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Vitamin D-mediated suppression of mammary tumorigenesis and mechanism of action
Descriptive
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Text
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Title
Vitamin D-mediated suppression of mammary tumorigenesis and mechanism of action
SubTitle
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ETD_1131
Identifier
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http://hdl.rutgers.edu/1782.2/rucore10001600001.ETD.000051764
Language
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eng
Genre
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theses
Subject
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(authority = RUETD)
Topic
Food Science
Subject
(ID = SBJ-2);
(authority = ETD-LCSH)
Topic
Breast--Cancer--Treatment
Subject
(ID = SBJ-3);
(authority = ETD-LCSH)
Topic
Breast--Cancer--Prevention
Subject
(ID = SBJ-4);
(authority = ETD-LCSH)
Topic
Vitamin D--Therapeutic use
Abstract
Numerous 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.
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.
PhysicalDescription
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electronic resource
Extent
xiv, 149 p. : ill.
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application/pdf
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text/xml
Note
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Ph.D.
Note
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Includes bibliographical references (p. 78-97)
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by Hong Jin Lee
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Lee
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Hong Jin
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author
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Hong Jin Lee
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Suh
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Nanjoo
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chair
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Advisory Committee
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Nanjoo Suh
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(type = family)
Quadro
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(type = given)
Loredana
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internal member
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Advisory Committee
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Loredana Quadro
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(type = family)
Chen
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Suzie
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internal member
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Advisory Committee
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Suzie Chen
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(type = family)
Liu
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(type = given)
Fang
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outside member
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Advisory Committee
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Fang Liu
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Reiss
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Michael
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outside member
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Advisory Committee
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Michael Reiss
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Rutgers University
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degree grantor
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Graduate School - New Brunswick
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school
OriginInfo
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2008
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2008-10
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xx
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TitleInfo
Title
Rutgers University Electronic Theses and Dissertations
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ETD
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Title
Graduate School - New Brunswick Electronic Theses and Dissertations
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rucore19991600001
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(displayLabel = Rutgers, The State University of New Jersey)
NjNbRU
Identifier
(type = doi)
doi:10.7282/T3NG4QTS
Genre
(authority = ExL-Esploro)
ETD doctoral
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Rights
RightsDeclaration
(AUTHORITY = GS);
(ID = rulibRdec0006)
The author owns the copyright to this work.
Copyright
Status
Copyright protected
Notice
Note
Availability
Status
Open
Reason
Permission or license
Note
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(type = personal)
Name
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Lee
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Hong Jin
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Permission or license
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Copyright holder
Name
Hong Jin Lee
Affiliation
Rutgers University. Graduate School - New Brunswick
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Author Agreement License
Detail
I hereby grant to the Rutgers University Libraries and to my school the non-exclusive right to archive, reproduce and distribute my thesis or dissertation, in whole or in part, and/or my abstract, in whole or in part, in and from an electronic format, subject to the release date subsequently stipulated in this submittal form and approved by my school. I represent and stipulate that the thesis or dissertation and its abstract are my original work, that they do not infringe or violate any rights of others, and that I make these grants as the sole owner of the rights to my thesis or dissertation and its abstract. I represent that I have obtained written permissions, when necessary, from the owner(s) of each third party copyrighted matter to be included in my thesis or dissertation and will supply copies of such upon request by my school. I acknowledge that RU ETD and my school will not distribute my thesis or dissertation or its abstract if, in their reasonable judgment, they believe all such rights have not been secured. I acknowledge that I retain ownership rights to the copyright of my work. I also retain the right to use all or part of this thesis or dissertation in future works, such as articles or books.
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application/x-tar
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3420160
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