Estrogen-related receptor alpha is critical for the growth of estrogen receptor-negative breast cancer.
Estrogen-related receptor alpha is critical for the growth of estrogen receptor-negative breast cancer.
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DOI：
10.1158/0008-5472.can-08-1594
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发表时间：
2008-11-01
期刊：
影响因子：
11.2
通讯作者：
McDonnell DP
中科院分区：
文献类型：
--
作者：
Stein RA;Chang CY;Kazmin DA;Way J;Schroeder T;Wergin M;Dewhirst MW;McDonnell DP
雌激素相关受体α (ERRα)的表达最近被证明在乳腺癌和卵巢癌中具有阴性预后意义。然而，这种孤儿核受体在肿瘤生长和进展中的具体作用尚不完全清楚。雌激素受体α (ERα)和ERRα之间的显著同源性最初表明这些受体可能具有相似的转录靶点。利用具有良好特征的er α阳性MCF-7乳腺癌细胞系，我们试图使用无偏倚微阵列方法获得ERα-ERRα串扰的全基因组图像。除了产生大量新的ERRα靶基因外，该研究还得出了令人惊讶的结果，即大多数ERRα调控基因与雌激素信号传导无关。ERα和ERRα调控的基因数量相对较少，这使得我们将研究扩展到更具侵袭性和临床治疗较少的ERα阴性乳腺癌。在这种情况下，我们发现ERRα表达是许多已知和新的ERRα靶基因表达的基础水平所必需的。在高侵袭性乳腺癌MDA-MB-231细胞系中引入指向ERRα的siRNA可显著降低这些细胞的迁移潜力。虽然稳定下调MDA-MB-231细胞中ERRα的表达对体外细胞增殖没有影响，但当这些细胞作为异种移植物植入时，观察到肿瘤生长速度显著降低。我们的研究结果证实了ERRα在乳腺癌生长中的作用，并强调了它作为雌激素受体阴性乳腺癌的潜在治疗靶点。
Expression of estrogen-related receptor alpha (ERRα) has recently been shown to carry negative prognostic significance in breast and ovarian cancers. The specific role of this orphan nuclear receptor in tumor growth and progression, however, is yet to be fully understood. The significant homology between estrogen receptor alpha (ERα) and ERRα initially suggested that these receptors may have similar transcriptional targets. Using the well-characterized ERα-positive MCF-7 breast cancer cell line, we sought to gain a genome-wide picture of ERα-ERRα cross-talk using an unbiased microarray approach. In addition to generating a host of novel ERRα target genes, this study yielded the surprising result that most ERRα-regulated genes are unrelated to estrogen-signaling. The relatively small number of genes regulated by both ERα and ERRα led us to expand our study to the more aggressive and less clinically treatable ERα-negative class of breast cancers. In this setting we found that ERRα expression is required for the basal level of expression of many known and novel ERRα target genes. Introduction of an siRNA directed to ERRα into the highly aggressive breast carcinoma MDA-MB-231 cell line dramatically reduced the migratory potential of these cells. Although stable knockdown of ERRα expression in MDA-MB-231 cells had no impact on in vitro cell proliferation, a significant reduction of tumor growth rate was observed when these cells were implanted as xenografts. Our results confirm a role for ERRα in breast cancer growth and highlight it as a potential therapeutic target for estrogen receptor-negative breast cancer.