Dlx4 Homeprotein Enhances The Invasiveness Of Hs578t Er-Negative Breast Cancer Cells

Tumor invasion and metastasis remain a major cause of mortality in breast cancer patients. It was reported that BP1, a homeobox isoform of DLX4, is overexpressed in 80% of breast cancer patients and in 100% of estrogen receptor negative (ER-) tumors. The prevalence of BP1 positive cells and the intensity of BP1 immunoreactivity increased with the extent of ductal proliferation and tumorigenesis. These findings imply that BP1 may play an important role in ER- breast cancer. We sought to determine the effects and mechanisms of BP1 on cell proliferation and metastasis using ER- Hs578T cells as a model. Cells were transfected with either pcDNA3.2 plasmid containing BP1 gene, or pcDNA3.2 vector, then selected and cloned. Overexpression of BP1 increased cell proliferation rate by 2-5 fold (p =2.0. Of those genes, 49 were up-regulated and 22 were down-regulated. Further analysis has identified several important molecular pathways using the differentially expressed gene list, including CREB signaling, BCL2L1, AKT signaling, apoptosis, androgen receptor pathways, etc. CREB1, as an oncogenic transcription factor, induces transcription of genes in response to hormonal stimulation of the cAMP pathway. CREB1 can be activated through phosphorylation by a number of kinases, including AKT, protein kinase A, and calcium/calmodulin-dependent kinases and regulates genes whose deregulated expression promotes oncogenesis, including cyclins, BCL2 family members, and EGR1. It was reported that BP1 can directly bind to and activate the expression of BCL1, which is an antiapoptotic gene and considered to be an oncogene. BCL2L1 is a BCL2 protein family member that acts as anti- or pro-apoptotic regulators involving in a wide variety of cellular activities. These data demonstrated that overexpression of BP1 significantly enhanced cell proliferation and metastatic potential in ER- Hs578T cells. Further analysis with more ER- cell lines and patient samples is warranted to establish BP1 as a therapeutic target. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3910.