Foxa1 is essential for mammary duct formation.
Foxa1 is essential for mammary duct formation.
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DOI：
10.1002/dvg.22929
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发表时间：
2016-05
期刊：
影响因子：
--
通讯作者：
Li Z
中科院分区：
文献类型：
--
作者：
Liu Y;Zhao Y;Skerry B;Wang X;Colin-Cassin C;Radisky DC;Kaestner KH;Li Z
转录因子Forkhead box Protein A1(FOXA1)在人乳腺癌细胞，尤其是雌激素受体α(ERα)阳性的腔内癌细胞的增殖中起关键作用。然而，由于缺乏有条件的基因消融，FOXA1在小鼠乳腺肿瘤形成中所需的遗传学研究一直受到阻碍。我们研究了三种乳腺特异消融乳腺导管上皮细胞FOXA1的小鼠模型，以确定完全和乳腺特异消融FOXA1的最佳系统。我们发现，在Foxa1loxP/loxP小鼠中，MMTV-Cre和MMTV-RTTA；Tet-on-Cre导致FOXA1的部分缺失和乳管形成的减少，而Krt14-Cre则导致FOXA1的完全消融和乳管的形成。这些结果表明FOXA1在乳腺导管的形成中是必不可少的，并揭示了一系列可以减弱或完全阻断FOXA1在乳腺中的表达的小鼠模型。我们的研究还提出了一个潜在的强大的模型，通过Krt14驱动的Cre以可诱导的方式表达FOXA1，例如Krt14-RTTA；Tet-on-Cre。该模型系统将有助于进一步在体内研究FOXA1或其他在乳腺发育和肿瘤形成和进展中的因子的功能。
The transcription factor forkhead box protein A1 (FOXA1) plays a critical role in the proliferation of human breast cancer cells, particularly estrogen receptor alpha (ERα)-positive luminal breast cancer cells. However, genetic studies of the requirement for Foxa1 in mammary tumor formation in mice have been hampered by the lack of a conditional gene ablation. We examined three mouse models of mammary-specific ablation of Foxa1 in ductal epithelial cells to identify the best system for complete and mammary-specific ablation of Foxa1. We found that MMTV-Cre and MMTV-rtTA;Tet-On-Cre led to partial deletion of Foxa1 and attenuated mammary duct formation, whereas Krt14-Cre led to complete ablation of Foxa1 and abolished mammary duct formation, in Foxa1loxP/loxP mice. These results demonstrate that Foxa1 is essential for mammary duct formation, and reveal a series of mouse models in which mammary expression of Foxa1 can be attenuated or completely blocked. Our study also suggests a potentially powerful model for complete ablation of Foxa1 in mammary epithelial cells using Krt14-driven Cre expression in an inducible manner, such as Krt14-rtTA;Tet-On-Cre. This model system will facilitate further in vivo functional studies of Foxa1 or other factors in mammary gland development and tumor formation and progression.