摘要
目的 探讨乳腺癌组织中雌激素受体α(ER α)的异质性表达与多种缺氧标志的关系。方法 5 1例经配体结合法证实ER阳性的乳腺癌患者 ,采用免疫组织化学染色的方法观察其ER α的异质性表达与多种缺氧标志的关系 ,同时观察体外缺氧环境对乳腺癌细胞系ER α表达的影响及其特异性。结果 4 9例乳腺癌为ER α阳性。无论乳腺导管内癌 (2 9例 )还是浸润性癌 (2 0例 ) ,ER α蛋白在邻近坏死灶的区域均下调 (P值分别≤ 0 .0 0 0 1) ;ER α的区域性下调还与缺氧诱导基因CA IX和Glut 1的表达有关 (P <0 .0 0 0 1)。缺氧可以直接诱导乳腺癌细胞系ER α蛋白和mRNA水平的下降 ,但其他一些应激因素 ,如低pH值、低糖及缺氧细胞的培养液等却无此作用。长时间、间歇性缺氧可以导致MCF 7细胞ER α表达的持久抑制。结论 乳腺癌ER α区域性的表达下降与缺氧有关 ,长时间、间歇性的缺氧可以持续性抑制ER α的表达。缺氧可能促使乳腺癌在进展过程中向ER α阴性的表型演变 ,并可能导致对内分泌治疗的耐药。
Objective To demonstrate the impact of hypoxia on ER-α in both breast cancer tissue and cell line, and its relationship with hypoxia-related parameters. Methods Expression of ER-α in 51 breast cancer patients with ER positive determined by ligand-binding assay was examined by immunohistochemistry and compared with CA-IX and Glut-1. Impact of hypoxia on breast cancer cell line MCF-7 (ER-α positive) was observed by Western Blot and RT-PCR. Results Of 51 breast cancer patients, 49 were ER-α positive. Regional decrease of ER-α expression was consistently observed in peri-necrotic regions as compared to distant regions in both in-situ carcinomas (n=29, P<0.0001) and invasive carcinomas (n=20, P=0.0001), which was closely associated with the induction of CA-IX and Glut-1 in hypoxia (P<0.0001). The decreased expression of ER-α protein and mRNA in breast cancer cell lines were attributed to hypoxia and not to other stress factors, such as reduced glucose, low pH, and products released from necrotic or hypoxic cells. Chronic intermittent hypoxia could cause persistent down-regulation of ER-α in the MCF-7 breast cancer cell line. Conclusion Regional hypoxia in breast cancer is associated with the reduced ER-α expression, and intermittent hypoxia can cause persistent down-regulation. Hypoxia may therefore contribute to the progression of ER-α negative status and potentially to the development of resistance to endocrine therapy.
出处
《中华肿瘤杂志》
CAS
CSCD
北大核心
2004年第11期664-668,共5页
Chinese Journal of Oncology
基金
国际抗癌联盟 (UICC)ICRETT基金资助项目 (2 0 0 2 76)
