Synthetic triterpenoid 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid induces growth arrest in HER2-overexpressing breast cancer cells.
HER2 overexpression is one of the most recognizable molecular alterations in breast tumors known to be associated with a poor prognosis. In the study described here, we explored the effect of HER2 overexpression on the sensitivity of breast cancer cells to the growth-inhibitory effects of 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid (CDDO), a synthetic triterpenoid, both in vitro and in vivo in a xenograft model of breast cancer. Both cell growth and colony formation in the soft agar assay, a hallmark of the transformation phenotype, were preferentially suppressed in HER2-overexpressing cell lines at low concentrations of CDDO, whereas growth-inhibitory effects at high concentrations did not correlate with the expression level of HER2. CDDO dose-dependently inhibited phosphorylation of HER2 in HER2-overexpressing cells and diminished HER2 kinase activity in vitro. CDDO induced the transactivation of the nuclear receptor peroxisome proliferator-activated receptor-gamma in both vector control and HER2-transfected MCF7 cells. Dose-response studies showed that the growth inhibition seen at lower concentrations of CDDO correlated with induction of the tumor suppressor gene caveolin-1, which is known to inhibit breast cancer cell growth. CDDO also reduced cyclin D1 mRNA and protein expression. In vivo studies with liposomally encapsulated CDDO showed complete abrogation of the growth of the highly tumorigenic MCF7/HER2 cells in a xenograft model of breast cancer. These findings provide the first in vitro and in vivo evidence that CDDO effectively inhibits HER2 tyrosine kinase activity and potently suppresses the growth of HER2-overexpressing breast cancer cells and suggest that CDDO has a therapeutic potential in advanced breast cancer.
Konopleva
Marina
M
Section of Molecular Hematology and Therapy, Department of Blood and Marrow Transplantation, The University of Texas M.D. Anderson Cancer Center, Unit 448, 1400 Holcombe Boulevard, Houston, TX 77030, USA.
Zhang
Weiguo
W
Shi
Yue-Xi
YX
McQueen
Teresa
T
Tsao
Twee
T
Abdelrahim
Maen
M
Munsell
Mark F
MF
Johansen
Mary
M
Yu
Dihua
D
Madden
Timothy
T
Safe
Stephen H
SH
Hung
Mien-Chie
MC
Andreeff
Michael
M
D000818:Animals; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D051242:Caveolin 1 / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism; D005260:Female; D006801:Humans; D051379:Mice; D008817:Mice, Mutant Strains; D009828:Oleanolic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D047495:PPAR gamma / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors*; D015533:Transcriptional Activation; D023041:Xenograft Model Antitumor Assays
D051242:Caveolin 1; D019938:Cyclin D1; D009828:Oleanolic Acid; D047495:PPAR gamma; D012333:RNA, Messenger; D020794:Receptor Protein-Tyrosine Kinases; D018719:Erb-b2 Receptor Tyrosine Kinases; C116817:2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid