Shahi Payam, Wang Chih-Yang, Lawson Devon A, Slorach Euan M, Lu Angela, Yu Ying, Lai Ming-Derg, Gonzalez Velozo Hugo, Werb Zena
Department of Anatomy and the Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA 94143.
Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan.
Proc Natl Acad Sci U S A. 2017 Mar 21;114(12):3169-3174. doi: 10.1073/pnas.1701690114. Epub 2017 Mar 3.
The transcription factor GATA3 is the master regulator that drives mammary luminal epithelial cell differentiation and maintains mammary gland homeostasis. Loss of is associated with aggressive breast cancer development. We have identified ZNF503/ZEPPO2 zinc-finger elbow-related proline domain protein 2 (ZPO2) as a transcriptional repressor of expression and transcriptional activity that induces mammary epithelial cell proliferation and breast cancer development. We show that ZPO2 is recruited to promoter in association with ZBTB32 (Repressor of GATA, ROG) and that ZBTB32 is essential for down-regulation of via ZPO2. Through this modulation of GATA3 activity, ZPO2 promotes aggressive breast cancer development. Our data provide insight into a mechanism of GATA3 regulation, and identify ZPO2 as a possible candidate gene for future diagnostic and therapeutic strategies.
转录因子GATA3是驱动乳腺管腔上皮细胞分化并维持乳腺内环境稳定的主要调节因子。GATA3缺失与侵袭性乳腺癌的发生有关。我们已确定ZNF503/ZEPPO2锌指肘部相关脯氨酸结构域蛋白2(ZPO2)是GATA3表达和转录活性的转录抑制因子,其可诱导乳腺上皮细胞增殖和乳腺癌发展。我们发现ZPO2与ZBTB32(GATA抑制因子,ROG)一起被招募至GATA3启动子,且ZBTB32对于通过ZPO2下调GATA3至关重要。通过这种对GATA3活性的调节,ZPO2促进侵袭性乳腺癌发展。我们的数据为GATA3的调控机制提供了见解,并确定ZPO2为未来诊断和治疗策略的一个可能候选基因。