被探索。AR的类固醇生成配体在女性体内由性腺产生，并作为肾上腺分泌的性类固醇前体。这些雄激素提供了丰富的储备库，所有雌激素随后都从中合成，并且在乳腺癌进行标准激素治疗干预时其水平不会降低。已知类固醇水平会因饮食和运动等生活方式因素而改变；因此，了解它们在决定AR在乳腺癌发生中的功能方面的潜在作用可能对这种疾病的预防和治疗产生广泛影响。本综述将概述基因组和非基因组AR激活的内源性生化驱动因素，以及它们如何被当前的激素疗法调节。
