AR Expression in Breast Cancer CTCs Associates with Bone Metastases.
AR Expression in Breast Cancer CTCs Associates with Bone Metastases.
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DOI：
10.1158/1541-7786.mcr-17-0480
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发表时间：
2018-04
期刊：
影响因子：
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通讯作者：
Maheswaran S
中科院分区：
文献类型：
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作者：
Aceto N;Bardia A;Wittner BS;Donaldson MC;O'Keefe R;Engstrom A;Bersani F;Zheng Y;Comaills V;Niederhoffer K;Zhu H;Mackenzie O;Shioda T;Sgroi D;Kapur R;Ting DT;Moy B;Ramaswamy S;Toner M;Haber DA;Maheswaran S
人类癌症骨转移的分子驱动因素尚不清楚，部分原因是骨组织采样的限制。本研究对转移性雌激素受体(ER)+乳腺癌患者血液样本中分离的循环肿瘤细胞（ctc）进行了RNA测序（RNA-seq），比较了骨骼和内脏器官进展的病例。在骨显性乳腺癌的ctc中，雄激素受体（AR）信号通路是激活的细胞通路之一。AR基因的表达是显而易见的，其组成活性剪接变体AR-v7也是如此。ctc内AR表达与芳香酶抑制剂治疗的持续时间相关，表明它有助于获得性内分泌治疗耐药。在一个已建立的乳腺癌异种移植模型中，一种致骨衍生物显示出AR表达增加，其遗传或药理学抑制可减少骨转移而非肺转移。总之，这些观察结果确定了骨显性ER+乳腺癌女性ctc中的AR信号，并为在这类患者中检测雄激素抑制剂提供了理论依据。
Molecular drivers underlying bone metastases in human cancer are not well understood, in part due to constraints in bone tissue sampling. Here, RNA sequencing (RNA-seq) was performed of circulating tumor cells (CTCs) isolated from blood samples of women with metastatic estrogen receptor (ER)+ breast cancer, comparing cases with progression in bone versus visceral organs. Among the activated cellular pathways in CTCs from bone-predominant breast cancer is androgen receptor (AR) signaling. AR gene expression is evident, as is its constitutively active splice variant AR-v7. AR expression within CTCs is correlated with the duration of treatment with aromatase inhibitors, suggesting that it contributes to acquired resistance to endocrine therapy. In an established breast cancer xenograft model, a bone-tropic derivative displays increased AR expression, whose genetic or pharmacologic suppression reduces metastases to bone but not to lungs. Together, these observations identify AR signaling in CTCs from women with bone-predominant ER+ breast cancer, and provide a rationale for testing androgen inhibitors in this subset of patients.