HER1 Signaling Mediates Extravillous Trophoblast Differentiation in Humans: HER2 Signaling

These data, together with the phenotype-specific expression profile of HER isoforms in EVT, suggests that different members of the EGF family may be capable of initiating distinct signaling events in proliferative and invasive EVT. A wealth of studies has established roles for HER signaling in a variety of cellular functions. In particular, HER1 has been reported to be an important signal mediator of mitotic events, and a growing number of studies report that HER2 signaling is involved in invasive processes such as those underlying breast cancer metastasis. The involvement of HER1 and HER2 in each of these respective processes, their EVT phenotype-specific expression pattern, and the detection of many EGF family ligands at the maternal/fetal interface, such as HBEGF, transforming growth factor-a (TGF), and amphiregulin (AREG), support a role for these proteins in the expression of EVT phenotype.
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In the present study, we examine the role of HER1 signaling in mediating the differentiation cascade by which proliferative EVT transform into invasive EVT. We used two models of trophoblast differentiation. First, we used the JAR choriocarcinoma cell line as a model of proliferative EVT on the basis of its common expression of many EVT phenotype markers, as found on EVT in vivo. While this cell line is derived from a term trophoblast tumor, these cells express Cx40 and HER1 just as proliferative EVT do; moreover, under serum-free medium conditions, JAR cells are proliferative and nonmigratory. However, just as placental villous EVT become invasive when treated with DCM, so too do JAR cells become migratory under these conditions. Secondly, we confirmed our observations from JAR cultures using cultures of first trimester placental villous explant outgrowths since this model more closely approximates the in vivo milieu. To assess the role of HER1 in the differentiation of invasive EVT, we treated JAR cells and placental explants with either DCM or EGF and assessed the expression of HER receptors. Furthermore, we attenuated these HER1-mediated differentiation effects using AG1478. We also assessed JAR cell migration in response to an alternative HER1 ligand, HBEGF, and determined the role of HER1 and HER2 in this process using the receptor-specific inhibitors, AG1478 and AG825, as well as specific inhibitors of the mitogen-activated protein kinase (MAPK) pathway, protein kinase C (PKC) pathway, and phosphoinositol 3 kinase (PIK3) pathway. Finally, we investigated HER1 phosphorylation status and downstream MAPK and PIK3 signaling pathway activation following treatment with either EGF or HBEGF.

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