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1.
Oncotarget ; 5(23): 11827-46, 2014 Dec 15.
Article in English | MEDLINE | ID: mdl-25460500

ABSTRACT

Carriers of germline mutations in the BRCA1 gene have a significant increased lifetime risk for being diagnosed with breast cancer. The incomplete penetrance of BRCA1 suggests that environmental and/or genetic factors modify the risk and incidence among mutation carriers. Nutrition and particular micronutrients play a central role in modifying the phenotypic expression of a given genotype by regulating chromatin structure and gene expression. The active form of vitamin D, 1α,25-dihydroxyvitamin D3, is a potent inhibitor of breast cancer growth. Here we report that two non-calcemic analogues of 1α,25-dihydroxyvitamin D3, seocalcitol (EB1089) and QW-1624F2-2, collaborate with BRCA1 in mediating growth inhibition of breast cancer cells and breast cancer stem-like cells. EB1089 induces a G1/S phase growth arrest that coincides with induction of p21waf1 expression only in BRCA1-expressing cells. A complete knockdown of BRCA1 or p21waf1 renders the cells unresponsive to EB1089. Furthermore, we show that in the presence of ligand, BRCA1 associates with vitamin D receptor (VDR) and the complex co-occupies vitamin D responsive elements (VDRE) at the CDKN1A (p21waf1) promoter and enhances acetylation of histone H3 and H4 at these sites. Thus, BRCA1 expression is critical for mediating the biological impact of vitamin D3 in breast tumor cells.


Subject(s)
BRCA1 Protein/metabolism , Breast Neoplasms/pathology , Cell Proliferation , Cholecalciferol/metabolism , Cyclin-Dependent Kinase Inhibitor p21/metabolism , Neoplastic Stem Cells/pathology , Promoter Regions, Genetic , Acetylation , BRCA1 Protein/genetics , Breast Neoplasms/genetics , Breast Neoplasms/metabolism , Cell Line, Tumor , Cholecalciferol/pharmacology , Chromatin Immunoprecipitation , Cyclin-Dependent Kinase Inhibitor p21/genetics , Flow Cytometry , Fluorescent Antibody Technique , Histones/metabolism , Humans , Immunoblotting , Immunoprecipitation , Neoplastic Stem Cells/metabolism , Promoter Regions, Genetic/genetics , Receptors, Calcitriol/metabolism , Reverse Transcriptase Polymerase Chain Reaction , Transfection
2.
Biochem Biophys Res Commun ; 368(4): 930-6, 2008 Apr 18.
Article in English | MEDLINE | ID: mdl-18279661

ABSTRACT

ABC transporters are often found to be inherently expressed in a wide variety of stem cells, where they provide improved protection from toxins. We found a subpopulation of human melanoma cells expressing multidrug-resistance gene product 1 (MDR1). This fraction co-expresses the ABC transporters, ABCB5 and ABCC2 in addition to the stem cell markers, nanog and human telomerase reverse transcriptase (hTERT). The clonogenicity and self-renewal capacity of MDR1(+) melanoma cells were investigated in single cell settings using the limiting dilution assay. We found that the MDR1(+) cells, isolated by FACS sorting, demonstrated a higher self-renewal capacity than the MDR1(-) fraction, a key stem cell feature. Moreover, MDR1(+) cells had higher ability to form spheres in low attachment conditions, a hallmark of cancer. In conclusion, these novel findings imply that the MDR1(+) cells represent melanoma stem cells and thus should be considered as a unique cellular target for future anti-melanoma therapies.


Subject(s)
ATP Binding Cassette Transporter, Subfamily B, Member 1/biosynthesis , Melanoma/pathology , Neoplastic Stem Cells/metabolism , ATP Binding Cassette Transporter, Subfamily B , DNA-Binding Proteins/biosynthesis , Homeodomain Proteins/biosynthesis , Humans , Melanoma/metabolism , Membrane Transport Proteins/biosynthesis , Multidrug Resistance-Associated Protein 2 , Multidrug Resistance-Associated Proteins/biosynthesis , Nanog Homeobox Protein , Telomerase/biosynthesis , Tumor Cells, Cultured
3.
J Comp Neurol ; 504(6): 690-701, 2007 Oct 20.
Article in English | MEDLINE | ID: mdl-17722033

ABSTRACT

We examined the potential of bone marrow transplantation (BMT) to rescue dopaminergic neurons in a mouse model of Parkinson's disease (PD). A BMT from mice transgenic for green fluorescent protein (GFP(+)) given either before or after administration of the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) led to the accumulation of transplanted adult GFP(+) bone-marrow-derived cells (BMDC) in the substantia nigra, where dopaminergic neurodegeneration occurs in PD. Post-BMT, mice exposed to MPTP had substantially greater numbers of endogenous tyrosine hydroxylase-positive neuronal cell bodies in the substantia nigra and increased dopamine transporter-positive projections into the striatum compared to controls. Moreover, motor function was restored to normal within 1 month post-MPTP in BMT-treated mice assayed by a rotarod behavioral test. The effect of BMT on PD was indirect, as no evidence of BMDC fusion with or transdifferentiation into dopaminergic neurons was observed. BMDC activated by BMT or associated factors could play a trophic role in rescuing damaged cells. Alternatively, the beneficial effects of BMT are due to immunosuppression reflected by a reduction in the proportion of T-cells and a reduction of T-cell proliferation in BMT mice. These findings highlight that when immunosuppression is required for transplantation studies, the amelioration of symptoms may not be due to the transplant itself. Further, they suggest that the immune system plays a role in the development of characteristics typical of PD.


Subject(s)
Bone Marrow Transplantation/methods , Immune Tolerance/physiology , MPTP Poisoning , Motor Activity/physiology , Neurons/physiology , Analysis of Variance , Animals , Cell Count , Cell Proliferation/drug effects , Cell Survival/physiology , Concanavalin A/pharmacology , Disease Models, Animal , Green Fluorescent Proteins/biosynthesis , Green Fluorescent Proteins/metabolism , MPTP Poisoning/pathology , MPTP Poisoning/physiopathology , MPTP Poisoning/surgery , Mice , Mitogens/pharmacology , Substantia Nigra/metabolism , Substantia Nigra/physiopathology , T-Lymphocytes/physiology , Time Factors , Tyrosine 3-Monooxygenase/metabolism
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