PEA3 transcription factors are expressed in tissues undergoing branching morphogenesis and promote formation of duct-like structures by mammary epithelial cells in vitro

Abstract

The genetic program that controls reciprocal tissue interactions during epithelial organogenesis is still poorly understood. Erm, Er81 and Pea3 are three highly related transcription factors belonging to the Ets family, within which they form the PEA3 group. Little information is yet available regarding the function of these transcription factors. We have previously used in situ hybridization to compare their expression pattern during critical stages of murine embryogenesis [Oncogene 15 (1997), 937; Mech. Dev. 108 (2001), 191]. In this study, we have examined the expression of PEA3 group members during organogenesis of the lung, salivary gland, kidney, and mammary gland. In all of these developmental settings, we observed a tight correlation between branching morphogenesis and the expression of specific members of the PEA3 group. To assess the functional relevance of these findings, Erm and Pea3 were overexpressed in the TAC-2.1 mammary epithelial cell line, which has the ability to form branching duct-like structures when grown in collagen gels. We found that overexpression of Erm and Pea3 markedly enhances branching tubulogenesis of TAC-2.1 cells and also promotes their invasion into a collagen matrix. Collectively, these findings suggest that the differential expression of PEA3 group transcription factors has an important role in the regulation of branching morphogenesis and raise the question of their implication in branching signaling.

Candidate regulators of mammary branching morphogenesis identified by genome‐wide transcript analysis

“…The matrix metalloproteinases MMP-14 (MT1-MMP) and MMP-3 (stromelysin-1) are enriched in the stroma of the TEBs and mature ducts, respectively (Wiseman et al, 2003). The transcription factor Ets-5 is enriched in the TEB epithelium, whereas cytokeratins 8 and 18 are expressed throughout the epithelium of TEBs and the luminal epithelium of mature ducts (Chotteau-Lelievre et al, 2003). The microarray data correctly recapitulated the expression localization of these genes ( Fig.…”

Analysis of transcriptional modulation of the presenilin 1 gene promoter by ZNF237, a candidate binding partner of the Ets transcription factor ERM

“…Their specific function is unknown, however they have been associated with various cellular processes, including cell proliferation, differentiation [3,4], and tumorigenesis [22,23]. To date most identified target genes of the PEA3 group have been proteases involved in the degradation of cell matrix [6,12].…”

Loss of a Negative Feedback Loop Involving Pea3 and Cyclin D2 Is Required for Pea3-Induced Migration in Transformed Mammary Epithelial Cells

“…TAC and MMT cells were obtained and cultured as described (16,22,30). Briefly, cells were maintained in DMEM supplemented with 10% FBS (Life Technologies).…”

“…pcDNA3-Pea3 and pTracer-Pea3 plasmids were described previously (16,31). pLPCX-Pea3-V5 was generated by PCR amplification of the mouse pea3-V5-tagged cDNA of the pTracer-Pea3 construct and cloned into a pLPCX retroviral vector (Clontech).…”

“…Noteworthy, PEA3 factors directly influence the outcome of mammary tumorigenesis induced by the Erbb2, SRC1, and Wnt1 oncogenes (13)(14)(15). Moreover, we have previously developed an epithelial cell line model, overexpressing the Pea3 transcription factor and shown that Pea3 confers the ability to colonize a collagen matrix independently of a morphogenic stimuli such as hepatocyte growth factor treatment as well as tumorigenic like properties such as loss of contact inhibition and enhanced cell invasiveness (16). However, the cellular and molecular mechanisms regulated by the PEA3 factors during mammary cancer progression are still poorly understood.…”