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Superb new years news-- utilizing adenovirus component to specifically attack her2+
cancer cells
done in her2+ human breast cancer cell lines only, not yet in patients--did not harm normal cells
Not yet ready for prime time, but very hopeful
Genes Cancer. 2011 Jul;2(7):737-44.
Expression of the Adenovirus Early Gene 1A Transcription-Repression Domain Alone Downregulates HER2 and Results in the Death of Human Breast Cancer Cells Upregulated for the HER2 Proto-Oncogene.
Loewenstein PM, Green M.
Source
Saint Louis University School of Medicine, Institute for Molecular Virology, Saint Louis, MO, USA.
Abstract
Adenovirus (Ad) early gene 1A 243 residue protein (E1A 243R) possesses a potent transcription-repression function within the N-terminal 80 amino acids (E1A 1-80). We examined the ability of E1A 243R and E1A 1-80 to repress transcription of both an exogenous and the endogenous HER2 promoter in a human breast cancer cell line upregulated for the HER2 proto-oncogene (SK-BR-3). Both moieties repressed HER2 expression by over 90%. When E1A 1-80 was expressed from a nonreplicative Ad vector, levels of expression were lower than anticipated. Addition of nonspecific sequences to the E1A 1-80 C-terminus (E1A 1-80 C+) enhanced its expression 10- to 20-fold. Because "oncogene addiction" suggests that repression of HER2 could kill HER2 upregulated cells, we examined the ability of full-length E1A 243R and E1A 1-80 C+ delivered by an Ad vector to kill HER2 upregulated SK-BR-3 cells. Expression of both E1A 243R and E1A 1-80 C+ killed SK-BR-3 cells but not normal breast cells. E1A 1-80 C+ is a particularly effective killer of SK-BR-3 cells. At 144 h post infection, over 85% of SK-BR-3 cells were killed by a 100 moi of the Ad vector expressing E1A 1-80 C+. As controls, Ad vectors expressing E1A 243R with deletion of all known functional domains or expressing unrelated β-galactosidase had no effect. Three additional human breast cancer cells lines reported to be upregulated for HER2 or another EGF family member (EGFR) were found to be efficiently killed by expression of E1A 1-80 C+, whereas three additional "normal" cell lines (two derived from breast and one from foreskin) were not. The ability of the E1A transcription-repression domain alone to kill HER2 upregulated breast cancer cells has potential for development of therapies for treatment of aggressive human breast cancers and potentially other human cancers that overexpress HER2.
PMID: 22207899
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