Abstract P1-07-05: The cell fate factor DACH1 represses YB-1-mediated oncogenic transcription and translation

The epithelial-mesenchymal transition (EMT) enhances cellular invasiveness and confers tumor cells with cancer stem cell like characteristics, through transcriptional and translational mechanisms. The mechanisms maintaining transcriptional and translational repression of EMT and cellular invasion are poorly understood. The Drosophila homologue of DACH1, the Dac gene is a key member of the retinal determination gene network that specifies organismal development. The dachshund (dac), eya1, eyes-absent (eya), twin of eyeless (toy), teashirt (tsh) and sinoculues (so) are expressed in progenitor cells, contributing to development of the eye and genitalia. Loss of DACH1 expression contributes to the expansion of neural progenitors, muscle satellite cell differentiation and breast cancer stem cells. In recent studies Dachshund repressed breast cancer stem cell expansion. DACH1 expression is reduced in a variety of human cancers including prostate, ovarian and human breast cancer. Herein, the cell fate-determination factor Dachshund (DACH1), suppressed EMT via repression of cytoplasmic translational induction of Snail by inactivating the Y box-binding protein (YB-1). In the nucleus, DACH1 antagonized YB-1-mediated oncogenic transcriptional modules governing cell invasion. DACH1 blocked YB-1-induced mammary tumor growth and EMT in mice. In basal-like breast cancer (BLBC) the reduced expression of DACH1 and increased YB-1, correlated with poor metastasis free survival. The loss of DACH1 suppression of both cytoplasmic translational and nuclear transcriptional events governing EMT and tumor invasion may contribute to poor prognosis in BLBC. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P1-07-05.