Identification of TMEM2 as a SOX4 Transcriptional Target Involved in Breast Cancer Metastasis

The transcription factor SRY (sex determining region Y)-box 4 (SOX4) regulates embryonic development and has been shown to drive the progression and metastasis of multiple solid cancer types. A common transcriptional target of SOX4 that mediates its effects in multiple cancer types has yet to be identified. Through a systematic molecular and genomic approach, we identify the transmembrane protein 2 (TMEM2) gene as a direct transcriptional target of SOX4. TMEM2 is transcriptionally activated by SOX4 in both breast cancer and lung adenocarcinoma cells and mediates pro-invasive and pro-migratory effects of SOX4. TMEM2, like SOX4, is sufficient to promote breast cancer metastatic colonization and its expression in high-risk primary breast tumors associates with metastatic relapse likelihood. Interestingly, independent studies wherein SOX4 or TMEM2 have been genetically inactivated have resulted in similar cardiac developmental defects, suggesting that TMEM2, in addition to mediating the pathologic effects of SOX4 on cancer progression, may also mediate its developmental effects