Bluewater Biotech LLC, PO Box 1010, New Providence, NJ, 07974, USA.
Division of Endocrinology, Diabetes & Metabolism, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA.
Cell Oncol (Dordr). 2020 Apr;43(2):321-333. doi: 10.1007/s13402-019-00492-6. Epub 2020 Jan 13.
Androgen receptor (AR) antagonists are currently tested in multiple clinical trials for different breast cancer (BC) subtypes, which emphasizes the need for clarifying the role of AR in this type of cancer. Previous studies showed that AR expression was associated with a favorable prognosis in ER-positive BC. However, the true biological effect of AR signaling in BC is not clear.
An AR pathway signature was generated to compute AR pathway activity in BCs (n = 6439) from 46 microarray datasets. Associations of AR pathway activity and AR expression with BC prognosis were compared by survival analysis.
AR pathway activity showed moderate positive and negative correlations with AR expression in HER2-positive and HER2-negative BCs, respectively. AR pathway activity increased while AR expression decreased in ER-negative BCs. Like ER and progesterone receptor (PR) expression, AR expression was also negatively associated with tumor grade, neoadjuvant response, and recurrence risk in BC. By contrast, AR pathway activity was positively, and more significantly, associated with these clinical features. Moreover, the AR pathway, but not AR expression, was significantly associated with recurrence risk in BC patients treated with endocrine therapy. These data suggest that, although AR expression probably reflects well-differentiated states of BC and is thus associated with favorable prognosis in BC, the biological effects of AR signaling confers worse outcomes in BC.
Our findings encourage the continued evaluation of AR antagonists for BC treatment and support that AR pathway activity serves as a better prognostic factor than AR expression in BC.
雄激素受体（AR）拮抗剂目前正在多种临床试验中针对不同的乳腺癌（BC）亚型进行测试，这强调了需要阐明 AR 在这种癌症中的作用。先前的研究表明，AR 表达与 ER 阳性 BC 的预后良好相关。然而，AR 信号在 BC 中的真正生物学效应尚不清楚。
生成了一个 AR 通路特征，以计算来自 46 个微阵列数据集的 6439 例 BC 中的 AR 通路活性。通过生存分析比较了 AR 通路活性和 AR 表达与 BC 预后的关联。
AR 通路活性与 HER2 阳性和 HER2 阴性 BC 中的 AR 表达呈中度正相关和负相关。在 ER 阴性 BC 中，AR 通路活性增加而 AR 表达降低。与 ER 和孕激素受体（PR）表达一样，AR 表达也与 BC 的肿瘤分级、新辅助反应和复发风险呈负相关。相比之下，AR 通路活性与这些临床特征呈正相关，且更为显著。此外，AR 通路而不是 AR 表达与接受内分泌治疗的 BC 患者的复发风险显著相关。这些数据表明，尽管 AR 表达可能反映了 BC 的分化良好状态，因此与 BC 的预后良好相关，但 AR 信号的生物学效应在 BC 中赋予了更差的结局。
我们的发现鼓励继续评估 AR 拮抗剂在 BC 治疗中的应用，并支持 AR 通路活性作为 BC 中比 AR 表达更好的预后因素。
