ErbB4 Splice Variants Cyt1 and Cyt2 Differ by 16 Amino Acids and Exert Opposing Effects on the Mammary Epithelium In Vivo
ErbB4 Splice Variants Cyt1 and Cyt2 Differ by 16 Amino Acids and Exert Opposing Effects on the Mammary Epithelium In Vivo
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DOI：
10.1128/mcb.01705-08
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发表时间：
2009-09-15
影响因子：
5.3
通讯作者：
Earp, H. Shelton, III
中科院分区：
文献类型：
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作者：
Muraoka-Cook, Rebecca S.;Sandahl, Melissa A.;Earp, H. Shelton, III
关于ErbB 4在乳腺癌中的预后价值和对细胞生长的影响的数据在已发表的报告中有所不同，这可能是由于细胞内蛋白水解ErbB 4 s80（HER 4）片段表达的未知信号传导结果，或者由于选择性剪接的ErbB 4亚型的不同信号传导能力。一种亚型（Cyt 1）含有一个16残基的细胞内序列，而另一种亚型（Cyt 2）则没有。我们在HC 11乳腺上皮细胞中表达s80（Cyt 1）和s80（Cyt 2），发现对三维基质中集落的生长和组织有截然相反的影响。而s80（Cyt 1）的表达减少了生长，并增加了三维管腔形成的速度，s80（Cyt 2）的增加增殖，而不促进管腔形成。这些结果在体内重演，使用强力霉素诱导，小鼠乳房转基因表达的s80（Cyt 1）和s80（Cyt 2）。s80（Cyt 1）的表达降低了乳腺导管上皮细胞的生长，导致过早的STAT 5a激活和催乳分化，并增加了细胞表面E-钙粘蛋白水平。值得注意的是，导管生长抑制s80（Cyt 1）发生的同时，小叶肺泡生长，是畅通无阻的s80（Cyt 1），这表明ErbB 4的反应可能会受到影响的上皮亚型。与此相反，s80（Cyt 2）的表达引起上皮增生，增加Wnt和核β-连环蛋白的表达，并在乳腺上皮c-myc和细胞周期蛋白D1的表达升高。这些结果表明，细胞色素1和细胞色素2 ErbB 4亚型，不同的只有16个氨基酸，表现出显着相反的乳腺上皮细胞的生长和分化的影响。
Data concerning the prognostic value of ErbB4 in breast cancer and effects on cell growth have varied in published reports, perhaps due to the unknown signaling consequences of expression of the intracellular proteolytic ErbB4 s80(HER4) fragment or due to differing signaling capabilities of alternatively spliced ErbB4 isoforms. One isoform (Cyt1) contains a 16-residue intracellular sequence that is absent from the other (Cyt2). We expressed s80(Cyt1) and s80(Cyt2) in HC11 mammary epithelial cells, finding diametrically opposed effects on the growth and organization of colonies in three-dimensional matrices. Whereas expression of s80(Cyt1) decreased growth and increased the rate of three-dimensional lumen formation, that of s80(Cyt2) increased proliferation without promoting lumen formation. These results were recapitulated in vivo, using doxycycline-inducible, mouse breast-transgenic expression of s80(Cyt1) amd s80(Cyt2). Expression of s80(Cyt1) decreased growth of the mammary ductal epithelium, caused precocious STAT5a activation and lactogenic differentiation, and increased cell surface E-cadherin levels. Remarkably, ductal growth inhibition by s80(Cyt1) occurred simultaneously with lobuloalveolar growth that was unimpeded by s80(Cyt1), suggesting that the response to ErbB4 may be influenced by the epithelial subtype. In contrast, expression of s80(Cyt2) caused epithelial hyperplasia, increased Wnt and nuclear beta-catenin expression, and elevated expression of c-myc and cyclin D1 in the mammary epithelium. These results demonstrate that the Cyt1 and Cyt2 ErbB4 isoforms, differing by only 16 amino acids, exhibit markedly opposing effects on mammary epithelium growth and differentiation.