Abstract
The NET (nocA, Nlz, elB, TLP-1) subfamily of zinc finger proteins is an important mediator during developmental processes. The evolutionary conserved zinc finger protein ZNF503/Zeppo2 (zinc finger elbow-related proline domain protein 2, Zpo2) plays critical roles during embryogenesis. We found that Zpo2 is expressed in adult tissue and examined its function. We found that ZPO2 is a nuclearly targeted transcriptional repressor that is expressed in mammary epithelial cells. Elevated Zpo2 levels increase mammary epithelial cell proliferation. Zpo2 promotes cellular invasion through down-regulation of E-cadherin and regulates the invasive phenotype in a RAC1-dependent manner. We detect elevated Zpo2 expression during breast cancer progression in a MMTV-PyMT transgenic mouse model. Tumor transplant experiments indicated that overexpression of Zpo2 in MMTV-PyMT mammary tumor cell lines enhances lung metastasis. Our findings suggest that Zpo2 plays a significant role in mammary gland homeostasis and that deregulation of Zpo2 may promote breast cancer development.
Highlights
ZNF503/Zeppo2 regulates the development of the hindbrain and limbs
We found that ZPO2 is a nuclearly targeted transcriptional repressor that is expressed in mammary epithelial cells
Our findings suggest that Zpo2 plays a significant role in mammary gland homeostasis and that deregulation of Zpo2 may promote breast cancer development
Summary
ZNF503/Zeppo regulates the development of the hindbrain and limbs. Results: Zeppo is a transcriptional repressor that promotes mammary cell proliferation and migration. Our findings suggest that Zpo plays a significant role in mammary gland homeostasis and that deregulation of Zpo may promote breast cancer development. The members of the NET subfamily of zinc finger proteins that are related to the Sp family of transcription factors have been identified as important regulators during development. ZNF503/ Zeppo (zinc finger elbow-related proline domain protein 2, Zpo2/Nolz1/Zfp503) is a regulatory factor that is conserved across many species. Overexpression of ZPO1 induces cellular invasion and promotes breast cancer metastasis through alteration of p120-CATENIN isoform expression [5]. Zpo expression is up-regulated during breast cancer progression, and overexpression of Zpo leads to higher tumor seeding in recipient lungs during mammary tumor transplant experiments. Our findings identify Zpo as a new candidate gene in the maintenance of mammary gland homeostasis
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