Re-expression of detachment-inducible chloride channel mCLCA5 suppresses growth of metastatic breast cancer cells
Re-expression of detachment-inducible chloride channel mCLCA5 suppresses growth of metastatic breast cancer cells
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DOI：
10.1074/jbc.m408334200
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发表时间：
2004-10-01
影响因子：
4.8
通讯作者：
Elble, RC
中科院分区：
文献类型：
--
作者：
Beckley, JR;Pauli, BU;Elble, RC
钙激活的氯离子通道hCLCA 2已被确定为人类乳腺癌的候选肿瘤抑制因子。它在乳腺癌中被大大下调，并且它的重新表达通过未知的机制抑制肿瘤发生。为了建立小鼠模型，我们鉴定了hCLCA 2的小鼠直系同源物，称为mCLCA 5，并研究了其在乳腺上皮细胞系和组织中的行为。在永生化细胞系HC 11中的表达与缓慢或停滞的生长相关。虽然快速分裂，稀疏铺板的细胞有低水平的表达，mCLCA 5诱导10倍时，细胞变得融合和30倍时，细胞被剥夺的生长因子或锚定。平行诱导凋亡效应物Bax。与hCLCA 2一样，mCLCA 5在转移性乳腺肿瘤细胞系如4 T1和CSML-100中下调。在4 T1细胞中的异位再表达导致集落存活相对于载体对照减少20倍。稳定克隆中高mCLCA 5表达抑制增殖并增强对脱离的敏感性。此外，mCLCA 5在泌乳和退化乳腺中被诱导，与分化和细胞凋亡的发生相关。总之，这些结果确立了mCLCA 5作为hCLCA 2的小鼠直系同源物，证明mCLCA 5是一种对肿瘤敏感的生长抑制剂，并提出了这些通道可拮抗乳腺肿瘤进展的机制。
The calcium-activated chloride channel hCLCA2 has been identified as a candidate tumor suppressor in human breast cancer. It is greatly down-regulated in breast cancer, and its re-expression suppresses tumorigenesis by an unknown mechanism. To establish a mouse model, we identified the mouse ortholog of hCLCA2, termed mCLCA5, and investigated its behavior in mammary epithelial cell lines and tissues. Expression in the immortalized cell line HC11 correlated with slow or arrested growth. Although rapidly dividing, sparsely plated cells had low levels of expression, mCLCA5 was induced by 10-fold when cells became confluent and 30-fold when cells were deprived of growth factors or anchorage. The apoptosis effector Bax was induced in parallel. Like hCLCA2, mCLCA5 was down-regulated in metastatic mammary tumor cell lines such as 4T1 and CSML-100. Ectopic re-expression in 4T1 cells caused a 20-fold reduction in colony survival relative to vector control. High mCLCA5 expression in stable clones inhibited proliferation and enhanced sensitivity to detachment. Moreover, mCLCA5 was induced in lactating and involuting mammary gland, correlating with differentiation and onset of apoptosis. Together, these results establish mCLCA5 as the mouse ortholog of hCLCA2, demonstrate that mCLCA5 is a detachment-sensitive growth inhibitor, and suggest a mechanism whereby these channels may antagonize mammary tumor progression.