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Estrogen-independent activation of erbBs signaling and estrogen receptor α in the mouse vagina exposed neonatally to diethylstilbestrol

Abstract

Growth factors and estrogen receptor (ER) signaling cooperate to play essential roles in cell proliferation, differentiation and tumor progression in mouse reproductive organs. Treatment of neonatal mice with diethylstilbestrol (DES) induces an estrogen-independent persistent proliferation and cornification of the vaginal epithelium, which results in cancerous lesions later in life. However, the mechanisms of the estrogen-dependent and -independent pathways essentially remain unknown. We characterized the expression of epidermal growth factor (EGF)-like growth factors (EGF, transforming growth factor α (TGF-α), heparin-binding EGF-like growth factor (HB-EGF), betacellulin (BTC), amphiregulin (APR), epiregulin (EPR) and neuregulin (NRG) 1) and erbB receptors (EGF receptor (EGFR), erbB2/neu, erbB3 and erbB4) in the vaginae of mice treated either neonatally (0–4 day) or as adults (55–59 day) with estrogens. EGFR and erbB2 were activated in the vaginal epithelium of mice by estrogen treatment. This activation was also encountered in vaginae from neonatally DES-exposed mice, along with the expression of EGF, TGF-α, HB-EGF, BTC, APR, EPR and NRG1. Immunohistochemical analysis indicated that erbB2 was primarily expressed in vaginal epithelium. Finally, we found that serine 118 and 167 located in the AF-1 domain of ERα were phosphorylated in these vaginae. AG825, AG1478 or ICI 182,780 administration blocked proliferation of vaginal epithelium induced by neonatal DES exposure. Thus, signal transduction via EGFR and erbB2 could be related to the estrogen-induced vaginal changes and persistent erbBs phosphorylation and sustained expression of EGF-like growth factors, leading to ERα activation that may result in cancerous lesions in vaginae from neonatally DES-exposed mice later in life.

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Acknowledgements

We are grateful to Dr Raphael Guzman, Cancer Research Laboratory and Department of Molecular Cell Biology, University of California at Berkeley, Dr Bruce Blumberg, Department of Developmental and Cell Biology, University of California at Irvine and Dr Louis Guillette Jr, Department of Zoology, University of Florida, for their critical readings of the manuscript. This work was supported in part by a grant-in-aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan, and Health Sciences Research Grant from the Ministry of Health, Labour and Welfare, Japan.

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Correspondence to Taisen Iguchi.

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Miyagawa, S., Katsu, Y., Watanabe, H. et al. Estrogen-independent activation of erbBs signaling and estrogen receptor α in the mouse vagina exposed neonatally to diethylstilbestrol. Oncogene 23, 340–349 (2004). https://doi.org/10.1038/sj.onc.1207207

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