Antisense oligonucleotides specific for the HER2/neu oncogene inhibit the growth of human breast carcinoma cells that overexpress HER2/neu.
The HER2/neu oncogene encodes a cell surface protein which plays a role in growth factor-stimulated mitogenic signaling. HER2/neu is overexpressed in 30-40% of human breast carcinomas. This study tested the hypothesis that inhibiting HER2/neu expression using a phosphorothioate antisense (AS) oligonucleotide would inhibit the growth of breast cancer cells that overexpress this gene. A human breast carcinoma cell line, BT474, which overexpresses the HER2/neu oncogene was exposed to AS, sense (S), or scrambled antisense (SC) phosphorothioate oligonucleotides in tissue culture. Treatment with AS oligonucleotides specifically downregulated HER2/neu mRNA expression and resulted in lower levels of the HER2/neu protein product, p185; control oligonucleotides had no such effect. AS oligonucleotide treatment significantly inhibited the in vitro growth of BT474 cells, whereas S and SC controls had little effect on BT474 growth. HER2/neu AS oligonucleotide treatment had no effect on the growth of a distinct breast cancer line, MCF7, which expresses low levels of the HER2/neu oncogene. Breast carcinoma cells which overexpress the HER2/neu gene appear to be dependent on continued expression of this oncogene for cell growth. AS oligonucleotide pharmaceuticals which interfere with the expression of the HER2/neu oncogene may be of use in the therapy of some patients with breast carcinoma.
Department of Surgery, Washington University School of Medicine, St. Louis, Missouri, 63110, USA.
H
H
Roh
J
J
Pippin
C
C
Boswell
J A
JA
Drebin
D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology*; D002455:Cell Division / Q000187:drug effects; D005260:Female; D015870:Gene Expression / Q000502:physiology; D006801:Humans; D016376:Oligonucleotides, Antisense / Q000235:genetics* / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism; D014407:Tumor Cells, Cultured
D016376:Oligonucleotides, Antisense; D012333:RNA, Messenger; D018719:Erb-b2 Receptor Tyrosine Kinases