Transforming acidic coiled coil 1 promotes transformation and mammary tumorigenesis
Transforming acidic coiled coil 1 promotes transformation and mammary tumorigenesis
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DOI：
10.1158/0008-5472.can-05-1633
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发表时间：
2005-11-15
期刊：
影响因子：
11.2
通讯作者：
Mak, TW
中科院分区：
文献类型：
--
作者：
Cully, M;Shiu, J;Mak, TW
转化酸性卷曲螺旋1（TACC 1）是一种假定的癌基因，位于人类染色体8 p11上发现的乳腺癌扩增子内。虽然TACC 1已被报道转化成纤维细胞，它也被下调的蒽环类药物治疗的乳腺肿瘤的子集。在这里，我们表明，异位TACC 1过表达可以与Ras合作，诱导小鼠成纤维细胞培养物中的病灶形成，并防止Pten或蛋白激酶B（PKB）/Akt的显性负性形式的过表达引起的死亡。在小鼠乳腺肿瘤病毒启动子控制下携带TACC 1的转基因小鼠中，TACC 1表达减少了乳腺退化过程中的细胞凋亡，增加了pten（+/-）背景下乳腺肿瘤的发生率，并降低了基于多瘤中T的磷脂酰肌醇T-激酶（PI 3 K）解耦突变体的小鼠模型中乳腺肿瘤发病的平均年龄。在含有TACC 1转基因的乳腺组织中发现磷酸化PKB和磷酸化细胞外信号调节激酶水平升高。因此，TACC 1正调控Ras和PI 3 K通路，促进Ras介导的转化，并防止由PI 3 K通路抑制诱导的细胞凋亡。TACC 1还与PI 3 K通路中的致瘤突变协同作用，从而在鼠乳腺中的肿瘤形成中发挥致癌作用。
Transforming acidic coiled coil 1 (TACC1) is a putative oncogene located within a breast cancer amplicon found on human chromosome 8p11. Although TACC1 has been reported to transform fibroblasts, it is also down-regulated in a subset of mammary tumors treated with anthracyclin. Here, we show that ectopic TACC1 overexpression can cooperate with Ras to induce focus formation in murine fibroblast cultures and prevent death caused by overexpression of Pten or a dominant-negative form of protein kinase B (PKB)/Akt. In transgenic mice carrying TACC1 under the control of the mouse mammary tumor virus promoter, TACC1 expression reduced apoptosis during mammary gland involution, increased the penetrance of mammary tumors in a pten(+/-) background, and decreased the average age of mammary tumor onset in a mouse model based on a phosphatidylinositol T-kinase (PI3K)-decoupled mutant of polyoma middle T. Elevated levels of both phospho-PKB and phospho-extracellular signal-regulated kinase were found in mammary tissue containing the TACC1 transgene. Thus, TACC1 positively regulates the Ras and PI3K pathways, promotes Ras-mediated transformation, and prevents apoptosis induced by PI3K pathway inhibition. TACC1 also cooperates with tumorigenic mutations in the PI3K pathway and thereby plays an oncogenic role in tumor formation in the murine mammary gland.