RESUMEN

K vitamins are well known as essential cofactors for hepatic γ-carboxylation of coagulation factors, but their potential role in chronic diseases including cancer is understudied. K2, the most abundant form of vitamin K in tissues, exerts anti-cancer effects via diverse mechanisms which are not completely understood. Our studies were prompted by previous work demonstrating that the K2 precursor menadione synergized with 1,25 dihydroxyvitamin D3 (1,25(OH)2D3) to inhibit growth of MCF7 luminal breast cancer cells. Here we assessed whether K2 modified the anti-cancer effects of 1,25(OH)2D3 in triple negative breast cancer (TNBC) cell models. We examined the independent and combined effects of these vitamins on morphology, cell viability, mammosphere formation, cell cycle, apoptosis and protein expression in three TNBC cell models (MDA-MB-453, SUM159PT, Hs578T). We found that all three TNBC cell lines expressed low levels of the vitamin D receptor (VDR) and were modestly growth inhibited by 1,25(OH)2D3 in association with cell cycle arrest in G0/G1. Induction of differentiated morphology by 1,25(OH)2D3 was observed in two of the cell lines (MDA-MB-453, Hs578T). Treatment with K2 alone reduced viability of MDA-MB-453 and SUM159PT cells but not Hs578T cells. Co-treatment with 1,25(OH)2D3 and K2 significantly reduced viable cell number relative to either treatment alone in Hs578T and SUM159PT cells. The combination treatment induced G0/G1 arrest in MDA-MB-453 cells, Hs578T and SUM159PT cells. Combination treatment altered mammosphere size and morphology in a cell specific manner. Of particular interest, treatment with K2 increased VDR expression in SUM159PT cells suggesting that the synergistic effects in these cells may be secondary to increased sensitivity to 1,25(OH)2D3. The phenotypic effects of K2 in TNBC cells did not correlate with γ-carboxylation suggesting non-canonical actions. In summary, 1,25(OH)2D3 and K2 exert tumor suppressive effects in TNBC cells, inducing cell cycle arrest leading to differentiation and/or apoptosis depending on the specific cell line. Further mechanistic studies to clarify common and unique targets of these two fat soluble vitamins in TNBC are warranted.

Asunto(s)

Calcitriol , Neoplasias de la Mama Triple Negativas , Humanos , Calcitriol/farmacología , Vitamina K 2/farmacología , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Células Tumorales Cultivadas , Receptores de Calcitriol/metabolismo , Vitamina K , Vitaminas/farmacología

RESUMEN

Phylloquinone (vitamin K1) and menaquinones (vitamin K2 family) are essential for post-translational γ-carboxylation of a small number of proteins, including clotting factors. These modified proteins have now been implicated in diverse physiological and pathological processes including cancer. Vitamin K intake has been inversely associated with cancer incidence and mortality in observational studies. Newly discovered functions of vitamin K in cancer cells include activation of the steroid and xenobiotic receptor (SXR) and regulation of oxidative stress, apoptosis, and autophagy. We provide an update of vitamin K biology, non-canonical mechanisms of vitamin K actions, the potential functions of vitamin K-dependent proteins in cancer, and observational trials on vitamin K intake and cancer.

Asunto(s)

Neoplasias , Vitamina K , Biología , Humanos , Neoplasias/etiología , Receptor X de Pregnano , Proteínas , Vitamina K/metabolismo , Vitamina K 1/metabolismo , Vitamina K 2/metabolismo

RESUMEN

1,25-Dihydroxyvitamin D3 (1,25D3) induces growth arrest and apoptosis in breast cancer cells in vivo and in vitro, however the exact mechanisms are unclear. Although the vitamin D receptor (VDR), a ligand dependent transcription factor, is required for growth regulation by vitamin D, the specific target genes that trigger these effects are unknown. Genomic profiling of murine mammary tumor cells with differential VDR expression identified 35 transcripts that were altered by the 1,25D3-VDR complex including Hyaluronan Synthase-2 (Has2). Here we confirmed that 1,25D3 reduces both HAS2 gene expression and hyaluronic acid (HA) synthesis in multiple models of breast cancer. Furthermore, we show that the growth inhibitory effects of 1,25D3 are partially reversed in the presence of high molecular weight HA. HAS2 expression and HA production are elevated in immortalized human mammary epithelial cells induced to undergo epithelial-mesenchymal transition (EMT) through stable expression of TGFß, SNAIL or TWIST and in those expressing oncogenic H-RASV12, indicating that deregulation of HA production may be an early and frequent event in breast tumorigenesis. 1,25D3 also reduces HA secretion and acts additively with an HA synthesis inhibitor to slow growth of cells expressing TGFß, SNAIL and TWIST. Analysis of mammary gland and tumors from Vdr knockout mice suggest that loss of VDR is associated with enhanced HAS2 expression and HA production in vivo. These data define a novel role for 1,25D3 and the VDR in control of HA synthesis in epithelial tissues that likely contributes to its anti-cancer actions.

