title: Oral administration of a gemini vitamin D analog, a synthetic triterpenoid and the combination prevents mammary tumorigenesis driven by ErbB2 overexpression.
abstract: HER2 (or ErbB2), a member of ErbB receptor tyrosine kinases, is overexpressed in approximately 20% of human breast cancer, and the ErbB2 signaling pathway is a critical therapeutic target for ErbB2-overexpressing breast cancer. We investigated the inhibitory effects of the Gemini vitamin D analog BXL0124, the synthetic triterpenoid CDDO-Im and the combination on the tumorigenesis of ErbB2-overexpressing breast cancer. MMTV-ErbB2/neu transgenic mice were treated with BXL0124, CDDO-Im, or the combination from three months of age until the end of the experiment. Formation and growth of MMTV-ErbB2/neu mammary tumors were monitored every week, and all three treatments delayed the development of mammary tumors without significant toxicity. Decreased activation of ErbB2 as well as other ErbB receptors, ErbB1 and ErbB3, in MMTV-ErbB2/neu mammary tumors was shown by all treatments. Protein levels of downstream targets of the ErbB2 signaling pathway, including activated-Erk1/2, activated-Akt, c-Myc, CycD1, and Bcl2, were repressed by all three treatments, with the combination treatment exhibiting the strongest effects. To investigate therapeutic efficacy, the combination of BXL0124 and CDDO-Im was given to MMTV-ErbB2/neu mice after mammary tumors were established between 23 and 30 weeks of age. Short-term treatment with the combination did not show effects on tumor growth nor the ErbB2 signaling pathway. The present study shows BXL0124, CDDO-Im, and the combination as potential agents for prevention, but not treatment, against the tumorigenesis of ErbB2-overexpressing breast cancer.
authors.affiliation: Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, 164 Frelinghuysen Road, Piscataway, NJ 08854, USA.
authors.forename: Jae Young
authors.initials: JY
authors.lastname: So
authors.forename: Joseph E
authors.initials: JE
authors.lastname: Wahler
authors.forename: Taesook
authors.initials: T
authors.lastname: Yoon
authors.forename: Amanda K
authors.initials: AK
authors.lastname: Smolarek
authors.forename: Yong
authors.initials: Y
authors.lastname: Lin
authors.forename: Weichung Joe
authors.initials: WJ
authors.lastname: Shih
authors.forename: Hubert
authors.initials: H
authors.lastname: Maehr
authors.forename: Milan
authors.initials: M
authors.lastname: Uskokovic
authors.forename: Karen T
authors.initials: KT
authors.lastname: Liby
authors.forename: Michael B
authors.initials: MB
authors.lastname: Sporn
authors.forename: Nanjoo
authors.initials: N
authors.lastname: Suh
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols; D015153:Blotting, Western; D002117:Calcitriol / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D002471:Cell Transformation, Neoplastic / Q000187:drug effects* / Q000473:pathology; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage* / Q000494:pharmacology; D015674:Mammary Neoplasms, Animal / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D008324:Mammary Tumor Virus, Mouse / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D008856:Microscopy, Fluorescence; D009828:Oleanolic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D002117:Calcitriol; D007093:Imidazoles; D009828:Oleanolic Acid; D012333:RNA, Messenger; D018719:Erb-b2 Receptor Tyrosine Kinases; C552206:1,25-dihydroxy-21-(3-hydroxy-3-methyl-4,4,4-tributyl)-23-yne-26,27-hexafluorocholecalciferol; C472829:1-(2-cyano-3,12-dioxooleana-1,9-dien-28-oyl) imidazole