Progression of mammary carcinogenesis involves numerous alterations in signaling pathways and transcription factors. We are studying two types of nuclear receptor ligands, a novel vitamin D receptor ligand (a non- hypercalcemic Gemini vitamin D analog) and a PPARg ligand (a unique triterpenoid), for inhibition of breast cancer progression. Our preliminary data show that Gemini vitamin D analogs and triterpenoids regulate the Smad signaling pathway and synergize to inhibit the proliferation of cultured MCF10 breast cancer cells. We hypothesize that Gemini vitamin D analogs and triterpenoids regulate nuclear receptor signaling and the TGF- b/Smad system, and these effects contribute to their inhibition of the progression of breast cancer in vivo. To test this hypothesis, we plan to pursue the following Specific Aims: (1) investigate the molecular mechanism of a representative Gemini vitamin D analog and a triterpenoid, alone and in combination, in cultured MCF10 breast cancer cell lines (with different degrees of progression), (2) determine the in vivo efficacy of a Gemini vitamin D analog and a triterpenoid in an animal model of MCF10 breast cancer and elucidate the mechanisms of action involved, and (3) verify the in vivo efficacy of the Gemini vitamin D analog and a triterpenoid in an animal model of MMTV-neu estrogen receptor (ER)-negative breast cancer. To study the in vivo efficacy and molecular mechanisms of these agents against breast cancer progression, we will use the MCF10 cell lines that represent different stages of progression when injected into immunodeficient mice. We will investigate the molecular mechanism of synergy of these agents by examining (a) interactions of nuclear receptors and coactivators, (b) regulation of transcriptional activation and target genes, and (c) regulation of Smad signaling and post-translational modification by a Gemini vitamin D analog and a triterpenoid in the MCF10 breast cell lines. The MCF10 breast cancer xenograft model and the MMTV-neu breast cancer transgenic mouse model will be used for determining in vivo efficacy of a Gemini vitamin D analog and a triterpenoid, alone and in combination, in ER-negative breast cancer. Our proposal focuses on the identification of novel nuclear receptor ligands as promising agents for the inhibition of ER-negative breast cancer. This is important because there are currently only a limited number of agents for the prevention/treatment of ER-negative breast cancer. Our research with a novel non-hypercalcemic Gemini vitamin D analog and a novel triterpenoid that inhibits breast cancer progression will provide important preclinical data for the prevention of ER-negative breast cancer.Project Summary/Narrative This proposal is to study two nuclear receptor ligands, a novel non-hypercalcemic Gemini vitamin D analog and a novel triterpenoid, as agents for inhibition of breast cancer formation and progression. We will investigate the regulation of nuclear receptor signaling with a focus on the TGF-b/Smad signaling pathway by these two agents, and we will determine their in vivo efficacy in animal models of estrogen receptor negative breast cancer progression. We anticipate finding synergistic inhibition of breast cancer progression by the combination of a Gemini vitamin D analog and a unique triterpenoid. This research will be an important precursor for a clinical cancer prevention trial in patients with a high risk of estrogen receptor negative breast cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA127645-05
Application #
8231508
Study Section
Chemo/Dietary Prevention Study Section (CDP)
Program Officer
Perloff, Marjorie
Project Start
2008-05-01
Project End
2014-02-28
Budget Start
2012-03-01
Budget End
2014-02-28
Support Year
5
Fiscal Year
2012
Total Cost
$241,812
Indirect Cost
$80,792
Name
Rutgers University
Department
Biology
Type
Schools of Pharmacy
DUNS #
001912864
City
New Brunswick
State
NJ
Country
United States
Zip Code
08901
So, Jae Young; Suh, Nanjoo (2015) Targeting cancer stem cells in solid tumors by vitamin D. J Steroid Biochem Mol Biol 148:79-85
Wahler, Joseph; So, Jae Young; Cheng, Larry C et al. (2015) Vitamin D compounds reduce mammosphere formation and decrease expression of putative stem cell markers in breast cancer. J Steroid Biochem Mol Biol 148:148-55
Wahler, Joseph; So, Jae Young; Kim, Yeoun Chan et al. (2014) Inhibition of the transition of ductal carcinoma in situ to invasive ductal carcinoma by a Gemini vitamin D analog. Cancer Prev Res (Phila) 7:617-26
So, Jae Young; Lin, Janice J; Wahler, Joseph et al. (2014) A synthetic triterpenoid CDDO-Im inhibits tumorsphere formation by regulating stem cell signaling pathways in triple-negative breast cancer. PLoS One 9:e107616
So, Jae Young; Smolarek, Amanda K; Salerno, David M et al. (2013) Targeting CD44-STAT3 signaling by Gemini vitamin D analog leads to inhibition of invasion in basal-like breast cancer. PLoS One 8:e54020
So, Jae Young; Wahler, Joseph E; Yoon, Taesook et al. (2013) Oral administration of a gemini vitamin D analog, a synthetic triterpenoid and the combination prevents mammary tumorigenesis driven by ErbB2 overexpression. Cancer Prev Res (Phila) 6:959-70
So, Jae Young; Lee, Hong Jin; Smolarek, Amanda K et al. (2011) A novel Gemini vitamin D analog represses the expression of a stem cell marker CD44 in breast cancer. Mol Pharmacol 79:360-7
Huet, Tiphaine; Maehr, Hubert; Lee, Hong Jin et al. (2011) Structure-function study of gemini derivatives with two different side chains at C-20, Gemini-0072 and Gemini-0097. Medchemcomm 2:424-429
Lee, Hong Jin; So, Jae-Young; DeCastro, Andrew et al. (2010) Gemini vitamin D analog suppresses ErbB2-positive mammary tumor growth via inhibition of ErbB2/AKT/ERK signaling. J Steroid Biochem Mol Biol 121:408-12
Maehr, Hubert; Lee, Hong Jin; Perry, Bradford et al. (2009) Calcitriol derivatives with two different side chains at C-20. V. Potent inhibitors of mammary carcinogenesis and inducers of leukemia differentiation. J Med Chem 52:5505-19

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