Fas/FasL System in c-Myc Expressing Mammary Carcinoma Cells
Abstract
The c-Myc oncogene is amplified or overexpressed in the majority of human breast cancers where it contributes to genomic instability, abrogation of cell cycle check points, cell proliferation, and apoptosis. In search of survival pathways that abrogate c-Myc's apoptotic function, our lab has uncovered a novel survival-signaling pathway that regulates Akt activation. In mammary carcinoma cells that overexpress c-Myc, calcium and calmodulin mediate EGF-induced activation of Akt. Inhibition of calmodulin with W7 leads to a rapid abrogation of ligand initiated activation of Akt. This phenomenon was observed in a number of mouse mammary carcinoma cell lines and human mammary epithelial cells regardless of c-Myc expression, however only c-Myc overexpressing cells underwent apoptosis when calmodulin was inhibited by W7, suggesting that calmodulin was providing a fundamental survival signal in those cells. Calmodulin and calmodulin-dependent kinase's (CaM kinases) role in the mammary epithelium is virtually unknown. A novel CaM kinase, Pnck (pregnancy upregualted nonubiquitous CaM kinase) was recently discovered and its expression profile has been described. Pnck is upregulated in the mouse mammary gland during development and in late stage pregnancy in a subset of epithelial cells that appear to be undergoing differentiation. Pnck is again upregulated in the mouse mammary glands undergoing postlactational involution, suggesting that Pnck expression is correlated with differentiation and apoptosis. In human breast tumors, Pnck expression was upregulated, but not in adjacent benign tissue, as well in a subset of human breast cancer cell lines. Interestingly, in mouse mammary tumors, Pnck was upregulated in MMTV-c-Myc derived tumors, but not other MMW-oncogene derived tumors, suggesting that Pnck may be expressed in a c-Myc associated manner.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jun 01, 2004
- Accession Number
- ADA431981
Entities
People
- Christine M. Coticchia
Organizations
- Georgetown University