Cooperative Dynamics of AR and ER Activity in Breast Cancer.
Cooperative Dynamics of AR and ER Activity in Breast Cancer.
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DOI：
10.1158/1541-7786.mcr-16-0167
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发表时间：
2016-11
期刊：
影响因子：
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通讯作者：
Richer JK
中科院分区：
文献类型：
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作者：
D'Amato NC;Gordon MA;Babbs B;Spoelstra NS;Carson Butterfield KT;Torkko KC;Phan VT;Barton VN;Rogers TJ;Sartorius CA;Elias A;Gertz J;Jacobsen BM;Richer JK
雄激素受体（AR）在90%的雌激素受体α阳性（ER+）乳腺肿瘤中表达，但其在肿瘤生长和进展中的作用仍存在争议。使用两种抑制AR核定位的抗雄激素（恩杂鲁胺和MJC 13）显示，AR是最大ER基因组结合所需的。在这里，一个新的全球检查AR染色质结合发现，雌二醇诱导AR结合在独特的网站相比，双氢睾酮（DHT）。雌激素诱导的AR结合位点富含雌激素反应元件，并与ER结合位点有显著重叠。此外，AR抑制可降低多种ER+/AR+乳腺癌细胞系中基线和雌二醇介导的增殖，并与他莫昔芬和氟维司群具有协同作用。在体内，Enzalutamide显著降低了他莫昔芬耐药MCF 7异种移植肿瘤和ER+/AR+患者来源模型的存活率。Enzalutamide还降低了心脏注射后的转移负荷。最后，在ER+/AR+原发性肿瘤与患者匹配的局部复发或远处转移的比较中，即使ER减少或缺失，AR表达也经常维持。这些数据提供了临床前证据，即抑制AR核定位的抗雄激素影响AR和ER，并且与当前的乳腺癌治疗组合有效。此外，单药疗效可能在对传统内分泌治疗耐药的肿瘤中发挥作用，因为复发性疾病的临床标本表明，在ER缺失或难治性的肿瘤中存在AR表达。这项研究表明，AR在支持ER+/AR+乳腺癌细胞中E2介导的ER活性方面发挥了先前未被认识到的作用，Enzalutamide可能是ER+/AR+乳腺癌的有效治疗药物。
Androgen receptor (AR) is expressed in 90% of estrogen receptor alpha positive (ER+) breast tumors, but its role in tumor growth and progression remains controversial. Use of two anti-androgens that inhibit AR nuclear localization, enzalutamide and MJC13, revealed that AR is required for maximum ER genomic binding. Here, a novel global examination of AR chromatin binding found that estradiol induced AR binding at unique sites compared to dihydrotestosterone (DHT). Estradiol-induced AR binding sites were enriched for estrogen response elements and had significant overlap with ER binding sites. Furthermore, AR inhibition reduced baseline and estradiol-mediated proliferation in multiple ER+/AR+ breast cancer cell lines, and synergized with tamoxifen and fulvestrant. In vivo, enzalutamide significantly reduced viability of tamoxifen-resistant MCF7 xenograft tumors and an ER+/AR+ patient-derived model. Enzalutamide also reduced metastatic burden following cardiac injection. Lastly, in a comparison of ER+/AR+ primary tumors versus patient-matched local recurrences or distant metastases, AR expression was often maintained even when ER was reduced or absent. These data provide pre-clinical evidence that anti-androgens that inhibit AR nuclear localization affect both AR and ER, and are effective in combination with current breast cancer therapies. In addition, single agent efficacy may be possible in tumors resistant to traditional endocrine therapy, since clinical specimens of recurrent disease demonstrate AR expression in tumors with absent or refractory ER. This study suggests that AR plays a previously-unrecognized role in supporting E2-mediated ER activity in ER+/AR+ breast cancer cells, and that enzalutamide may be an effective therapeutic in ER+/AR+ breast cancers.