RESUMEN

BACKGROUND/AIM: Glioblastoma multiforme is an aggressive primary tumor that arises in the glial cells of the brain. Standardized first-line treatment has considerable morbidity and less than one-year median survival after intervention. Ultra-low intensity electromagnetic fields have been shown to interact with biological organisms without anticipated deleterious side-effects. The aim of the study was to determine if a novel, non-invasive application of non-ionizing radiation has an inhibitory effect on proliferation of glioblastoma multiforme cells. MATERIALS AND METHODS: U-87 MG cells were continuously exposed for 54 h to an electromagnetic field tuned to simultaneously interact with DNA/RNA oligonucleotides (mutated alpha-kinase 2 gene/Hsa-miR-381-5p respectively) and proteins (HSP70/CHI3L1). RESULTS: Exposed cells demonstrated a significant inhibition of cell growth and concurrent increase in cell death. CONCLUSION: This technology induces cell death by novel non-cytotoxic mechanisms unlikely to induce side-effects in patients; can be customized for individual tumors and may contribute to the emerging strategy of personalized medicine.

Asunto(s)

Puntos de Control del Ciclo Celular/efectos de la radiación , Proliferación Celular/efectos de la radiación , Campos Electromagnéticos , Redes Reguladoras de Genes/efectos de la radiación , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patología , Puntos de Control del Ciclo Celular/genética , Línea Celular Tumoral , Proliferación Celular/genética , Supervivencia Celular/genética , Supervivencia Celular/efectos de la radiación , Perfilación de la Expresión Génica/métodos , Regulación Neoplásica de la Expresión Génica/efectos de la radiación , Redes Reguladoras de Genes/genética , Glioblastoma/genética , Glioblastoma/metabolismo , Glioblastoma/patología , Humanos , MicroARNs/genética

RESUMEN

To elucidate potential mediators of vitamin D receptor (VDR) action in breast cancer, we profiled the genomic effects of its ligand 1,25-dihydroxyvitamin D3 (1,25D) in cells derived from normal mammary tissue and breast cancer. In non-transformed hTERT-HME cells, 483 1,25D responsive entities in 42 pathways were identified, whereas in MCF7 breast cancer cells, 249 1,25D responsive entities in 31 pathways were identified. Only 21 annotated genes were commonly altered by 1,25D in both MCF7 and hTERT-HME cells. Gene set enrichment analysis highlighted eight pathways (including senescence/autophagy, TGFß signaling, endochondral ossification, and adipogenesis) commonly altered by 1,25D in hTERT-HME and MCF7 cells. Regulation of a subset of immune (CD14, IL1RL1, MALL, CAMP, SEMA6D, TREM1, CSF1, IL33, TLR4) and metabolic (ITGB3, SLC1A1, G6PD, GLUL, HIF1A, KDR, BIRC3) genes by 1,25D was confirmed in hTERT-HME cells and similar changes were observed in another comparable non-transformed mammary cell line (HME cells). The effects of 1,25D on these genes were retained in HME cells expressing SV40 large T antigen but were selectively abrogated in HME cells expressing SV40 + RAS and in MCF7 cells. Integration of the datasets from hTERT-HME and MCF7 cells with publically available RNA-SEQ data from 1,25D treated SKBR3 breast cancer cells enabled identification of an 11-gene signature representative of 1,25D exposure in all three breast-derived cell lines. Four of these 11 genes (CYP24A1, CLMN, EFTUD1, and SERPINB1) were also identified as 1,25D responsive in human breast tumor explants, suggesting that this gene signature may prove useful as a biomarker of vitamin D exposure in breast tissue.

