Constitutively active androgen receptor supports the metastatic phenotype of endocrine-resistant hormone receptor-positive breast cancer.
Constitutively active androgen receptor supports the metastatic phenotype of endocrine-resistant hormone receptor-positive breast cancer.
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DOI：
10.1186/s12964-020-00649-z
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发表时间：
2020-09-18
期刊：
影响因子：
--
通讯作者：
Bawa-Khalfe T
中科院分区：
文献类型：
--
作者：
Bahnassy S;Thangavel H;Quttina M;Khan AF;Dhanyalayam D;Ritho J;Karami S;Ren J;Bawa-Khalfe T
激素受体阳性（HR+）乳腺癌（BCa）是最常见的诊断亚型。对常规内分泌治疗（ET）的获得性和内在抗性通常发生并提示不可治愈的转移性疾病。因此，ET耐药（ET-R）HR+ BCa提出了治疗挑战。先前的研究表明，升高的雄激素受体（AR）支持对ET他莫昔芬的耐药性，并与HR+ BCa转移相关。然而，令人惊讶的是，AR阻断剂Enzalutamide（Enz）在ET-R HR+ BCa中的研究显示了相互矛盾的结果。我们现在报告，一个组成型活性，独特的从典型的酶靶向，AR积累内分泌抵抗HR+ BCa细胞。通过无细胞修饰试验、内部体内SUMO化试验和PLA成像确定获得性和内在ET-R HR + -BCa中的AR蛋白谱。天然AR和修饰的AR模拟物的基因组活性用报告基因测定和有限的转录组分析进行测试。球体生长和迁移研究用于评价Enz和组合疗法的抑制作用。持续的较高分子量SUMO修饰的AR（SUMO-AR）在获得性和内在ET-R BCa细胞系中持续存在。同时，SUMO同种型和全局SUMO修饰的蛋白质组也在相同的细胞系中积累。我们确定AR为SUMO-E3连接酶HSPB 1/Hsp 27的新底物。SUMO-AR不依赖于配体，对泛素介导的蛋白酶体降解有弹性，在细胞核中富集，容易与染色质结合，并且具有转录活性。组成型SUMO-AR启动有利于上皮-间充质转化的基因表达谱。Enz联合SUMO抑制剂可减弱ET-R HR+ BCa的迁移和转移表型。靶向未修饰和SUMO修饰的AR可防止HR+ BCa与ET-R的转移进展。视频摘要
Hormone receptor positive (HR+) breast cancer (BCa) is the most frequently diagnosed subtype. Acquired and intrinsic resistance to conventional endocrine therapy (ET) commonly occurs and prompts incurable metastatic disease. Hence, ET-resistant (ET-R) HR+ BCa presents a therapeutic challenge. Previous studies show elevated androgen receptor (AR) that supports resistance to ET tamoxifen and correlates with HR+ BCa metastasis. Yet surprisingly, studies with AR-blocker enzalutamide (Enz) in ET-R HR+ BCa present conflicting results. We now report that a constitutively active, unique from canonical Enz-targeted, AR accumulates in endocrine resistant HR+ BCa cells. AR protein profiles in acquired and intrinsic ET-R HR + -BCa were defined with cell-free modification tests, in-house in-vivo SUMOylation assays, and PLA imaging. Genomic activity of native AR and modified-AR mimetic was tested with reporter assays and limited transcriptome analysis. Spheroid growth and migration studies were used to evaluate inhibitory actions of Enz and combinatorial therapy. Sustained higher molecular weight SUMO-modified AR (SUMO-AR) persists in acquired and intrinsic ET-R BCa cell lines. Concurrently, SUMO isoforms and global SUMO-modified proteome also accumulates in the same cell lines. We identified AR as a novel substrate for the SUMO-E3 ligase HSPB1/Hsp27. Independent of ligand, SUMO-AR is resilient to ubiquitin-mediated proteasomal degradation, enriched in the nucleus, readily chromatin-bound, and transcriptionally active. Constitutive SUMO-AR initiates a gene-expression profile that favors epithelial-mesenchymal transition. Enz combined with a SUMO inhibitor attenuates migration and metastatic phenotype of ET-R HR+ BCa. Targeting both unmodified and SUMO-modified AR prevents the metastatic progression of HR+ BCa with ET-R. Video abstract
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DOI：
10.1186/s13046-018-0762-y
发表时间：
2018-04-27
期刊：
Journal of experimental & clinical cancer research : CR
影响因子：
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作者：
Liu X;Feng C;Liu J;Cao L;Xiang G;Liu F;Wang S;Jiao J;Niu Y
通讯作者：
Niu Y
雄激素和 AR 有助于乳腺癌的发展和转移：机制的见解。
影响因子：
8
作者：
Feng, J.;Li, L.;Huang, B.
通讯作者：
Huang, B.
DOI：
10.1126/science.1212728
发表时间：
2012-01-20
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Kessler JD;Kahle KT;Sun T;Meerbrey KL;Schlabach MR;Schmitt EM;Skinner SO;Xu Q;Li MZ;Hartman ZC;Rao M;Yu P;Dominguez-Vidana R;Liang AC;Solimini NL;Bernardi RJ;Yu B;Hsu T;Golding I;Luo J;Osborne CK;Creighton CJ;Hilsenbeck SG;Schiff R;Shaw CA;Elledge SJ;Westbrook TF
通讯作者：
Westbrook TF
DOI：
10.1007/978-1-4939-6358-4_15
发表时间：
2016-01-01
期刊：
SUMO: METHODS AND PROTOCOLS
影响因子：
--
作者：
Bawa-Khalfe, Tasneem
通讯作者：
Bawa-Khalfe, Tasneem
DOI：
10.1158/1541-7786.mcr-16-0167
发表时间：
2016-11
期刊：
Molecular cancer research : MCR
影响因子：
--
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
通讯作者：
Richer JK