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Background  Xp11.2 translocation renal cell carcinoma (tRCC) is defined by translocation of the transcription factor E3 ( TFE3 ) gene located on chromosome Xp11.2. Due to the high incidence in women, 17β-estradiol (E2) may be a factor influencing  TFE3  breaks, and the topoisomerase II (TOP2) poison is considered one of the important risk factors in mediating DNA breaks. In this study, we investigated the potential pathogenesis of Xp11.2 tRCC using the renal epithelial cell line HK-2.    Methods  Immunofluorescence assay was performed to analyze DNA breaks by quantifying phosphorylation of H2AX (γH2AX), and the micronuclei (MN) assay was designed for monitoring chromosome breaks. The chromatin immunoprecipitation (CHIP) was used to detect whether proteins bound to specific DNA site, and the co-immunoprecipitation (Co-IP) was used to confirm whether proteins bound to other proteins. In some experiments, siRNA and shRNA were transfected to knockdown target genes.    Results  Our results demonstrated that DNA double-strand breaks were mediated by TOP2β in HK-2 cells, and this process could be amplified through estrogen receptor α (ERα)-dependent pathway induced by E2. After performing translocation site analysis using target region sequencing data in two Xp11.2 tRCC cell lines and ten Xp11.2 tRCC patients, we confirmed that TOP2β and ERα could both bind to  TFE3  translocation sites directly to mediate DNA breaks in a E2-dependent manner. However, TOP2β and ERα were not observed to have direct interaction, indicating that their collaborative may be implemented in other ways. Besides,  TFE3  was found to be upregulated through NRF1 with increasing E2 concentration, which could increase the risk of  TFE3  breaks.    Conclusion  Our results indicate that E2 amplifies TOP2β-mediated  TFE3  breaks by ERα-dependent pathway, and E2 upregulates  TFE3  by NRF1 to increase the risk of  TFE3  breaks. This suggests that E2 is an important pathogenic factor for Xp11.2 tRCC pathogenesis.Video AbstractSupplementary Information  The online version contains supplementary material available at 10.1186/s12964-021-00790-3.

Estradiol increases risk of topoisomerase IIβ-mediated DNA strand breaks to initiate Xp11.2 translocation renal cell carcinoma