Asunto(s)

Neoplasias de la Mama/genética , Calcitriol/farmacología , Regulación de la Expresión Génica/efectos de los fármacos , Glándulas Mamarias Humanas/efectos de los fármacos , Vitaminas/farmacología , Línea Celular , Femenino , Perfilación de la Expresión Génica/métodos , Humanos , Células MCF-7 , Glándulas Mamarias Humanas/metabolismo , Análisis de Secuencia por Matrices de Oligonucleótidos/métodos

RESUMEN

Nuclear receptors exert profound effects on mammary gland physiology and have complex roles in the etiology of breast cancer. In addition to receptors for classic steroid hormones such as estrogen and progesterone, the nuclear vitamin D receptor (VDR) interacts with its ligand 1α,25(OH)2D3 to modulate the normal mammary epithelial cell genome and subsequent phenotype. Observational studies suggest that vitamin D deficiency is common in breast cancer patients and that low vitamin D status enhances the risk for disease development or progression. Genomic profiling has characterized many 1α,25(OH)2D3 responsive targets in normal mammary cells and in breast cancers, providing insight into the molecular actions of 1α,25(OH)2D3 and the VDR in regulation of cell cycle, apoptosis, and differentiation. New areas of emphasis include regulation of tumor metabolism and innate immune responses. However, the role of VDR in individual cell types (i.e., epithelial, adipose, fibroblast, endothelial, immune) of normal and tumor tissues remains to be clarified. Furthermore, the mechanisms by which VDR integrates signaling between diverse cell types and controls soluble signals and paracrine pathways in the tissue/tumor microenvironment remain to be defined. Model systems of carcinogenesis have provided evidence that both VDR expression and 1α,25(OH)2D3 actions change with transformation but clinical data regarding vitamin D responsiveness of established tumors is limited and inconclusive. Because breast cancer is heterogeneous, analysis of VDR actions in specific molecular subtypes of the disease may help to clarify the conflicting data. The expanded use of genomic, proteomic and metabolomic approaches on a diverse array of in vitro and in vivo model systems is clearly warranted to comprehensively understand the network of vitamin D regulated pathways in the context of breast cancer.

RESUMEN

Calcitriol or 1,25(OH)(2)D(3) is a negative growth regulator of breast cancer cells. The aim of this study was to determine whether L-buthionine-S,R-sulfoximine, a glutathione-depleting drug, modifies the antiproliferative effects of 1,25(OH)(2)D(3) on MCF-7 cells. For comparison, we included studies in MCF-7 cells selected for vitamin D resistance and in human mammary epithelial cells transformed with SV40 and ras. Our data indicate that L-buthionine-S,R-sulfoximine enhances the growth inhibition of 1,25(OH)(2)D(3) in all transformed breast cell lines. This effect is mediated by ROS leading to apoptosis. In conclusion, BSO alters redox state and sensitizes breast cancer cells to 1,25(OH)(2)D(3)-mediated apoptosis.

Asunto(s)

Apoptosis/efectos de los fármacos , Neoplasias de la Mama/metabolismo , Butionina Sulfoximina/farmacología , Especies Reactivas de Oxígeno/metabolismo , Vitamina D/análogos & derivados , Caspasas/metabolismo , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Activación Enzimática/efectos de los fármacos , Femenino , Humanos , Oxidación-Reducción/efectos de los fármacos , Vitamina D/farmacología

RESUMEN

These studies focus on identification of vitamin D regulated pathways that impact development or progression of breast cancer. In mouse experiments, we assessed genomic profiles of glandular tissue and established tumors from MMTV-neu mice fed adequate (250 IU/kg) or high (5000 IU/kg) vitamin D (cholecalciferol). Genomic profiles were also obtained in murine mammary cells that differentially express VDR that were cultured in vitro with 100 nM 1,25-dihydroxyvitamin D (1,25D). Ten candidate genes were identified that were commonly regulated in murine cells treated with 1,25D in vitro and in mammary gland of mice fed high dietary vitamin D. In complementary studies, the vitamin D pathway was evaluated in human mammary epithelial cells as a function of transformation. Genes regulated by 1,25D in human mammary epithelial cells included those involved in innate immunity (CD14), differentiation (Bmp6), extracellular matrix remodeling (Plau) and cell survival (Birc3). Transformation reduced VDR content and blunted the induction of some, but not all, target genes by 1,25D in human mammary cells. Collectively, these in vivo and in vitro data demonstrate that vitamin D signaling impacts on common pathways that drive differentiation, alter metabolism, remodel the extracellular matrix and trigger innate immunity in mammary tissue.

