Estrogen receptor activates SRC and ERK1/2 and promotes tumorigenesis in human testicular embryonic carcinoma cells NT2/D1.

Testicular germ cell tumors have the highest incidence in young men (between 15 and 44 years of age) and its etiology is still unclear, but its emergence on puberty suggests a hormone-dependent mechanism for the development of these tumors and their progression. We previously identified the estrogen receptor ESR1, ESR2, GPER and an isoform of ESR1, the ESR1-36 in human testicular embryonic carcinoma NT2/D1 cells, and the activation of SRC induced by ESR1 and ESR2 in these cells. Therefore, this study aimed to analyze the role of ER in the activation of ERK1/2, and the involvement of SRC and ERK1/2 on proliferation, migration, and invasion of the NT2/D1 cells. Our results showed that the activation of ESR1 (using ESR1-selective agonist PPT) or ESR2 (using ESR2-selective agonist DPN) increased phosphorylation of ERK1/2 in NT2/D1 cells. In the presence of the selective inhibitor for SRC-family kinases PP2, or the MEK specific inhibitor U0126, the effects of 17β-estradiol (E2) or PPT were blocked on proliferation and invasion of NT2/D1 cells. Finally, the proliferation, migration, and invasion of NT2/D1 cells simulated by E2 or ESR2 were also blocked by PP2 and U0126. This study provides novel insights into molecular mechanisms of ER in NT2/D1 cells by demonstrating that ER activates rapid responses molecules, including SRC and ERK1/2, which enhance the tumorigenic potential of testicular cancer cells.