Tamoxifen-induced ER-α-SRC-3 interaction in HER2 positive human breast cancer;: a possible mechanism for ER isoform specific recurrence
Tamoxifen-induced ER-α-SRC-3 interaction in HER2 positive human breast cancer;: a possible mechanism for ER isoform specific recurrence
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DOI：
10.1677/erc.1.01222
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发表时间：
2006-12-01
影响因子：
3.9
通讯作者：
Young, Leonie S.
中科院分区：
文献类型：
--
作者：
Mc Ilroy, Marie;Fleming, Fergal J.;Young, Leonie S.
两种雌激素受体（ER）异构体在他莫昔芬存在下的差异信号传导已被描述。我们假设，类固醇受体共激活剂SRC-3对ER- α和ER- β的不同募集可能部分解释了ER亚型与内分泌治疗反应之间的关联。SRC-3定位于乳腺肿瘤组织上皮细胞内，并与er - α和er - β共定位（n= 112）。SRC-3的表达与er - α呈正相关（P= 0.0021），与er - β呈负相关（P < 0.0001）。独特的是，这项研究利用了来自患者肿瘤的原代细胞培养，从而提供了在大多数分子模型系统中不易获得的样本。这些样本使我们能够研究生长因子途径对类固醇受体-共激活剂相互作用的影响。在HER2（人表皮生长因子受体2）阳性的原发肿瘤细胞培养中，17 β -雌二醇诱导SRC-3表达降低，而上调SRC-3表达。此外，他莫昔芬治疗诱导SRC-3募集到er -雌激素反应元件，并增强SRC-3与er - α的相互作用，而不是er - β。SRC-3的敲低导致雌激素靶基因pS2的表达缺失。此外，SRC-3的沉默使内分泌抵抗的HER2阳性细胞对他莫昔芬的抗增殖作用重新敏感。在他莫昔芬存在的情况下，ER-a而不是ER- p招募SRC-3的能力可能部分解释了ER异构体与人类乳腺癌复发的差异。
Differential signalling between the two oestrogen receptor (ER) isoforms in the presence of tamoxifen has been described. We hypothesise that differential recruitment of the steroid receptor co-activator, SRC-3 to ER-alpha and ER-beta may in part explain associations between ER isoforms and response to endocrine treatment. SRC-3 was localised within epithelial cells of breast tumour tissue and was co-localised with ER-alpha and ER-beta, (n= 112). Expression of SRC-3 was found to be positively associated with ER-alpha (P= 0.0021) and inversely with ER-beta (P < 0.0001). Uniquely, this study utilises primary cell cultures derived from patient tumours, thus providing samples not readily available in most molecular model systems. These samples have enabled us to investigate the influence of growth factor pathways on steroid receptor-co-activator interactions. In HER2 (human epidermal growth factor receptor 2) positive primary tumour cell cultures 17 beta-estradiol induced a decrease in SRC-3, whereas upregulated SRC-3 expression. Furthermore, treatment with tamoxifen-induced SRC-3 recruitment to the ER-oestrogen response element and enhanced interaction between SRC-3 and ER-alpha, but not ER-beta. Knockdown of SRC-3 results in a concomitant loss of expression of the oestrogen target gene pS2. Furthermore, silencing of SRC-3 resensitizes endocrine resistant, HER2 positive cells to the anti-proliferative effects of tamoxifen. The ability of ER-a, but not ER-P to recruit SRC-3 in the presence of tamoxifen may in part explain the differential ER isoform associations with recurrence in human breast cancer.