Zpo2 Promotes Aggressive Breast Cancer Development Through Downregulation Of Gata3

Metastatic breast cancer is the major cause of poor prognosis and death in women. The transcription factor GATA3 is a key mediator of luminal cell fate determination and homeostasis in adult mammary gland. Loss of GATA3 has been associated with development of metastatic mammary tumors. Here we describe a novel role for transcriptional repressor, Zeppo2 (zinc finger elbow-related proline domain protein2; Zpo2) (ZNF503) in promoting metastatic breast cancer through modulation of GATA3. We demonstrate that Zpo2, through its interaction with repressor of GATA (ROG) is capable of modulating GATA3 transcription in mammary epithelial cells. Overexpression of Zpo2 results in upregulation of EMT associated genes, decreased cell-cell adhesion and increased cellular invasiveness in 3D cultures. Additionally, overexpression of Zpo2 in mammary tumor cells results in enhancement of tumor growth and increased metastasis in orthotopic transplant models. Furthermore, to investigate the importance of Zpo2 in human breast cancer metastasis, we utilized a series of new patient-derived xenograft (PDX) models (primary human xenograft models). The PDX models ranged from poorly metastatic to highly metastatic as was observed in the (affected) original patients. Interestingly, higher Zpo2 expression levels correlate with more aggressive xenograft tumor models. Collectively, our data suggests that Zpo2 plays a potentially significant role in initiating aggressive breast cancer by modulating GATA3 in mammary epithelial cells. Citation Format: Payam Shahi, Euan M. Slorach, Jonathan Chou, Devon Lawson, Ying Yu, Zena Werb. Zpo2 promotes aggressive breast cancer development through downregulation of GATA3. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2475. doi:10.1158/1538-7445.AM2014-2475