Asunto(s)

Neoplasias de la Mama/metabolismo , Calcifediol/metabolismo , Animales , Mama/metabolismo , Diferenciación Celular , Supervivencia Celular , Modelos Animales de Enfermedad , Femenino , Humanos , Inmunidad Innata , Glándulas Mamarias Animales/metabolismo , Ratones , Modelos Biológicos , Receptores de Calcitriol/metabolismo , Transducción de Señal

RESUMEN

BACKGROUND: The active form of Vitamin D, 1,25-dihydroxyvitamin D3 (1,25D), has strong anti-proliferative effects, yet the molecular mechanisms underneath this effect remain unclear. In contrast, the molecular mechanism of 1,25D for the regulation of calcium homeostasis has principally been resolved, demonstrating a pivotal role for the vitamin D receptor (VDR). RESULTS: We first addressed the question whether the anti-proliferative effects of 1,25D are influenced by VDR. Knockdown of VDR by siRNA did not affect the anti-proliferative effects of 1,25D in MCF7 breast cancer cells. This unanticipated finding led us to take an alternative approach using genome wide screens to study the molecular mechanisms of 1,25D in proliferation. For that purpose, four independently developed and stable 1,25D resistant MCF7 cell lines were analyzed. Array CGH identified a copy number alteration in a region of 13.5 Mb at chromosome 11q13.4-14.1 common to all four 1,25D resistant cell lines. Expression arrays revealed that no single gene was differentially expressed between the sensitive and resistant cells, but multiple membrane receptor signaling pathways were altered in the 1,25D resistant cell lines. Importantly, in the genome wide experiments neither VDR, CYP24A1 nor other known vitamin D signaling pathway genes were associated with 1,25D resistance. CONCLUSION: In conclusion, siRNA and genome wide studies both suggest that the anti-proliferative effects of 1,25D in MCF7 breast tumor cell lines do not rely on classical Vitamin D pathway per se.

Asunto(s)

ARN Interferente Pequeño/genética , Receptores de Calcitriol/deficiencia , Receptores de Calcitriol/genética , Vitamina D/farmacología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Cromosomas Humanos Par 11/genética , Resistencia a Antineoplásicos/genética , Dosificación de Gen/genética , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Técnicas de Silenciamiento del Gen , Humanos , Receptores de Calcitriol/metabolismo

RESUMEN

Calcitriol or 1,25(OH)(2)D(3) is a negative growth regulator of MCF-7 breast cancer cells. The growth arrest is due to apoptosis activation, which involves mitochondrial disruption. This effect is blunted in vitamin D resistant cells (MCF-7(DRes) cells). Menadione (MEN), a glutathione (GSH)-depleting compound, may potentiate antitumoral effects of anticancer drugs. The aim of this study was to investigate whether MEN enhances cellular responsiveness of MCF-7 cells to 1,25(OH)(2)D(3). Cells were cultured and treated with different concentrations of 1,25(OH)(2)D(3)+/-MEN or vehicle for 96 h. GSH levels and the activity of antioxidant enzymes were determined by spectrophotometry and ROS production by flow cytometry. Both drugs decreased growth and enhanced ROS in MCF-7 cells, obtaining the maximal effects when 1,25(OH)(2)D(3) was combined with MEN (P<0.01 vs. Control and vs. each compound alone). MCF-7(DRes) cells were not responsive to 1,25(OH)(2)D(3), but the cell proliferation was slightly inhibited by the combined treatment. Calcitriol and MEN separately enhanced antioxidant enzyme activities, but when they were used in combination, the effect was more pronounced (P<0.05 vs. Control and vs. each compound alone). MEN, calcitriol and the combined treatment decreased GSH levels (P<0.05 vs. Control). The data indicate that MEN potentiates the effect of 1,25(OH)(2)D(3) on growth arrest in MCF-7 cells by oxidative stress and increases the activities of antioxidant enzymes, probably as a compensatory mechanism.

Asunto(s)

Neoplasias de la Mama/tratamiento farmacológico , Calcitriol , Línea Celular Tumoral/efectos de los fármacos , Vitamina K 3 , Vitaminas , Animales , Antioxidantes/metabolismo , Calcitriol/farmacología , Calcitriol/uso terapéutico , Línea Celular Tumoral/citología , Forma de la Célula/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Sinergismo Farmacológico , Femenino , Humanos , Estrés Oxidativo , Especies Reactivas de Oxígeno/metabolismo , Vitamina K 3/farmacología , Vitamina K 3/uso terapéutico , Vitaminas/farmacología , Vitaminas/uso terapéutico

