Department of Anatomy and Cell Biology, University of Western Ontario, London, Ontario, Canada.
Oncogene. 2011 Apr 7;30(14):1681-92. doi: 10.1038/onc.2010.551. Epub 2010 Dec 13.
Gap junctions, the channels formed by the connexin (Cx) family of proteins, are responsible for direct intercellular communication. Although connexins are considered as tumor suppressors, their overall role in cancer onset, progression and metastasis is somewhat controversial. This study uses a novel Cx43 mutant mouse model (G60S mice) and cross-breeding strategies to determine the role of Cx43 in all stages of breast tumorigenesis. G60S mice were cross-bred with ErbB2 overexpressing mice, and spontaneous and 7,12-dimethylbenz[α]anthracene (DMBA)-induced tumor development was evaluated. Mice were killed when tumors reached ∼1 cm(3) or when mice showed signs of critical illness. In both spontaneous and DMBA studies, onset of palpable tumors was delayed in G60S mice compared with mice in control groups. Moreover, while tumors from control mice reached the size threshold, most DMBA-exposed Cx43 mutant mice were killed prematurely because of labored breathing, independent of the presence of a palpable tumor. Reduced Cx43 levels in Cx43 mutant mice were accompanied by extensive mammary gland hyperplasia. Lung histology revealed that all Cx43 mutant mice exhibited mammaglobin-positive mammary gland metastases to the lung, and the number of metastases was increased by threefold in Cx43 mutant mice on treatment with DMBA. Thus, while reduced levels of Cx43 delayed the onset of palpable tumors, normal Cx43 levels inhibited mammary gland tumor metastasis to the lungs. Understanding the mechanisms of how Cx43, which is expressed primarily in myoepithelial cells, inhibits mammary gland tumor metastasis is critical as Cx43 is assessed as a candidate for therapeutic intervention.
间隙连接是由连接蛋白（Cx）家族蛋白形成的通道，负责细胞间的直接通讯。尽管连接蛋白被认为是肿瘤抑制因子，但它们在癌症发生、进展和转移中的整体作用仍存在争议。本研究使用一种新型 Cx43 突变小鼠模型（G60S 小鼠）和杂交策略来确定 Cx43 在乳腺癌发生的所有阶段中的作用。将 G60S 小鼠与过表达 ErbB2 的小鼠杂交，并评估自发性和 7,12-二甲基苯并[a]蒽（DMBA）诱导的肿瘤发生。当肿瘤达到约 1cm³或当小鼠出现病危迹象时，杀死小鼠。在自发性和 DMBA 研究中，与对照组相比，G60S 小鼠的可触及肿瘤的发病时间延迟。此外，虽然对照组小鼠的肿瘤达到了大小阈值，但由于呼吸困难，大多数 DMBA 暴露的 Cx43 突变小鼠过早死亡，而与是否有可触及的肿瘤无关。Cx43 突变小鼠中 Cx43 水平降低伴随着广泛的乳腺增生。肺组织学显示，所有 Cx43 突变小鼠的肺中均有乳腺球蛋白阳性的乳腺转移，并且在 Cx43 突变小鼠中用 DMBA 处理后，转移的数量增加了三倍。因此，虽然 Cx43 水平降低延迟了可触及肿瘤的发生，但正常的 Cx43 水平抑制了乳腺肿瘤向肺部的转移。了解 Cx43（主要在肌上皮细胞中表达）如何抑制乳腺肿瘤转移的机制至关重要，因为 Cx43 被评估为治疗干预的候选物。
