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.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 50 print issues and online access
$259.00 per year
only $5.18 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Atanaskova N, Keshamouni VG, Krueger JS, Schwartz JA, Miller F and Reddy KB . (2002). Oncogene, 21, 4000–4008.
Berry M, Metzger D and Chambon P . (1990). EMBO J., 9, 2811–2818.
Buchanan DL, Kurita T, Taylor JA, Lubahn DB, Cunha GR and Cooke PS . (1998). Endocrinology, 139, 4345–4352.
Cunha GR, Lung B and Kato K . (1977). Dev. Biol., 56, 52–67.
Curtis SW, Washburn T, Sewall C, DiAugustine R, Lindzey J, Couse JF and Korach KS . (1996). Proc. Natl. Acad. Sci. USA, 93, 12626–12630.
Das SK, Chakraborty I, Paria BC, Wang XN, Plowman G and Dey SK . (1995). Mol. Endocrinol., 9, 691–705.
DiAugustine RP, Petrusz P, Bell GI, Brown CF, Korach KS, McLachlan JA and Teng CT . (1988). Endocrinology, 122, 2355–2363.
Dickson RB and Lippman ME . (1995). Endocr. Rev., 16, 559–589.
Dunn TB and Green AW . (1963). J. Natl. Cancer Inst., 31, 425–455.
Falck L and Forsberg JG . (1996). Anat. Rec., 245, 459–471.
Forsberg JG . (1979). Natl. Cancer Inst. Monogr., 41–56.
Hashimoto K, Higashiyama S, Asada H, Hashimura E, Kobayashi T, Sudo K, Nakagawa T, Damm D, Yoshikawa K and Taniguchi N . (1994). J. Biol. Chem., 269, 20060–20066.
Herbst AL . (2000). Gynecol. Oncol., 76, 147–156.
Herbst AL, Ulfelder H and Poskanzer DC . (1971). N. Engl. J. Med., 284, 878–881.
Hynes NE and Stern DF . (1994). Biochim. Biophys. Acta, 1198, 165–184.
Ignar-Trowbridge DM, Nelson KG, Bidwell MC, Curtis SW, Washburn TF, McLachlan JA and Korach KS . (1992). Proc. Natl. Acad. Sci. USA, 89, 4658–4662.
Iguchi T . (1992). Int. Rev. Cytol., 139, 1–57.
Iguchi T, Edery M, Tasi PS, Ozawa S, Sato T and Bern HA . (1993). Proc. Soc. Exp. Biol. Med., 204, 110–116.
Iguchi T, Takei T, Takase M and Takasugi N . (1986). Acta Anat. (Basel), 127, 110–114.
Iguchi T, Uchima FD, Ostrander PL and Bern HA . (1983). Proc. Natl. Acad. Sci. USA, 80, 3743–3747.
Joel PB, Smith J, Sturgill TW, Fisher TL, Blenis J and Lannigan DA . (1998). Mol. Cell. Biol., 18, 1978–1984.
Kato S, Kitamoto T, Masuhiro Y and Yanagisawa J . (1998). Oncology, 55 (Suppl. 1), 5–10.
Kato S, Masuhiro Y, Watanabe M, Kobayashi Y, Takeyama KI, Endoh H and Yanagisawa J . (2000). Genes Cells, 5, 593–601.
Klotz DM, Hewitt SC, Ciana P, Raviscioni M, Lindzey JK, Foley J, Maggi A, DiAugustine RP and Korach KS . (2002). J. Biol. Chem., 277, 8531–8537.
Klotz DM, Hewitt SC, Korach KS and Diaugustine RP . (2000). Endocrinology, 141, 3430–3439.
Kurokawa H, Lenferink AE, Simpson JF, Pisacane PI, Sliwkowski MX, Forbes JT and Arteaga CL . (2000). Cancer Res., 60, 5887–5894.
Lahooti H, White R, Hoare SA, Rahman D, Pappin DJ and Parker MG . (1995). J. Steroid Biochem. Mol. Biol., 55, 305–313.
Lannigan DA . (2003). Steroids, 68, 1–9.
Marselos M and Tomatis L . (1992a). Eur. J. Cancer, 28A, 1182–1189.
Marselos M and Tomatis L . (1992b). Eur. J. Cancer, 29A, 149–155.
McDonnell DP, Clemm DL, Hermann T, Goldman ME and Pike JW . (1995). Mol. Endocrinol., 9, 659–669.
McLachlan JA . (2001). Endocr. Rev., 22, 319–341.
McLachlan JA, Newbold RR and Bullock BC . (1980). Cancer Res., 40, 3988–3999.
Metzger D, Berry M, Ali S and Chambon P . (1995). Mol. Endocrinol., 9, 579–591.
Nelson KG, Sakai Y, Eitzman B, Steed T and McLachlan J . (1994). Cell Growth Differ., 5, 595–606.
Nelson KG, Takahashi T, Bossert NL, Walmer DK and McLachlan JA . (1991). Proc. Natl. Acad. Sci. USA, 88, 21–25.
Nelson KG, Takahashi T, Lee DC, Luetteke NC, Bossert NL, Ross K, Eitzman BE and McLachlan JA . (1992). Endocrinology, 131, 1657–1664.
Normanno N, Selvam MP, Qi CF, Saeki T, Johnson G, Kim N, Ciardiello F, Shoyab M, Plowman G, Brandt R, Todaro G and Salomon DS . (1994). Proc. Natl. Acad. Sci. USA, 91, 2790–2794.
Pastan I and Willingham MC . (1983). Trends Biochem. Sci., 8, 250–254.
Piepkorn M, Lo C and Plowman G . (1994). J. Cell. Physiol., 159, 114–120.
Sato T, Fukazawa Y, Kojima H, Ohta Y and Iguchi T . (2003). Reprod. Toxicol., 17, 289–297.
Sato T, Fukazawa Y, Kojima H, Ohta Y, Tomooka Y and Iguchi T . (1996a). Proceedings of the 10th International Congress on Endocrinology, San Francisco, San Francisco, pp. 1–254.
Sato T, Ohta Y, Okamura H, Hayashi S and Iguchi T . (1996b). Anat. Rec., 244, 374–385.
Takasugi N . (1976). Int. Rev. Cytol., 44, 193–224.
Takasugi N, Bern HA and DeOme KB . (1962). Science, 138, 438–439.
Tsai PS, Uchima F-DA, Hamamoto ST and Bern HA . (1991). In vitro Cell Dev. Biol., 27A, 461–468.
Yee D and Lee AV . (2000). J. Mammary Gland Biol. Neoplasia, 5, 107–115.
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.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
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
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.onc.1207207
Keywords
This article is cited by
-
mTORC1 signaling pathway integrates estrogen and growth factor to coordinate vaginal epithelial cells proliferation and differentiation
Cell Death & Disease (2022)
-
Unique roles of estrogen-dependent Pten control in epithelial cell homeostasis of mouse vagina
Oncogene (2015)
-
ARTEMIN synergizes with TWIST1 to promote metastasis and poor survival outcome in patients with ER negative mammary carcinoma
Breast Cancer Research (2011)
-
Involvement of activin signaling in abnormalities of mouse vagina exposed neonatally to diethylstilbestrol
Cell and Tissue Research (2011)
-
Persistent trefoil factor 1 expression imprinted on mouse vaginal epithelium by neonatal estrogenization
Cell and Tissue Research (2006)