Overexpression of RbAp46 facilitates stress-induced apoptosis and suppresses tumorigenicity of neoplastigenic breast epithelial cells.
We have found previously that the retinoblastoma (Rb) suppressor associated protein 46 (RbAp46) is a gene upregulated by the Wilms' tumor suppressor, WT1, and functions as a potent growth inhibitor. To investigate the effect of RbAp46 overexpression on early development of breast cancer, we established stable cell lines from neoplastigenic breast epithelial cells, MCF10AT3B, a cell line derived from a model of human proliferative disease, to constitutively express exogenous RbAp46. We have found that expression of RbAp46 suppressed colony formation of MCF10AT3B cells in soft-agar, and inhibited tumor formation of these cells in nude mice. Expression of RbAp46 sensitized MCF10AT3B cells to apoptosis induced by serum deprivation and hydrocortisone withdrawal. Furthermore, we have found that the c-Jun NH2-terminal kinase (JNK) pathway and GADD45, a growth arrest- and DNA damage-inducible gene, are constitutively activated in RbAp46-expressing cells. Our data suggested that high levels of RbAp46 expression inhibit the tumorigenicity of neoplastigenic breast epithelial cells by facilitating JNK-dependent apoptotic cell death. Our data also suggested that dysregulation of RbAp46 gene may be involved in the early development of breast cancer.
Li
Guan-Cheng
GC
Division of Hematology and Oncology, Department of Medicine, Beth Israel-Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
Guan
Li-Shuang
LS
Wang
Zhao-Yi
ZY
D000818:Animals; D017209:Apoptosis; D001940:Breast / Q000166:cytology; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D002455:Cell Division; D002461:Cell Line, Transformed; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism; D005260:Female; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D048031:JNK Mitogen-Activated Protein Kinases; D008325:Mammary Neoplasms, Experimental / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D014176:Protein Biosynthesis; D011506:Proteins; D056524:Retinoblastoma-Binding Protein 7; D014162:Transfection; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D000097642:GADD45 Proteins
D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D009687:Nuclear Proteins; D011506:Proteins; D056524:Retinoblastoma-Binding Protein 7; D025521:Tumor Suppressor Proteins; D000097642:GADD45 Proteins; C490746:RBBP7 protein, human; C096378:Rbbp7 protein, mouse