The amplified WWP1 gene is a potential molecular target in breast cancer.
The amplification of the q21 band of chromosome 8 (8q21) occurs in a large percentage of breast cancers. WWP1, an HECT domain-containing ubiquitin E3 ligase located in the 8q21 region, negatively regulates the TGF-beta tumor suppressor pathway. To characterize the role of WWP1 in breast cancer, we analyzed WWP1 gene dosage and expression level as well as WWP1's function. A copy number gain of WWP1 was found in 51% (18/35) of breast cancer cell lines and in 41% (17/41) of primary breast tumors. Expression of WWP1 mRNA was analyzed with real-time RT-PCR, Northern blot, and Western blot. WWP1 mRNA is up-regulated in 58% (19/33) of breast cancer cell lines, and overexpression of WWP1 is significantly correlated with a gene copy number gain. In a panel of cDNA from primary breast tumors and normal tissues, expression of WWP1 in tumors is significantly higher than that in normal tissues. Functionally, RNAi-mediated WWP1 knockdown significantly induced cell growth arrest and apoptosis in the MCF7 and HCC1500 breast cancer cell lines. Consistently, WWP1 inhibition activated caspases. Forced overexpression of WWP1 by the lentiviral system in 2 immortalized breast epithelial cell lines MCF10A and 184B5 promoted cell proliferation. These results suggest that genomic aberrations of WWP1 may contribute to the pathogenesis of breast cancer.
Chen
Ceshi
C
The Center for Cell Biology and Cancer Research, Albany Medical College, Albany, NY 12208, USA. chenc@mail.amc.edu
Zhou
Zhongmei
Z
Ross
Jeffrey S
JS
Zhou
Wei
W
Dong
Jin-Tang
JT
D000328:Adult; D000368:Aged; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism; D005784:Gene Amplification / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008875:Middle Aged; D034741:RNA, Small Interfering / Q000235:genetics; D044767:Ubiquitin-Protein Ligases / Q000235:genetics* / Q000378:metabolism*; D015854:Up-Regulation
D034741:RNA, Small Interfering; C471642:WWP1 protein, human; D044767:Ubiquitin-Protein Ligases