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Estrogens Promote Human Testicular Germ Cell Cancer through a Membrane-Mediated Activation of Extracellular Regulated Kinase and Protein Kinase A

Unité Mixte de Recherche Institut National de la Santé et de la Recherche Médicale Unité 670 (A.B., M.N., B.M., F.B.-D., C.R., P.F.), University of Nice-Sophia-Antipolis (UNSA), 06100 Nice, France; and Department of Reproductive Endocrinology (F.B.-D., P.F.) University Hospital of Nice (CHUN), 06200 Nice, France

Address all correspondence and requests for reprints to: Professor Patrick Fénichel, Unité Mixte de Recherche Institut National de la Santé et de la Recherche Médicale Unité 670 Faculty of Medicine of Nice, Avenue de Vallombrose, 06102 Nice cedex 02, France. E-mail: fenichel.p{at}chu-nice.fr.

Clinical and experimental studies have suggested that estrogens, the archetype of female hormones, participate in the control of male germ cell proliferation and that fetal exposure to environmental estrogens may contribute to hypofertility and/or to testicular germ cell cancer. However, the underlying mechanisms remain to be elucidated. 17β-Estradiol (E2) conjugated to BSA was able to stimulate human testicular seminoma cell proliferation by triggering a rapid, nongenomic, membrane-mediated activation of ERK1/2 and cAMP-dependent protein kinase A (PKA). Both ERK1/2 and PKA participated in this promoting effect. This activation was associated with phosphorylation of the transcription factor cAMP response element-binding protein and the nuclear factor retinoblastoma protein. Enhanced proliferation together with ERK activation could be reversed by pertussis toxin, a G protein inhibitor. Estrogen receptors (ERs) in JKT-1 were characterized by immunofluorescence, subcellular fractioning, and Western blot. JKT-1 cells did not express ER but ERβ, which localized to the mitochondria and the nucleus but not to the membrane. Moreover, neither ICI-182,780, a classical ER antagonist, nor tamoxifen, a selective ER modulator, could reverse the 17β-estradiol-BSA-induced promoting effect. Estrogens contribute to human testicular germ cell cancer proliferation by rapid activation of ERK1/2 and PKA through a membrane nonclassical ER. This nongenomic effect represents a new basis for understanding the estrogenic control of spermatogenesis and evaluating the role of fetal exposure to xenoestrogens during malignant transformation of testicular germ stem cells.

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