RESUMEN

Increased adiposity is a feature of aging in both mice and humans, but the molecular mechanisms underlying age-related changes in adipose tissue stores remain unclear. In previous studies, we noted that 18-month-old normocalcemic vitamin D receptor (VDR) knockout (VDRKO) mice exhibited atrophy of the mammary adipose compartment relative to wild-type (WT) littermates, suggesting a role for VDR in adiposity. Here we monitored body fat depots, food intake, metabolic factors, and gene expression in WT and VDRKO mice on the C57BL6 and CD1 genetic backgrounds. Regardless of genetic background, both sc and visceral white adipose tissue depots were smaller in VDRKO mice than WT mice. The lean phenotype of VDRKO mice was associated with reduced serum leptin and compensatory increased food intake. Similar effects on adipose tissue, leptin and food intake were observed in mice lacking Cyp27b1, the 1alpha-hydroxylase enzyme that generates 1,25-dihydroxyvitamin D(3), the VDR ligand. Although VDR ablation did not reduce expression of peroxisome proliferator-activated receptor-gamma or fatty acid synthase, PCR array screening identified several differentially expressed genes in white adipose tissue from WT and VDRKO mice. Uncoupling protein-1, which mediates dissociation of cellular respiration from energy production, was greater than 25-fold elevated in VDRKO white adipose tissue. Consistent with elevation in uncoupling protein-1, VDRKO mice were resistant to high-fat diet-induced weight gain. Collectively, these studies identify a novel role for 1,25-dihydroxyvitamin D(3) and the VDR in the control of adipocyte metabolism and lipid storage in vivo.

Asunto(s)

Tejido Adiposo Blanco/metabolismo , Dieta Aterogénica , Canales Iónicos/genética , Proteínas Mitocondriales/genética , Obesidad/genética , Receptores de Calcitriol/genética , Delgadez/genética , Tejido Adiposo Blanco/patología , Adiposidad/efectos de los fármacos , Animales , Peso Corporal/efectos de los fármacos , Peso Corporal/genética , Grasas de la Dieta/farmacología , Ingestión de Alimentos/genética , Predisposición Genética a la Enfermedad/etiología , Canales Iónicos/metabolismo , Metabolismo de los Lípidos/genética , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Proteínas Mitocondriales/metabolismo , Obesidad/metabolismo , Tamaño de los Órganos/genética , Fenotipo , Delgadez/patología , Proteína Desacopladora 1 , Regulación hacia Arriba/genética , Deficiencia de Vitamina D/genética , Deficiencia de Vitamina D/patología

RESUMEN

The vitamin D-3 receptor (VDR) is a nuclear receptor that modulates gene expression when complexed with its ligand 1-alpha,25-dihydroxycholecalciferol [1,25(OH)(2)-D(3)], which is the biologically active form of vitamin D-3. The cellular effects of VDR signaling include growth arrest, differentiation and/or induction of apoptosis, which indicate that the vitamin D pathway participates in negative-growth regulation. Although much attention has been directed in recent years toward the development of synthetic vitamin D analogs as therapeutic agents for a variety of human cancers including those derived from the mammary gland, studies on vitamin D as a chemopreventive agent for breast cancer have been quite limited. The VDR is expressed in normal mammary gland, where it functions to oppose estrogen-driven proliferation and maintain differentiation; this suggests that 1,25(OH)(2)-D(3) participates in negative-growth regulation of mammary epithelial cells. Furthermore, preclinical studies show that vitamin D compounds can reduce breast cancer development in animals, and human data indicate that both vitamin D status and genetic variations in the VDR may affect breast cancer risk. Collectively, findings from cellular, molecular and population studies suggest that the VDR is a nutritionally modulated growth-regulatory gene that may represent a molecular target for chemoprevention of breast cancer.

Asunto(s)

Neoplasias de la Mama/prevención & control , Colecalciferol , Neoplasias Mamarias Animales/prevención & control , Biología Molecular , Receptores de Calcitriol , Vitamina D , Animales , Mama/metabolismo , Colecalciferol/metabolismo , Colecalciferol/fisiología , Femenino , Humanos , Masculino , Ratones , Ratones Noqueados , Receptores de Calcitriol/efectos de los fármacos , Receptores de Calcitriol/metabolismo , Receptores de Calcitriol/fisiología , Células Tumorales Cultivadas , Vitamina D/metabolismo , Vitamina D/fisiología , Vitamina D/uso terapéutico

