title: Inhibition of the transition of ductal carcinoma in situ to invasive ductal carcinoma by a Gemini vitamin D analog.
abstract: Ductal carcinoma in situ (DCIS) is a nonmalignant lesion of the breast with the potential to progress to invasive ductal carcinoma (IDC). The disappearance and breakdown of the myoepithelial cell layer and basement membrane in DCIS have been identified as major events in the development of breast cancer. The MCF10DCIS.com cell line is a well-established model, which recapitulates the progression of breast cancer from DCIS to IDC. We have previously reported that a novel Gemini vitamin D analog, 1α,25-dihydroxy-20R-21(3-hydroxy-3-deuteromethyl-4,4,4-trideuterobutyl)-23-yne-26,27-hexafluoro-cholecalciferol (BXL0124) is a potent inhibitor of the growth of MCF10DCIS.com xenografted tumors without hypercalcemic toxicity. In this study, we utilized the MCF10DCIS.com in vivo model to assess the effects of BXL0124 on breast cancer progression from weeks 1 to 4. Upon DCIS progression to IDC from weeks 3 to 4, tumors lost the myoepithelial cell layer and basement membrane as shown by immunofluorescence staining with smooth muscle actin and laminin 5, respectively. Administration of BXL0124 maintained the critical myoepithelial cell layer as well as basement membrane, and animals treated with BXL0124 showed a 43% reduction in tumor volume by week 4. BXL0124 treatment decreased cell proliferation and maintained vitamin D receptor levels in tumors. In addition, the BXL0124 treatment reduced the mRNA levels of matrix metalloproteinases starting at week 3, contributing to the inhibition of invasive transition. Our results suggest that the maintenance of DCIS plays a significant role in the cancer preventive action of the Gemini vitamin D BXL0124 during the progression of breast lesions.
authors.affiliation: Authors' Affiliations: Department of Chemical Biology, Ernest Mario School of Pharmacy; Center for Advanced Biotechnology and Medicine, Rutgers, The State University of New Jersey, Piscataway; and Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey.
authors.forename: Joseph
authors.initials: J
authors.lastname: Wahler
authors.affiliation: Authors' Affiliations: Department of Chemical Biology, Ernest Mario School of Pharmacy; Center for Advanced Biotechnology and Medicine, Rutgers, The State University of New Jersey, Piscataway; and Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey.
authors.forename: Jae Young
authors.initials: JY
authors.lastname: So
authors.affiliation: Authors' Affiliations: Department of Chemical Biology, Ernest Mario School of Pharmacy; Center for Advanced Biotechnology and Medicine, Rutgers, The State University of New Jersey, Piscataway; and Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey.
authors.forename: Yeoun Chan
authors.initials: YC
authors.lastname: Kim
authors.affiliation: Authors' Affiliations: Department of Chemical Biology, Ernest Mario School of Pharmacy; Center for Advanced Biotechnology and Medicine, Rutgers, The State University of New Jersey, Piscataway; and Rutgers Cancer Institute of New Jersey, New Brunswick, New JerseyAuthors' Affiliations: Department of Chemical Biology, Ernest Mario School of Pharmacy; Center for Advanced Biotechnology and Medicine, Rutgers, The State University of New Jersey, Piscataway; and Rutgers Cancer Institute of New Jersey, New Brunswick, New JerseyAuthors' Affiliations: Department of Chemical Biology, Ernest Mario School of Pharmacy; Center for Advanced Biotechnology and Medicine, Rutgers, The State University of New Jersey, Piscataway; and Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey.
authors.forename: Fang
authors.initials: F
authors.lastname: Liu
authors.affiliation: Authors' Affiliations: Department of Chemical Biology, Ernest Mario School of Pharmacy; Center for Advanced Biotechnology and Medicine, Rutgers, The State University of New Jersey, Piscataway; and Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey.
authors.forename: Hubert
authors.initials: H
authors.lastname: Maehr
authors.affiliation: Authors' Affiliations: Department of Chemical Biology, Ernest Mario School of Pharmacy; Center for Advanced Biotechnology and Medicine, Rutgers, The State University of New Jersey, Piscataway; and Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey.
authors.forename: Milan
authors.initials: M
authors.lastname: Uskokovic
authors.affiliation: Authors' Affiliations: Department of Chemical Biology, Ernest Mario School of Pharmacy; Center for Advanced Biotechnology and Medicine, Rutgers, The State University of New Jersey, Piscataway; and Rutgers Cancer Institute of New Jersey, New Brunswick, New JerseyAuthors' Affiliations: Department of Chemical Biology, Ernest Mario School of Pharmacy; Center for Advanced Biotechnology and Medicine, Rutgers, The State University of New Jersey, Piscataway; and Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey nsuh@pharmacy.rutgers.edu.
authors.forename: Nanjoo
authors.initials: N
authors.lastname: Suh
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D002117:Calcitriol / Q000031:analogs & derivatives* / Q000737:chemistry / Q000627:therapeutic use; D018270:Carcinoma, Ductal, Breast / Q000473:pathology / Q000517:prevention & control*; D002285:Carcinoma, Intraductal, Noninfiltrating / Q000188:drug therapy* / Q000473:pathology*; D049109:Cell Proliferation / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects*; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: C552206:1,25-dihydroxy-21-(3-hydroxy-3-methyl-4,4,4-tributyl)-23-yne-26,27-hexafluorocholecalciferol; C411462:1,25-dihydroxy-21-(3-hydroxy-3-methylbutyl)vitamin D(3); D002117:Calcitriol