Overexpression of the death-promoting gene bax-alpha which is downregulated in breast cancer restores sensitivity to different apoptotic stimuli and reduces tumor growth in SCID mice
Overexpression of the death-promoting gene bax-alpha which is downregulated in breast cancer restores sensitivity to different apoptotic stimuli and reduces tumor growth in SCID mice
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DOI：
10.1172/jci118715
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发表时间：
1996-06-01
影响因子：
15.9
通讯作者：
Dorken, B
中科院分区：
文献类型：
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作者：
Bargou, RC;Wagener, C;Dorken, B
我们研究了bcl-2家族成员在人乳腺癌中的表达。将这些基因在乳腺癌组织样品中的表达模式与在正常乳腺上皮中的表达模式进行比较。bcl-2和bcl-xL在正常乳腺上皮和癌组织中的表达无明显差异。与此相反，bax-α，一种促进细胞凋亡的bax剪接变体，在正常乳腺上皮中大量表达，而在迄今为止检查的40个癌组织样本中只有39个检测到微弱或无表达。有趣的是，在不同的组织学亚型中发现了bax-α的下调。此外，我们转染bax-α到乳腺癌细胞系的四环素依赖性表达系统的控制下。我们首次证明，乳腺癌细胞系中Bax表达的诱导可以恢复对血清饥饿和APO-I/Fas-触发的细胞凋亡的敏感性，并显着减少SCID小鼠的肿瘤生长。因此，我们提出，凋亡失调可能有助于乳腺癌的发病机制，至少部分是由于bcl-2基因家族成员之间的不平衡。
We have studied the expression of members of the bcl-2 family in human breast cancer. The expression pattern of these genes in breast cancer tissue samples was compared with the expression pattern in normal breast epithelium. No marked difference with regard to bcl-2 and bcl-xL expression was observed between normal breast epithelium and cancer tissue. In contrast, bax-alpha, a splice variant of bax, which promotes apoptosis, is expressed in high amounts in normal breast epithelium, whereas only weak or no expression could be detected in 39 out of 40 cancer tissue samples examined so far. Of interest, downregulation of bax-alpha was found in different histological subtypes. Furthermore, we transfected bax-alpha into breast cancer cell lines under the control of a tetracycline-dependent expression system. We were able to demonstrate for the first time that induction of bax expression in breast cancer cell lines restores sensitivity towards both serum starvation and APO-I/Fas-triggered apoptosis and significantly reduces tumor growth in SCID mice. Therefore, we propose that dysregulation of apoptosis might contribute to the pathogenesis of breast cancer at least in part due to an imbalance between members of the bcl-2 gene family.