Xp11.2 translocation renal cell carcinoma (tRCC) is characterized by translocation of the gene TFE3 on chromosome Xp11.2. Xp11.2 tRCC is much more common in women than men, suggesting that estrogen may be involved. In addition, the enzyme TOP2 is known to mediate translocation-enabling DNA breakage in some cancers, and TOP2-promoting drugs increase Xp11.2 tRCC risk, but whether and how estrogen, the estrogen receptor (ER), and TOP2 participate in the development of this cancer remain unclear. To learn more, researchers recently analyzed DNA breaks and protein binding in a kidney cell line. They found that TOP2β created DNA breaks and that estrogen signaling through ERα promoted this activity. Further analyses revealed that TOP2β and ERα both bound to TFE3 translocation sites in Xp11.2 tRCC cell lines and patients to mediate estrogen-dependent DNA breakage. However, TOP2β and ERα didn’t bind to each other. Furthermore, with increasing estrogen concentrations, TFE3 was upregulated via the protein NRF1, which increased the risk of DNA breaks. Although other factors need to be investigated, the results help clarify the mechanism of Xp11.2 tRCC pathogenesis and reveal estrogen as an important factor in this process.