Changes in the Expression of Many Ets Family Transcription Factors and of Potential Target Genes in Normal Mammary Tissue and Tumors

Christina K Galang,William J Muller,Gabriele Foos,Robert G Oshima,Craig A Hauser

doi:10.1074/jbc.m311887200

Christina K Galang, William J Muller + Show 3 more

Open Access

https://doi.org/10.1074/jbc.m311887200

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Abstract

Interfering with Ets transcription factor function reverses multiple aspects of the transformed phenotype of mouse or human tumor cells. However, the unknown number of individual Ets factors expressed in any cellular context and the similar DNA binding specificities of Ets family members complicates the identification of those that mediate transformation. By utilizing quantitative PCR assays for 25 mouse Ets factors, we analyzed the expression of essentially the entire Ets family in normal mammary tissue, mammary-related cell lines, and mammary tumors. In normal mammary tissue, 24 Ets factors were expressed. Even clonal derived cell lines expressed 14-20 Ets members. The most abundant Ets factor mRNAs measured in normal mammary tissue were Elk4, Elf1, and Ets2. Subtractive analysis of mammary tissue identified which Ets factors were predominantly expressed in the myeloid/lymphoid or epithelial cell compartments. Comparison of Ets factor expression in normal mammary tissue and mammary tumors identified significantly elevated expression of Pse/PDEF, Ese2/Elf5, Ese3/Ehf, TEL/Etv6, and Elf2/NERF in mammary tumors and confirmed previously reported alterations in expression of Ese1/Elf3 and the PEA3 subfamily. Expression of 13 Ets target genes, implicated in various aspects of tumor progression, was also analyzed. Altered expression of particular Ets target genes was significantly correlated with particular Ets factors (e.g. maspin and Ese2), suggesting specific in vivo regulatory roles. Together, this comprehensive analysis revealed unexpectedly diverse Ets family gene expression, characterized novel Ets factor changes in mammary tumors, and implicated specific Ets factors in the regulation of multiple genes involved in mammary tumor progression.

Highlights

The Ets family of transcription factors in mouse or humans is comprised of at least 26 unique family members that contain an evolutionarily conserved DNA binding domain called the Ets domain
Such Ets dominant negative studies have demonstrated the importance of Ets factors in the transformed phenotype of breast cancer cell lines [12, 13] and in a transgenic mouse mammary tumor model [14]
Because Ets dominant negative constructs can broadly interfere with Ets family function [15], these studies do not identify which of the ϳ26 Ets factors are key in transformation

Summary

Introduction

The Ets family of transcription factors in mouse or humans is comprised of at least 26 unique family members that contain an evolutionarily conserved DNA binding domain called the Ets domain. A number of the Ets factors we identified as predominantly lymph node-associated (Fli, PU.1, Ets1, SpiC, Elf4, and PE1) were expressed at a reduced level in the tumor samples relative to normal mammary tissues.

Results

Conclusion