Interaction of Developmental Transcription Factor HOXC11 with Steroid Receptor Coactivator SRC-1 Mediates Resistance to Endocrine Therapy in Breast Cancer
Interaction of Developmental Transcription Factor HOXC11 with Steroid Receptor Coactivator SRC-1 Mediates Resistance to Endocrine Therapy in Breast Cancer
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DOI：
10.1158/0008-5472.can-09-3713
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发表时间：
2010-02-15
期刊：
影响因子：
11.2
通讯作者：
Young, Leonie S.
中科院分区：
文献类型：
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作者：
McIlroy, Marie;McCartan, Damian;Young, Leonie S.
乳腺癌内分泌治疗获得性耐药的机制是一个主要的临床挑战，目前还知之甚少。我们已经使用基于质谱的筛选来鉴定与内分泌抵抗表型相关的蛋白质。在这项研究中，我们报告了一种新的内分泌治疗耐药途径的鉴定，该途径涉及发育转录HOXC 11与类固醇受体共激活蛋白SRC-1的相互作用，SRC-1是乳腺癌患者无病生存率降低的强有力预测因子。HOXC 11和SRC-1协同调节耐药乳腺癌细胞中钙结合蛋白S100 β的表达核HOXC 11和S100 β被发现强烈预测乳腺癌患者的无病生存率（n = 560;风险比：分别为5.79和5.82; P < 0.0001）。在患者中检测到的血清S100 β水平升高也预测无病生存率降低（n = 80;风险比：5.3; P = 0.004）。我们的研究结果定义了一个生物分子相互作用网络，该网络驱动对内分泌治疗的适应性反应，对乳腺癌的生存产生负面影响。Cancer Res; 70（4）; 1585-94. (C)2010年AACR。
Mechanisms of acquired resistance to endocrine therapy in breast cancer, a major clinical challenge, are poorly understood. We have used a mass spectrometry-based screen to identify proteins that are associated with the endocrine-resistant phenotype. In this study, we report the identification of a novel pathway of resistance to endocrine therapy involving interactions of the developmental transcription HOXC11 with the steroid receptor coactivator protein SRC-1, which is a strong predictor of reduced disease-free survival in breast cancer patients. HOXC11 and SRC-1 cooperate to regulate expression of the calcium-binding protein S100 beta in resistant breast cancer cells. Nuclear HOXC11 and S100 beta were found to strongly predict poor disease-free survival in breast cancer patients (n = 560; hazard ratios: 5.79 and 5.82, respectively; P < 0.0001). Elevated serum levels of S100 beta detected in patients also predicted reduced disease-free survival (n = 80; hazard ratio: 5.3; P = 0.004). Our findings define a biomolecular interaction network that drives an adaptive response to endocrine therapy with negative consequences for survival in breast cancer. Cancer Res; 70(4); 1585-94. (C) 2010 AACR.