Down-regulation of leucine zipper putative tumor suppressor 1 is associated with poor prognosis, increased cell motility and invasion, and epithelial-to-mesenchymal transition characteristics in human breast carcinoma.

Leucine zipper putative tumor suppressor 1 is down-regulated by promoter methylation, but not frequently, in human malignancies, including breast cancer. Recent studies suggest that leucine zipper putative tumor suppressor 1 is a candidate for the metastasis modifier locus on human chromosome 8p in melanoma. In this study, we evaluated whether leucine zipper putative tumor suppressor 1 plays a role in breast cancer metastasis. We found that leucine zipper putative tumor suppressor 1 protein expression was significantly reduced or absent in a series of 340 invasive breast carcinomas compared to normal breast tissue. Lower levels of leucine zipper putative tumor suppressor 1 correlated with high histologic grade, lymph node metastasis, and poor prognosis. Functional studies demonstrated that ectopic expression of leucine zipper putative tumor suppressor 1 in the highly malignant MDA-MB-231 breast cancer cell line suppressed cell proliferation, migration, and invasion in vitro. Expression of leucine zipper putative tumor suppressor 1 in MDA-MB-231 cells also induced a series of changes that are characteristic of mesenchymal-to-epithelial transition, including phenotypic change, up-regulation of epithelial markers E-cadherin, β-catenin, and cytokeratin and down-regulation of the mesenchymal marker vimentin. Expression of leucine zipper putative tumor suppressor 1 also repressed the transcription of Slug and Snail, which both repress E-cadherin expression during epithelial-to-mesenchymal transition. These findings suggest that epithelial-to-mesenchymal transition likely inhibits breast cancer metastasis by intervening in epithelial-to-mesenchymal transition in breast cancer.