Gata-3 Negatively Regulates the Tumor-Initiating Capacity of Mammary Luminal Progenitor Cells and Targets the Putative Tumor Suppressor Caspase-14
Gata-3 Negatively Regulates the Tumor-Initiating Capacity of Mammary Luminal Progenitor Cells and Targets the Putative Tumor Suppressor Caspase-14
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DOI：
10.1128/mcb.05766-11
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发表时间：
2011-11-01
影响因子：
5.3
通讯作者：
Visvader, Jane E.
中科院分区：
文献类型：
--
作者：
Asselin-Labat, Marie-Liesse;Sutherland, Kate D.;Visvader, Jane E.
转录因子加塔-3是管腔型乳腺癌的决定性标志物，也是乳腺形态发生的关键调节因子。在这里，我们已经探索了加塔-3在肿瘤起始中的作用和使用“管腔样”癌症的小鼠模型的潜在细胞机制。在携带小鼠乳腺肿瘤病毒启动子驱动的多瘤病毒中T抗原的小鼠（MMTV-PyMT小鼠）中，单个加塔-3等位基因的缺失显著加速了肿瘤进展，而加塔-3的过表达减少了肿瘤发生。通过鉴定乳腺中两种不同的管腔祖细胞，我们证明了加塔-3单倍不足增加了这些祖细胞的肿瘤起始能力，但不是干细胞富集的群体。PyMT模型中条件性加塔-3转基因的过表达促进了细胞分化，并导致肿瘤起始能力降低以及血管生成减少。转录谱研究确定半胱天冬酶-14作为加塔-3的新下游靶点，与其在分化和肿瘤发生中的作用一致。在浸润前导管癌原位样本中，加塔-3和caspase-14表达之间存在明显的强相关性，其中加塔-3也显示出预后意义。总之，这些研究通过其促进定向管腔祖细胞分化的能力将加塔-3鉴定为肿瘤起始的重要调节剂。
The transcription factor Gata-3 is a definitive marker of luminal breast cancers and a key regulator of mammary morphogenesis. Here we have explored a role for Gata-3 in tumor initiation and the underlying cellular mechanisms using a mouse model of "luminal-like" cancer. Loss of a single Gata-3 allele markedly accelerated tumor progression in mice carrying the mouse mammary tumor virus promoter-driven polyomavirus middle T antigen (MMTV-PyMT mice), while overexpression of Gata-3 curtailed tumorigenesis. Through the identification of two distinct luminal progenitor cells in the mammary gland, we demonstrate that Gata-3 haplo-insufficiency increases the tumor-initiating capacity of these progenitors but not the stem cell-enriched population. Overexpression of a conditional Gata-3 transgene in the PyMT model promoted cellular differentiation and led to reduced tumor-initiating capacity as well as diminished angiogenesis. Transcript profiling studies identified caspase-14 as a novel downstream target of Gata-3, in keeping with its roles in differentiation and tumorigenesis. A strong association was evident between GATA-3 and caspase-14 expression in preinvasive ductal carcinoma in situ samples, where GATA-3 also displayed prognostic significance. Overall, these studies identify GATA-3 as an important regulator of tumor initiation through its ability to promote the differentiation of committed luminal progenitor cells.