Abstract #1537: Regulation of angiopoietin-like protein 4 (ANGPTL4) expression in breast cancer and breast cancer cell lines
Authors: Selvakumar Elangovan, Puttur Prasad, Vadivel Ganapathy, Muthusamy Thangaraju
Journal: Cancer Research (2009)

Introduction : Breast cancer is one the most common life-threatening diseases in women. Most breast cancer-related deaths are not due to cancer at the primary site but due to metastasis, a process in which cancer cells spread from the primary site to distant sites such as the lung, bone and brain. The molecular mechanisms underlying breast cancer metastasis are poorly understood. Recent studies have shown that angiopoietin-like proteins, particularly angiopoietin like protein 4 (ANGPTL4), play a crucial role in the modulation of breast cancer metastasis. ANGPTL4, also known as fasting-induced adipose factor (FIAF), is a circulating protein, highly expressed in the liver, adipose tissue and placenta; it plays a role in adipogenesis, angiogenesis, carcinogenesis and metastasis. Recently it has been shown that transforming growth factor \#946;1 (TGF\#946;1) induces ANGPTL4 expression, which leads to lung metastasis of breast cancer through disruption of the endothelial barrier.  Methods : The expression of ANGPTL4 in human normal and breast cancer tissue as well as in normal and breast cancer cell lines was studied by RT-PCR. The expression was also monitored in human normal and colon cancer tissue, and in normal and colon cancer cell lines. Furthermore, the regulation of ANGPTL4 expression in breast cancer cell lines by various growth factors and their receptors, cytokines, and inhibitors of several signaling pathways was investigated. The transcriptional regulation of the gene by potential trans-activators was studied in the human metastatic breast cancer cell line MDA-MB231 by a reporter assay using a 2.2 kb human  ANGPTL4  promoter fragment, and luciferase (pGL3-Luc) and GFP (pU3RII-pEGFP) as the reporters.  Results : The levels of ANGPTL4 mRNA were higher in human breast cancer and in breast cancer cell lines, and in human colon cancer and colon cancer cell lines. TGF\#946;1 and IL-8 induced ANGPTL4 expression in metastatic breast cancer cells. Furthermore, DNA methyltransferases (DNMTs), particularly DNMT1 and DNMT3b, were involved in the regulation ANGPTL4 expression. Functional inactivation of these DNMTs, either by deletion of the genes by homologous recombination or by using pharmacological agents, decreased the expression of ANGPTL4. Treatment of MDA-MB231 cells with Lovastatin, an inhibitor of HMG-CoA reductase, down-regulated ANGPTL4 expression in this cell line. In addition, functional expression of oncogenic Ras, C/EBP\#946;, c-Myc and constitutively active Stat3 trans-activated  ANGPTL4  promoter in metastatic breast cancer cells.  Conclusions : These studies describe the molecular processes involved in the regulation of ANGPTL4 expression in breast cancer. In addition, these studies show that DNA methylation inhibitors and the lipid-lowering drug Lovastatin may have therapeutic potential in the treatment of breast cancer metastasis due to their ability to inhibit the expression of ANGPTL4.   Citation Information:  In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 1537.