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,
Vitamin D--Therapeutic use
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.
NoteIncludes bibliographical references (p. 78-97)
Noteby Hong Jin Lee
CollectionGraduate School - New Brunswick Electronic Theses and Dissertations
Organization NameRutgers, The State University of New Jersey
RightsThe author owns the copyright to this work.