Oral Administration of a Gemini Vitamin D Analog, a Synthetic Triterpenoid and the Combination Prevents Mammary Tumorigenesis Driven by ErbB2 Overexpression

• Published in: Cancer prevention research (Philadelphia, Pa.) Vol. 6; no. 9; pp. 959 - 970
• Main Authors: JAE YOUNG SO, WAHLER, Joseph E, NANJOO SUH, TAESOOK YOON, SMOLAREK, Amanda K, YONG LIN, WEICHUNG JOE SHIH, MAEHR, Hubert, USKOKOVIC, Milan, LIBY, Karen T, SPORN, Michael B
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01-09-2013
• Subjects: Administration, Oral; Animals; Antineoplastic Combined Chemotherapy Protocols; Biological and medical sciences; Blotting, Western; Calcitriol - administration & dosage; Calcitriol - analogs & derivatives; Calcitriol - pharmacology; Cell Transformation, Neoplastic - drug effects; Cell Transformation, Neoplastic - pathology; Female; Humans; Imidazoles - administration & dosage; Imidazoles - pharmacology; Mammary Neoplasms, Animal - metabolism; Mammary Neoplasms, Animal - pathology; Mammary Neoplasms, Animal - prevention & control; Mammary Tumor Virus, Mouse - genetics; Medical sciences; Mice; Mice, Transgenic; Microscopy, Fluorescence; Miscellaneous; Oleanolic Acid - administration & dosage; Oleanolic Acid - analogs & derivatives; Oleanolic Acid - pharmacology; Prevention and actions; Public health. Hygiene; Public health. Hygiene-occupational medicine; Real-Time Polymerase Chain Reaction; Receptor, ErbB-2 - physiology; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - genetics; Signal Transduction - drug effects; Oral administration; erbB2 Gene; Gene overexpression; Tumorigenicity; Carcinogenesis; Human Epidermal growth factor Receptor 2; Retinol; Prevention; Synthetic product; Vitamin D; Analog; C-Onc gene; Triterpene; Breast; Mammary gland; Protooncogene
• ISSN: 1940-6207; 1940-6215
• DOI: 10.1158/1940-6207.CAPR-13-0087

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.