Park Seho, Koh Eunjin, Koo Ja Seung, Kim Seung Il, Park Byeong-Woo, Kim Kyung-Sup
Department of Surgery, Yonsei University College of Medicine, Seoul, South Korea.
Frontier Research Institute of Convergence Sports Science, Yonsei University, Seoul, South Korea.
Oncotarget. 2017 Sep 15;8(47):82940-82955. doi: 10.18632/oncotarget.20937. eCollection 2017 Oct 10.
The present study aimed to examine the associations between androgen receptor (AR) and forkhead box A1 (FOXA1) and to investigate clinicopathological features and survival according to both biomarker status in estrogen receptor (ER)-positive breast cancers using study, patient cohort data, and the cBioPortal for Cancer Genomics and Kaplan-Meier Plotter websites. Experiments using T47D and ZR75-1 demonstrated AR-overexpressing cell lines decreased in cell proliferation through downregulation of ER, but FOXA1 did not change. Knockdown of FOXA1 resulted in a significantly reduced cell viability. Patients with immunohistochemically AR(-)/FOXA1(-) tumor frequently showed node metastasis, high grade, and high Ki-67 proliferation, therefore, significantly worse survival in ER-positive disease. AR and FOXA1 mRNA levels were significantly higher in ER-positive than in ER-negative tumors and AR-low/FOXA1-low tumors showed high grade, frequent basal-like subtype and worse disease-free survival in ER-positive cancers of public gene dataset, similarly to patient cohort results. The Kaplan-Meier Plotter analysis independently validated patients with both low AR/FOXA1 tumor were significantly associated with worse relapse-free survival in ER-positive cancers. This study suggests that distinctive clinicopathological features according to AR and FOXA1 are determined and a lack of both biomarkers is an independent poor prognostic factor in ER-positive tumors.
本研究旨在探讨雄激素受体（AR）与叉头框A1（FOXA1）之间的关联，并利用研究、患者队列数据以及癌症基因组学cBioPortal和Kaplan-Meier Plotter网站，根据雌激素受体（ER）阳性乳腺癌中这两种生物标志物的状态，研究其临床病理特征和生存率。使用T47D和ZR75-1细胞系进行的实验表明，AR过表达的细胞系通过下调ER导致细胞增殖减少，但FOXA1没有变化。敲低FOXA1导致细胞活力显著降低。免疫组化显示AR（-）/FOXA1（-）肿瘤的患者经常出现淋巴结转移、高级别和高Ki-67增殖，因此，ER阳性疾病患者的生存率显著较差。在公共基因数据集中，ER阳性肿瘤中的AR和FOXA1 mRNA水平显著高于ER阴性肿瘤，AR低/FOXA1低的肿瘤显示高级别、频繁的基底样亚型以及ER阳性癌症中较差的无病生存率，这与患者队列结果相似。Kaplan-Meier Plotter分析独立验证了AR/FOXA1均低的肿瘤患者在ER阳性癌症中与较差的无复发生存率显著相关。本研究表明，根据AR和FOXA1可确定独特的临床病理特征，且这两种生物标志物的缺乏是ER阳性肿瘤中一个独立的不良预后因素。
