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Published on: October 27, 2020
TMEM2 Is a SOX4-Regulated Gene That Mediates Metastatic Migration and Invasion in Breast Cancer
Hyeseung Lee1, Hani Goodarzi1, Sohail F Tavazoie2
1Laboratory of Systems Cancer Biology, Rockefeller University, New York, New York.
Abstract:
The developmental transcription factor SOX4 contributes to the metastatic spread of multiple solid cancer types, but its direct target genes that mediate cancer progression are not well defined. Using a systematic molecular and genomic approach, we identified the TMEM2 transmembrane protein gene as a direct transcriptional target of SOX4. TMEM2 was transcriptionally activated by SOX4 in breast cancer cells where, like SOX4, TMEM2 was found to mediate proinvasive and promigratory effects. Similarly, TMEM2 was sufficient to promote metastatic colonization of breast cancer cells and its expression in primary breast tumors associated with a higher likelihood of metastatic relapse. Given earlier evidence that genetic inactivation of SOX4 or TMEM2 yield similar defects in cardiac development, our findings lead us to propose that TMEM2 may not only mediate the pathologic effects of SOX4 on cancer progression but also potentially its contributions to embryonic development. Cancer Res; 76(17); 4994-5005. ©2016 AACR.
Insights
The developmental transcription factor SOX4 directly activates TMEM2, a transmembrane protein gene. TMEM2 promotes breast cancer metastasis and relapse, and may also play a role in embryonic development.
Area of Science:
- Molecular Biology
- Genetics
- Cancer Research
Background:
- SOX4 is a transcription factor implicated in the metastatic spread of solid cancers.
- The specific genes targeted by SOX4 that drive cancer progression remain largely undefined.
Purpose of the Study:
- To identify direct transcriptional targets of SOX4 involved in cancer progression.
- To investigate the role of TMEM2 in breast cancer metastasis and its potential link to embryonic development.
Main Methods:
- Systematic molecular and genomic analyses were employed.
- Transcriptional activation assays and functional studies in breast cancer cells were performed.
- Correlation between TMEM2 expression in primary tumors and metastatic relapse was analyzed.
Main Results:
- TMEM2 was identified as a direct transcriptional target of SOX4.
- SOX4 activates TMEM2 expression in breast cancer cells, mediating proinvasive and promigratory effects.
- TMEM2 expression promotes metastatic colonization and is associated with increased metastatic relapse in breast cancer patients.
Conclusions:
- TMEM2 mediates the pro-metastatic effects of SOX4 in breast cancer.
- TMEM2 may also contribute to SOX4's role in embryonic cardiac development, suggesting a shared mechanism.
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