Suppression of diacylglycerol levels by antibodies reactive with the c-erbB-2 (HER-2/neu) gene product p185c-erbB-2 in breast and ovarian cancer cell lines.
Seven of 10 murine monoclonal antibodies reactive with the extracellular domain of p185c-erbB-2 inhibited the anchorage independent growth of the SKBr3 breast cancer cell line that overexpressed p185c-erbB-2. Significant inhibition (56-72%) of diacylglycerol (DAG) levels (P < 0.0001) was observed with the 10 antibodies that inhibited SKBr3 growth (RC1, NB3, RC6, PB3, 741F8, DB5, ID5), whereas the 3 antibodies (TA1, 520C9, 454C11) that failed to inhibit SKBr3 growth also failed to affect DAG levels. Thus, DAG levels correlated with antibody-mediated growth regulation for each of the 10 monoclonal reagents. Antibody-induced inhibition of anchorage-independent growth of SKBr3 could be reversed by incubation with phorbol myristate acetate. The ID5 antibody inhibited growth of the SKBr3, SKOv3, and OVCA 432 tumor cell lines, but not of OVCA 420, OVCA 429, and OVCA 433. DAG levels were significantly decreased after ID5 treatment of the SKBr3 and SKOv3 cell lines, but not the OVCA 420, OVCA 429, and OVCA 433 lines. In the 432 line, there was a decrease which did not reach significance. Consequently, changes in DAG levels correlated with growth regulation in 5 of 6 breast and ovarian carcinoma cell lines tested with a trend toward correlation in the sixth. Decreases in DAG may be one mediator of the growth regulatory signals produced by anti-p185c-erbB-2 antibodies.
Department of Obstetrics and Gynecology, Duke University Medical Center, Durham, North Carolina 27710, USA.
M P
MP
Boente
A
A
Berchuck
R S
RS
Whitaker
A
A
Kalén
F J
FJ
Xu
D L
DL
Clarke-Pearson
R M
RM
Bell
R C
RC
Bast
D000911:Antibodies, Monoclonal; D001943:Breast Neoplasms / Q000201:enzymology* / Q000473:pathology; D002455:Cell Division; D019852:Diacylglycerol Kinase / Q000378:metabolism*; D005260:Female; D006801:Humans; D010051:Ovarian Neoplasms / Q000201:enzymology* / Q000473:pathology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000276:immunology*; D014407:Tumor Cells, Cultured
D000911:Antibodies, Monoclonal; D019852:Diacylglycerol Kinase; D018719:Erb-b2 Receptor Tyrosine Kinases