Oncogenic role of DDX3 in breast cancer biogenesis

Abstract

Benzo [a]pyrene diol epoxide (BPDE), the active metabolite of benzo [a]pyrene present in tobacco smoke, is a major cancer-causing compound. To evaluate the effects of BPDE on human breast epithelial cells, we exposed an immortalized human breast cell line, MCF 10A, to BPDE and characterized the gene expression pattern. Of the differential genes expressed, we found consistent activation of DDX3, a member of the DEAD box RNA helicase family. Overexpression of DDX3 in MCF 10A cells induced an epithelial-mesenchymal-like transformation, exhibited increased motility and invasive properties, and formed colonies in soft-agar assays. Besides the altered phenotype, MCF 10A-DDX3 cells repressed E-cadherin expression as demonstrated by both immunoblots and by E-cadherin promoter-reporter assays. In addition, an in vivo association of DDX3 and the E-cadherin promoter was demonstrated by chromatin immunoprecipitation assays. Collectively, these results demonstrate that the activation of DDX3 by BPDE, can promote growth, proliferation and neoplastic transformation of breast epithelial cells.

The current understanding of Ded1p/DDX3 homologs from yeast to human

“…For example, upon HIV infection and in a number of cancers, including acute myeloid leukemia and breast cancer, DDX3 expression is greatly upregulated. [37][38][39] Consequently, it would be of interest to investigate whether elevated levels of DDX3 might have any effect on cellular translation activities during HIV infection and during cancer progression.…”

“…Finally, DDX3, like Ded1p, has been implicated in cell growth control, although whether it plays a positive or negative role remains unclear. 22,30,37,46 At least in some cases, increased expression of DDX3 was found to promote cell growth, proliferation and even transformation. 22,30,37,46 Because a number of cellular proteins involved in regulating cell growth and programmed cell death are produced via IRES-mediated translation under stressed conditions, 47 it would be of interest to examine whether and how DDX3 participates in such cellular IRES-mediated translation.…”

DHX33 Transcriptionally Controls Genes Involved in the Cell Cycle

“…Many characterized RNA helicases have been found to be fundamental in essential cellular processes (1,26). In recent years, a few RNA helicases have been found to participate in cancer development even though their detailed molecular mechanisms remain largely undiscovered (27)(28)(29)(30)(31)(32)(33). Furthermore, despite the characterization of several DEAD/DEAH proteins, few specific inhibitors targeting these ATP-dependent helicases have been developed.…”

In vitro Anti-Cancer Activity of Rosuvastatin and Ketorolac Nanoformulations against DDX3

“…Moreover, elevated expression of DDX3 was found in a highly aggressive metastatic breast cancer cell line, MDA-MB-231, as compared with non-metastatic MCF-7 cells, which show its potential role in aggressive breast cancers and associated metastasis. 5,6 We have previously reported that overexpression of DDX3 in immortalized non-turmorigenic MCF10A cells promoted neoplastic transformation as indicated by down regulation of a cell adhesion molecule, E-cadherin. 5 Down-regulation of E-cadherin is a common feature of a variety of metastatic epithelial tumors, including those of the lung, breast and prostate cancer.…”

“…Moreover, elevated expression of DDX3 was found in a highly aggressive metastatic breast cancer cell line, MDA-MB-231, as compared with non-metastatic MCF-7 cells, which show its potential role in aggressive breast cancers and associated metastasis. 5,6 We have previously reported that overexpression of DDX3 in immortalized non-turmorigenic MCF10A cells promoted neoplastic transformation as indicated by down regulation of a cell adhesion molecule, E-cadherin.5 Down-regulation of E-cadherin is a common feature of a variety of metastatic epithelial tumors, including those of the lung, breast and prostate cancer.5,7-9 Hypoxic regions of solid tumors were considered to be the primary sites for the generation of the metastatic phenotype and have been demonstrated to be chemo and radio-resistant. [10][11][12][13][14] We have also reported that hypoxia inducible factor (HIF-1) induce the expression of DDX3 in two different breast cell lines by binding directly or indirectly to the hypoxia-response element (HRE) in the DDX3 proximal promoter.…”