脯氨酰羟化酶与缺氧诱导因子-1α和血管内皮生长因子在人乳腺癌中呈正相关，并对表阿霉素和他莫昔芬的原发性全身治疗有反应而改变。
The prolyl hydroxylase enzymes are positively associated with hypoxia-inducible factor-1α and vascular endothelial growth factor in human breast cancer and alter in response to primary systemic treatment with epirubicin and tamoxifen.
机构信息
Peter MacCallum Cancer Centre, St Andrews Place, East Melbourne, Victoria 3002, Australia.
出版信息
Breast Cancer Res. 2011 Feb 3;13(1):R16. doi: 10.1186/bcr2825.
INTRODUCTION
The purpose of the present study was to investigate the relationship of expression of hypoxia inducible factor (HIF)-1α-modifying enzymes prolyl hydroxylase (PHD)1, PHD2 and PHD3 to response of tumours and survival in breast cancer patients enrolled in a phase II trial of neoadjuvant anthracycline and tamoxifen therapy.
METHODS
The expression of PHD1, PHD2 and PHD3 together with HIF-1α and the HIF-inducible genes vascular endothelial cell growth factor (VEGF) and carbonic anhydrase IX were assessed by immunohistochemistry using a tissue microarray approach in 211 patients with T2-4 N0-1 breast cancer enrolled in a randomised trial comparing single-agent epirubicin versus epirubicin and tamoxifen as the primary systemic treatment.
RESULTS
PHD1, PHD2 and PHD3 were detected in 47/179 (26.7%), 85/163 (52.2%) and 69/177 (39%) of tumours at baseline. PHD2 and PHD3 expression was moderate/strong whereas PHD1 expression was generally weak. There was a significant positive correlation between HIF-1α and PHD1 (P = 0.002) and PHD3 (P < 0.05) but not PHD2 (P = 0.41). There was a significant positive relationship between VEGF and PHD1 (P < 0.008) and PHD3 (P = 0.001) but not PHD2 (P = 0.09). PHD1, PHD2 and PHD3 expression was significantly increased after epirubicin therapy (all P < 0.000) with no significant difference in PHD changes between the treatment arms. There was no significant difference in response in tumours that expressed PHDs and PHD expression was not associated with survival.
CONCLUSIONS
Although expression of the PHDs was not related to response or survival in patients receiving neoadjuvant epirubicin, our data provide the first evidence that these enzymes are upregulated on therapy in breast cancer and that the biological effects independent of HIF make them therapeutic targets.
简介
本研究的目的是探讨缺氧诱导因子（HIF）-1α修饰酶脯氨酰羟化酶（PHD）1、PHD2 和 PHD3 的表达与接受新辅助蒽环类和他莫昔芬治疗的乳腺癌患者肿瘤反应和生存的关系。
方法
采用组织微阵列方法，用免疫组化法检测 211 例 T2-4N0-1 期乳腺癌患者的 PHD1、PHD2 和 PHD3 以及 HIF-1α和 HIF 诱导基因血管内皮生长因子（VEGF）和碳酸酐酶 IX 的表达，这些患者入组了一项比较单药表柔比星与表柔比星联合他莫昔芬作为原发性全身治疗的随机试验。
结果
基线时，211 例患者中有 47/179（26.7%）、85/163（52.2%）和 69/177（39%）的肿瘤中检测到 PHD1、PHD2 和 PHD3。PHD2 和 PHD3 的表达为中/强，而 PHD1 的表达通常较弱。HIF-1α与 PHD1（P=0.002）和 PHD3（P<0.05）呈显著正相关，但与 PHD2（P=0.41）无显著相关性。VEGF 与 PHD1（P<0.008）和 PHD3（P=0.001）呈显著正相关，但与 PHD2（P=0.09）无显著相关性。表柔比星治疗后 PHD1、PHD2 和 PHD3 的表达均显著增加（均 P<0.000），但治疗组之间 PHD 变化无显著差异。在表达 PHD 的肿瘤中，反应无显著差异，PHD 表达与生存无关。
结论
尽管新辅助表柔比星治疗的患者中 PHD 的表达与反应或生存无关，但我们的数据首次提供了证据，表明这些酶在乳腺癌中治疗后上调，并且独立于 HIF 的生物学效应使它们成为治疗靶点。
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