Oncogenic role of DDX3 in breast cancer biogenesis.
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.
Botlagunta
M
M
Department of Radiology and Radiological Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Vesuna
F
F
Mironchik
Y
Y
Raman
A
A
Lisok
A
A
Winnard
P
P
Mukadam
S
S
Van Diest
P
P
Chen
J H
JH
Farabaugh
P
P
Patel
A H
AH
Raman
V
V
D015123:7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide; D001943:Breast Neoplasms / Q000378:metabolism*; D015820:Cadherins / Q000235:genetics; D002273:Carcinogens; D045744:Cell Line, Tumor; D002465:Cell Movement; D053487:DEAD-box RNA Helicases / Q000378:metabolism / Q000502:physiology*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D015151:Immunoblotting; D009362:Neoplasm Metastasis; D010641:Phenotype; D011401:Promoter Regions, Genetic; D012907:Smoking / Q000009:adverse effects; D014945:Wound Healing
D015820:Cadherins; D002273:Carcinogens; D015123:7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide; C119332:DDX3X protein, human; D053487:DEAD-box RNA Helicases