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Vitamin D-mediated suppression of mammary tumorigenesis and mechanism of action
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Lee, Hong Jin. Vitamin D-mediated suppression of mammary tumorigenesis and mechanism of action. Retrieved from https://doi.org/doi:10.7282/T3NG4QTS

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TitleVitamin D-mediated suppression of mammary tumorigenesis and mechanism of action
NameLee, Hong Jin (author); Suh, Nanjoo (chair); Quadro, Loredana (internal member); Chen, Suzie (internal member); Liu, Fang (outside member); Reiss, Michael (outside member); Rutgers University; Graduate School - New Brunswick
Date Created
Other Date2008-10 (degree)
SubjectFood Science, Breast--Cancer--Treatment, Breast--Cancer--Prevention, Vitamin D--Therapeutic use
Extentxiv, 149 p. : ill.
DescriptionNumerous preclinical, epidemiological and clinical studies with vitamin D and analogs have suggested the benefits of vitamin D and analogs for prevention and treatment of cancer. However, the hypercalcemic effects have limited the use of 1alpha,25(OH)2D3, the hormonally active form of vitamin D. Gemini vitamin D analogs with a unique structure of two six-carbon chains have shown activity in inhibiting tumor growth of colon cancer cells without inducing hypercalcemia. However, the molecular mechanism of Gemini vitamin D analogs has not been studied. Here, we have investigated the effects of novel Gemini vitamin D analogs on suppressing mammary tumorigenesis and the mechanism of action in breast cancer in vitro and in vivo.
We found that Gemini vitamin D analogs exhibited better inhibition of cell growth than 1alpha,25(OH)2D3 and regulated the cell proliferating related markers including the cyclin dependent kinase inhibitor, p21 and insulin-like growth factor binding protein 3 (IGFBP-3) in MCF10AT1 human breast epithelial cells. The transforming growth factor beta (TGF-beta) superfamily has been suggested to cross-talk with vitamin D signaling, and we determined that Gemini vitamin D analog Ro3582 activated Smads (Smad1/5), down-stream mediators of bone morphogenetic protein (BMP) signaling. In the study of upstream signaling pathways, we found that Ras/PKC alpha was involved in Smad activation and cell growth inhibition by Ro3582, suggesting that the Ras/PKC alpha-Smad signaling pathway may mediate the inhibition of cell proliferation by Gemini vitamin D analog Ro3582 in MCF10 human breast epithelial cells.
Gemini vitamin D analogs exerted significant in vivo suppression of mammary tumorigenesis without inducing hypercalcemic toxicity in three different animal models: 1) N-methyl-N-nitrosourea (NMU)-induced estrogen receptor (ER) positive breast cancer, 2) ER-negative MCF10DCIS xenografts, and 3) an MMTV-her2/neu transgenic mouse model. These results suggest that Gemini vitamin D analogs be used as potent agents in the prevention and/or inhibition of different subtypes of breast cancers including luminal, Her2 positive and basal-like breast cancer.
In conclusion, Gemini vitamin D analogs regulate Smad signaling via the Ras/PKC alpha pathway, and may be potent agents for the prevention and treatment of breast cancer without calcemic toxicity.
NotePh.D.
NoteIncludes bibliographical references (p. 78-97)
Noteby Hong Jin Lee
Genretheses, ETD doctoral
Persistent URLhttps://doi.org/doi:10.7282/T3NG4QTS
Languageeng
CollectionGraduate School - New Brunswick Electronic Theses and Dissertations
Organization NameRutgers, The State University of New Jersey
RightsThe author owns the copyright to this work.
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