GREB1 is a critical regulator of hormone dependent breast cancer growth
GREB1 is a critical regulator of hormone dependent breast cancer growth
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DOI：
10.1007/s10549-005-1483-4
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发表时间：
2005-07-01
影响因子：
3.8
通讯作者：
Lippman, ME
中科院分区：
文献类型：
--
作者：
Rae, JM;Johnson, MD;Lippman, ME
雌激素在乳腺癌的发病机制中起着核心作用，许多潜在的疾病发展危险因素可以用终生暴露于雌激素的增加来解释。虽然雌激素调节基因已经被确定，但那些与生长调节有关的关键基因仍然难以捉摸。为了确定参与雌激素刺激乳腺癌生长的候选基因，我们从三个雌激素受体α (ER α)阳性的乳腺癌细胞系中提取了DNA微阵列基因表达谱，这些细胞系在多种刺激和抑制条件下生长。结果17 β -雌二醇（E2）在3种细胞系中均对GREB1、基质细胞衍生因子1 （SDF-1）和三叶因子1 （pS2）三个基因有明显诱导作用。实时荧光定量PCR检测证实，在所有三种细胞系中，GREB1均可被E2诱导，而抗雌激素药物他莫昔芬（TAM）或ICI 182780不能诱导。在已知ER α表达状态的39株乳腺癌细胞系中，GREB1表达水平与ER α阳性呈强相关。E2对GREB1的诱导是快速的（MCF-7在2小时内达到7.3倍），并且反映了从雌激素剥夺诱导的细胞停滞中释放后进入s期的细胞比例。使用siRNA抑制GREB1可阻断雌激素诱导的MCF-7细胞生长，并引起E2诱导的生长抑制。结论GREB1在雌激素诱导的乳腺癌细胞生长过程中起重要作用，有可能成为内分泌治疗应答的临床标志物和潜在的治疗靶点。
Background Estrogen plays a central role in breast cancer pathogenesis and many potent risk factors for the development of the disease can be explained in terms of increased lifetime exposure to estrogen. Although estrogen regulated genes have been identified, those critically involved in growth regulation remain elusive.Methods. To identify candidate genes involved in estrogen stimulated breast cancer growth, DNA microarray based gene expression profiles were generated from three estrogen receptor alpha (ER alpha) positive breast cancer cell lines grown under multiple stimulatory and inhibitory conditions.Results Only three genes were significantly induced by 17 beta- estradiol (E2) relative to control in all three cell lines: GREB1, stromal cell-derived factor 1 (SDF-1) and trefoil factor 1 (pS2). Quantitative real-time PCR assays confirmed that in all three cell lines, GREB1 was induced by E2, but not by the antiestrogens tamoxifen (TAM) or ICI 182,780. GREB1 expression level was strongly correlated with ER alpha positivity in 39 breast cancer cell lines of known ER alpha expression status. GREB1 induction by E2 was rapid (7.3 fold by 2 h for MCF-7) and mirrored the fraction of cells entering S-phase when released from an estrogen deprivation induced cell arrest. Suppression of GREB1 using siRNA blocked estrogen induced growth in MCF-7 cells and caused a paradoxical E2 induced growth inhibition.Conclusion These data suggest that GREB1 is critically involved in the estrogen induced growth of breast cancer cells and has the potential of being a clinical marker for response to endocrine therapy as well as a potential therapeutic target.