Endocrine Oncology Research, Department of Surgery, RCSI University of Medicine and Health Sciences, Dublin, Ireland.
Data Science Centre, RCSI University of Medicine and Health Sciences, Dublin, Ireland.
Clin Cancer Res. 2021 Jul 15;27(14):3980-3989. doi: 10.1158/1078-0432.CCR-20-4135. Epub 2021 May 20.
There is strong epidemiologic evidence indicating that estrogens may not be the sole steroid drivers of breast cancer. We hypothesize that abundant adrenal androgenic steroid precursors, acting via the androgen receptor (AR), promote an endocrine-resistant breast cancer phenotype.
AR was evaluated in a primary breast cancer tissue microarray ( = 844). Androstenedione (4AD) levels were evaluated in serum samples ( = 42) from hormone receptor-positive, postmenopausal breast cancer. Levels of androgens, progesterone, and estradiol were quantified using LC/MS-MS in serum from age- and grade-matched recurrent and nonrecurrent patients ( = 6) before and after aromatase inhibitor (AI) therapy (>12 months). AR and estrogen receptor (ER) signaling pathway activities were analyzed in two independent AI-treated cohorts.
AR protein expression was associated with favorable progression-free survival in the total population (Wilcoxon, < 0.001). Pretherapy serum samples from breast cancer patients showed decreasing levels of 4AD with age only in the nonrecurrent group ( < 0.05). LC/MS-MS analysis of an AI-sensitive and AI-resistant cohort demonstrated the ability to detect altered levels of steroids in serum of patients before and after AI therapy. Transcriptional analysis showed an increased ratio of AR:ER signaling pathway activities in patients failing AI therapy ( test < 0.05); furthermore, 4AD mediated gene changes associated with acquired AI resistance.
This study highlights the importance of examining the therapeutic consequences of the steroid microenvironment and demonstrable receptor activation using indicative gene expression signatures.
有强有力的流行病学证据表明，雌激素可能不是乳腺癌的唯一类固醇驱动因素。我们假设丰富的肾上腺雄激素类固醇前体，通过雄激素受体 (AR) 发挥作用，促进内分泌抵抗型乳腺癌表型。
在原发性乳腺癌组织微阵列中评估 AR（=844）。评估来自激素受体阳性、绝经后乳腺癌患者的血清样本（=42）中的雄烯二酮（4AD）水平。使用 LC/MS-MS 在年龄和分级匹配的复发性和非复发性患者（=6）在芳香酶抑制剂（AI）治疗前后（>12 个月）的血清中定量雄激素、孕激素和雌二醇。在两个独立的 AI 治疗队列中分析 AR 和雌激素受体 (ER) 信号通路活性。
AR 蛋白表达与总人群的无进展生存预后良好相关（Wilcoxon，<0.001）。乳腺癌患者的治疗前血清样本仅在非复发性组中随年龄降低 4AD 水平（<0.05）。对 AI 敏感和 AI 耐药队列的 LC/MS-MS 分析表明，能够检测到 AI 治疗前后患者血清中类固醇水平的改变。转录分析显示，在 AI 治疗失败的患者中，AR：ER 信号通路活性的比值增加（test<0.05）；此外，4AD 介导与获得性 AI 耐药相关的基因变化。
本研究强调了检查类固醇微环境的治疗后果以及使用指示性基因表达谱证明受体激活的重要性。
