The neutrophil elastase inhibitor elafin triggers rb-mediated growth arrest and caspase-dependent apoptosis in breast cancer.
Elafin, an endogenous inhibitor of neutrophil elastase, is expressed in human mammary epithelial cells but is transcriptionally downregulated in breast cancer cells. We hypothesized that elafin may exert a tumor-suppressive activity in the context of breast cancer. In this study, we show that the retinoblastoma (Rb) pathway governs the antitumor properties of elafin. In breast cancer cells with functional Rb, the expression of elafin triggered Rb-dependent cell cycle arrest. Elafin also exhibited suppressive activity in breast cancer cell lines lacking Rb, but this was associated with an induction of caspase-3-dependent, p53-independent apoptotic cell death. Normal mammary epithelial cells were not affected by elafin. Collectively, these results argue that elafin mediates tumor-suppressive effects that are cytostatic or cytotoxic depending on the Rb status. Our findings suggest that elafin could be engineered as a therapeutic modality to treat breast cancer without toxicity to normal proliferating cells.
Caruso
Joseph A
JA
Departments of Experimental Radiation Oncology and Surgical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030-4095, USA.
Hunt
Kelly K
KK
Keyomarsi
Khandan
K
D000256:Adenoviridae / Q000235:genetics / Q000378:metabolism; D017209:Apoptosis / Q000502:physiology*; D001943:Breast Neoplasms / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D053148:Caspase 3 / Q000378:metabolism; D061945:Caspase Inhibitors; D048708:Cell Growth Processes / Q000502:physiology; D045744:Cell Line, Tumor; D053492:Elafin / Q000096:biosynthesis* / Q000235:genetics; D005260:Female; D016193:G1 Phase / Q000502:physiology; D055785:Gene Knockdown Techniques; D006801:Humans; D019272:Leukocyte Elastase / Q000037:antagonists & inhibitors*; D053491:Proteinase Inhibitory Proteins, Secretory / Q000096:biosynthesis / Q000235:genetics; D016192:Resting Phase, Cell Cycle / Q000502:physiology; D016160:Retinoblastoma Protein / Q000378:metabolism*
D061945:Caspase Inhibitors; D053492:Elafin; D053491:Proteinase Inhibitory Proteins, Secretory; D016160:Retinoblastoma Protein; D019272:Leukocyte Elastase; D053148:Caspase 3
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