In human breast cancer metastasis, it is not the primary tumor that is the cause of mortality but tumor metastasis to distant sites. Therefore, it is important to elucidate the biological mechanism that underlies the metastatic processes. Previous work noted that, when MMTV-Myc mouse model was crossed with various activator E2Fs mutants, loss of various E2Fs transcription factors affected tumor latency and incidence. Specifically, loss of E2F1 increased incidence and decreased latency whereas loss of E2F2 or E2F3 decreased incidence and increased latency in the MMTV-Myc mice crossed with E2F1, E2F2, or E2F3 mutant background. Surprisingly, the percentage of mice with pulmonary metastases also increased when MMTV-Myc mice were crossed with E2F2-/- mice. Subsequently, these observations in mice were tested bioinformatically to examine whether they translate to human breast cancer. In addition, bioinformatic predictions were also generated to identify the genes that were involved in mediating metastasis after E2F2 loss. To examine the effects of E2F2 loss in human breast cancer, the cell line MDA-MB-231 was used. Reduced level of E2F2 expression in the MDA-MB-231 cell line resulted in increased migration in vitro and increased lung colonization in vivo. To elucidate the mechanism by which E2F2 mediates metastasis, genes that were differentially regulated between MMTV-Myc tumors, MMTV-Myc E2F2-/- tumors and lung metastasis lesions were examined. These genes were stratified based on their correlation with human distant metastasis survival, Cox-hazard ratio, or presence of putative E2F binding site. Subsequently, PTPRD was identified as a primary putative target gene. To further explore the role of PTPRD in E2F2-mediated breast cancer metastasis, knockdown of PTPRD was performed on MDA-MB-231. Decreased level of PTPRD was found to decrease migration in vitro and decreased metastatic lesion in vivo. Examination of protein-protein interaction network map showed that PTPRD may be related to E2F2 through BCAR1 or Myc and STAT3. Taken together, these findings demonstrated the role for E2F2 in human breast cancer metastasis.
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