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Background  The  DLX  gene family encodes for homeobox transcription factors involved in the control of morphogenesis and tissue homeostasis. Their expression can be regulated by Endothelin1 (ET1), a peptide associated with breast cancer invasive phenotype. Deregulation of  DLX  gene expression was found in human solid tumors and hematologic malignancies. In particular,  DLX4  overexpression represents a possible prognostic marker in ovarian cancer. We have investigated the role of  DLX  genes in human breast cancer progression.    Methods  MDA-MB-231 human breast carcinoma cells were grown in vitro or injected in nude mice, either subcutaneously, to mimic primary tumor growth, or intravenously, to mimic metastatic spreading. Expression of  DLX2 ,  DLX5  and  DLX6  was assessed in cultured cells, either treated or not with ET1, tumors and metastases by RT-PCR.  In situ  hybridization was used to confirm  DLX  gene expression in primary tumors and in lung and bone metastases. The expression of  DLX2  and  DLX5  was evaluated in 408 primary human breast cancers examining the GSE1456 and GSE3494 microarray datasets. Kaplan-Meier estimates for disease-free survival were calculated for the patients grouped on the basis of  DLX2 / DLX5  expression.    Results  Before injection, or after subcutaneous growth, MDA-MB-231 cells expressed  DLX2  but neither  DLX5  nor  DLX6 . Instead, in bone and lung metastases resulting from intravenous injection we detected expression of  DLX5/6  but not of  DLX2 , suggesting that  DLX5/6  are activated during metastasis formation, and that their expression is alternative to that of  DLX2 . The  in vitro  treatment of MDA-MB-231 cells with ET1, resulted in switch from  DLX2  to  DLX5  expression. By data mining in microarray datasets we found that expression of  DLX2  occurred in 21.6% of patients, and was significantly correlated with prolonged disease-free survival and reduced incidence of relapse. Instead,  DLX5  was expressed in a small subset of cases, 2.2% of total, displaying reduced disease-free survival and high incidence of relapse which was, however, non-significantly different from the other groups due to the small size of the  DLX+  cohort. In all cases, we found mutually exclusive expression of  DLX2  and  DLX5 .    Conclusions  Our studies indicate that  DLX  genes are involved in human breast cancer progression, and that  DLX2  and  DLX5  genes might serve as prognostic markers.

Mutually exclusive expression of DLX2 and DLX5/6 is associated with the metastatic potential of the human breast cancer cell line MDA-MB-231