Racial Differences in Androgen Receptor (AR) and AR Splice Variants (AR-SVs) Expression in Treatment-Naïve Androgen-Dependent Prostate Cancer.
Racial Differences in Androgen Receptor (AR) and AR Splice Variants (AR-SVs) Expression in Treatment-Naïve Androgen-Dependent Prostate Cancer.
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DOI：
10.3390/biomedicines11030648
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发表时间：
2023-02-21
期刊：
影响因子：
4.7
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中科院分区：
文献类型：
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雄激素受体剪接变异体（AR-SVs）有助于去势抵抗性前列腺癌（CRPC）的侵袭性生长。AR-SVs，包括AR-V7，在约30%的CRPC中表达，但在treatment-naïve原发性前列腺癌（PCa）中表达最少。与高加索美国人（CA）相比，非洲裔美国人（AA）男性更容易被诊断为侵袭性/潜在致命性PCa，无病生存期更短。在一名AA患者原发PCa标本的患者源异种移植物中表达截断的AR，这使我们假设AR- svs的表达可能是AA男性PCa进展和CRPC阶段侵袭性生长的一个指标。利用118例AA和115例CA treatment-naïve PCa患者的福尔马林固定石蜡包埋（FFPE）前列腺切除术肿瘤块构建组织微阵列（tma）。tma用AR- v7特异性抗体和AR的n -末端结构域（NTD）和配体结合结构域（LBD）结合的抗体进行染色。由于已经鉴定了超过20种AR- svs，并且大多数AR- svs尚未具有特异性抗体，因此我们认为NTD与LBD染色的2.0倍或更大差异是AR- sv潜在表达的指示。2例AA，无CA，患者肿瘤AR-V7染色阳性。在大多数患者中，用NTD和LBD抗体进行AR染色是稳健的，21%的患者NTD的染色至少是LBD的2倍，这表明除了AR- v7之外，AR- svs在原发性treatment-naïve PCa中表达。约24%的患者为AR阴性，种族间AR表达差异无统计学意义。这些结果表明AR-SVs不仅局限于CRPC，而且在原发性PCa中的表达率也高于先前报道。未来对NTD与LBD AR-SVs相对表达的研究可以指导在治疗范式中更早地使用针对NTD的新开发的治疗方法。
Androgen receptor splice variants (AR-SVs) contribute to the aggressive growth of castration-resistant prostate cancer (CRPC). AR-SVs, including AR-V7, are expressed in ~30% of CRPC, but minimally in treatment-naïve primary prostate cancer (PCa). Compared to Caucasian American (CA) men, African American (AA) men are more likely to be diagnosed with aggressive/potentially lethal PCa and have shorter disease-free survival. Expression of a truncated AR in an aggressively growing patient-derived xenograft developed with a primary PCa specimen from an AA patient led us to hypothesize that the expression of AR-SVs could be an indicator of aggressive growth both in PCa progression and at the CRPC stage in AA men. Tissue microarrays (TMAs) were created from formalin-fixed paraffin-embedded (FFPE) prostatectomy tumor blocks from 118 AA and 115 CA treatment-naïve PCa patients. TMAs were stained with AR-V7-speicifc antibody and with antibodies binding to the N-terminus domain (NTD) and ligand-binding domain (LBD) of the AR. Since over 20 AR-SVs have been identified, and most AR-SVs do not as yet have a specific antibody, we considered a 2.0-fold or greater difference in the NTD vs. LBD staining as indication of potential AR-SV expression. Two AA, but no CA, patient tumors stained positively for AR-V7. AR staining with NTD and LBD antibodies was robust in most patients, with 21% of patients staining at least 2-fold more for NTD than LBD, indicating that AR-SVs other than AR-V7 are expressed in primary treatment-naïve PCa. About 24% of the patients were AR-negative, and race differences in AR expression were not statistically significant. These results indicate that AR-SVs are not restricted to CRPC, but also are expressed in primary PCa at higher rate than previously reported. Future investigation of the relative expression of NTD vs. LBD AR-SVs could guide the use of newly developed treatments targeting the NTD earlier in the treatment paradigm.
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DOI：
10.1073/pnas.1308587110
发表时间：
2013-10-22
影响因子：
11.1
作者：
Nyquist, Michael D.;Li, Yingming;Dehm, Scott M.
通讯作者：
Dehm, Scott M.
影响因子：
3.9
作者：
Dehm SM;Tindall DJ
通讯作者：
Tindall DJ
影响因子：
50.3
作者：
Andersen, Raymond J.;Mawji, Nasrin R.;Sadar, Marianne D.
通讯作者：
Sadar, Marianne D.
影响因子：
2.3
作者：
Cohen, JH;Schoenbach, VJ;Godley, PA
通讯作者：
Godley, PA
影响因子：
158.5
作者：
CRAWFORD, ED;EISENBERGER, MA;GOODMAN, PJ
通讯作者：
GOODMAN, PJ