RESUMEN

Vitamin D(3) compounds offer an alternative approach to anti-hormonal therapies for human breast cancer. 1,25-Dihydroxyvitamin D(3) (1,25-(OH)(2)D(3)) acts through the nuclear Vitamin D(3) receptor (VDR), a phosphoprotein and ligand-dependent transcription factor. Our lab has shown that 1,25-(OH)(2)D(3) induces apoptosis in MCF-7 cells by disruption of mitochondrial function which is associated with Bax translocation to mitochondria, cytochrome c release, and production of reactive oxygen species (ROS). TPA, a protein kinase C (PKC) activator, does not induce cytochrome c release or Bax translocation, thus demonstrating that it has no effect on mitochondria and apoptosis on its own. However, when the MCF-7(D(3)Res) cells (a Vitamin D(3)-resistant variant) are treated with 1,25-(OH)(2)D(3) in the presence of TPA, the cells displayed apoptotic morphology and redistribution of both cytochrome c and Bax. TPA pretreatment greatly enhances 1,25-(OH)(2)D(3) stimulated 24-hydroxylase luciferase activity and VDR protein expression, although transactivation is lower in the MCF-7(D(3)Res) cells compared to the parental cell line. The observation that the phorbol ester TPA sensitizes the Vitamin D(3)-resistant variant to the effects of 1,25-(OH)(2)D(3) suggests an important role for phosphorylation in dictating sensitivity to Vitamin D(3)-mediated apoptosis. This study demonstrates that the effects of 1,25-(OH)(2)D(3) on mitochondrial disruption might be sensitized through activators of PKC.

Asunto(s)

Apoptosis , Calcitriol/farmacología , Colecalciferol/farmacología , Resistencia a Antineoplásicos , Fosfatasa Alcalina/metabolismo , Carcinógenos , Membrana Celular/metabolismo , Sistema Enzimático del Citocromo P-450/metabolismo , Grupo Citocromo c/metabolismo , Citosol/metabolismo , Activación Enzimática , Citometría de Flujo , Humanos , Immunoblotting , Ligandos , Luciferasas/metabolismo , Microscopía Fluorescente , Mitocondrias/metabolismo , Oxigenasas de Función Mixta/metabolismo , Unión Proteica , Proteína Quinasa C/metabolismo , Transporte de Proteínas , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Especies Reactivas de Oxígeno , Esteroide Hidroxilasas/metabolismo , Fracciones Subcelulares/metabolismo , Acetato de Tetradecanoilforbol , Factores de Tiempo , Activación Transcripcional , Células Tumorales Cultivadas , Vitamina D3 24-Hidroxilasa , Proteína X Asociada a bcl-2

RESUMEN

1,25-Dihydroxyvitamin D(3) (1,25(OH)(2)D(3)) interacts with the Vitamin D(3) receptor (VDR) to modulate proliferation and apoptosis in a variety of cell types, including breast cancer cells. In this review, we discuss three issues related to the role of the VDR in growth control: first, whether mammary glands lacking VDR exhibit abnormal growth; second, whether the VDR is essential for induction of apoptosis by 1,25(OH)(2)D(3); and third, whether VDR up-regulation can sensitize cells to 1,25(OH)(2)D(3). Studies from our laboratory have demonstrated that mammary glands from VDR knockout (VDR KO) mice exhibit accelerated growth and branching during puberty, pregnancy and lactation as compared to wild-type (WT) mice. In addition, involution after weaning, a process driven by epithelial cell apoptosis, proceeds at a slower rate in VDR KO mice compared to WT mice. Using cells isolated from VDR KO and WT mice, we report that both normal and transformed mammary cells derived from WT mice are growth inhibited by 1,25(OH)(2)D(3), however, cells derived from VDR KO mice are completely unresponsive to 1,25(OH)(2)D(3). In human breast cancer cells, we have identified a variety of agents, including steroid hormones, phytoestrogens and growth factors, that up-regulate VDR expression and enhance sensitivity to 1,25(OH)(2)D(3)-mediated growth inhibition. Collectively, these studies support a role for 1,25(OH)(2)D(3) and the VDR in negative growth regulation of both normal mammary gland and breast cancer cells.

Asunto(s)

Neoplasias de la Mama/patología , Neoplasias Mamarias Animales/patología , Receptores de Calcitriol/genética , Receptores de Calcitriol/fisiología , Animales , Apoptosis , Mama/metabolismo , Mama/fisiología , División Celular , Humanos , Ratones , Ratones Noqueados , Modelos Biológicos , Regulación hacia Arriba