Ge K, Duhadaway J, Sakamuro D, Wechsler-Reya R, Reynolds C, Prendergast G C
The Wistar Institute, Philadelphia, PA, USA.
Int J Cancer. 2000 Feb 1;85(3):376-83.
Oncogenic activation of MYC occurs often in breast carcinoma and is associated with poor prognosis. Loss or inactivation of mechanisms that restrain MYC may therefore be involved in tumor progression. In this study, we show that the MYC-interacting adaptor protein BIN1 is frequently missing in malignant breast cells and that this loss is functionally significant. BIN1 was expressed in normal and benign cells and tissues but was undetectable in 6/6 estrogen receptor-positive or estrogen receptor-negative carcinoma cell lines examined. Similarly, complete or partial losses of BIN1 were documented in 30/50 (60%) cases of malignant breast tissue analyzed by immuno-histochemistry or RT-PCR. Abnormalities in the organization of the BIN1 gene were apparent in only a minority of these cases, suggesting that most losses were due to epigenetic causes. Nevertheless, they were functionally significant because ectopic BIN1 induced programmed cell death in malignant cells lacking endogenous BIN1 but had no effect on the viability of benign cells. We propose that loss of BIN1 may contribute to breast cancer progression by eliminating a mechanism that restrains the ability of activated MYC to drive cell division inappropriately.
MYC的致癌激活在乳腺癌中经常发生，并且与预后不良相关。因此，抑制MYC的机制丧失或失活可能参与肿瘤进展。在本研究中，我们表明与MYC相互作用的衔接蛋白BIN1在恶性乳腺细胞中经常缺失，并且这种缺失具有功能上的重要意义。BIN1在正常细胞和良性细胞及组织中表达，但在所检测的6/6雌激素受体阳性或雌激素受体阴性癌细胞系中均未检测到。同样，通过免疫组织化学或逆转录聚合酶链反应分析的50例恶性乳腺组织中有30例（60%）记录到BIN1完全或部分缺失。在这些病例中只有少数出现BIN1基因结构异常，这表明大多数缺失是由表观遗传原因导致的。然而，它们在功能上具有重要意义，因为异位表达的BIN1可诱导缺乏内源性BIN1的恶性细胞发生程序性细胞死亡，但对良性细胞的活力没有影响。我们认为，BIN1的缺失可能通过消除一种抑制活化的MYC驱动细胞异常分裂能力的机制，从而促进乳腺癌进展。
