Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0006142 (breast cancer)
 160,383 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1,25-Dihydroxycholecalciferol D3 (1,25(OH)2D3), the active metabolite of vitamin D, is a potent inhibitor of breast cancer cell growth both in vivo and in vitro. We have shown that MCF-7 cells treated with 100 nM 1,25(OH)2D3 exhibit characteristic apoptotic morphology (pyknotic nuclei, chromatin and cytoplasmic condensation, nuclear matrix protein reorganization) within 48 h. In the experiments reported here, we examined the interactions between 1,25(OH)2D3 and the antiestrogen 4-hydroxytamoxifen (TAM), which also induces apoptosis in MCF-7 cells. Our data suggest that TAM significantly potentiates the reduction in cell number induced by 1,25(OH)2D3 alone. Combined treatment with 1,25(OH)2D3 and TAM enhances the degree of apoptosis assessed using morphological markers that identify chromatin and nuclear matrix protein condensation. We have selected a subclone of MCF-7 cells resistant to 1,25(OH)2D3 (MCF-7D3Res). These cells express the vitamin D receptor and exhibit doubling times comparable to the parental MCF-7 cells, even when grown in 100 mM 1,25(OH)2D3. Treatment of both parental and resistant MCF-7 cells with TAM induces apoptosis and clusterin. These data emphasize that apoptosis can be induced in MCF-7 cells either by activation of vitamin-D-mediated signalling or disruption of estrogen-dependent signalling.
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PMID:Induction of apoptosis in breast cancer cells in response to vitamin D and antiestrogens. 765 27

1,25(OH)2-Vitamin D3 inhibits breast cancer cell proliferation through interaction with the vitamin D receptor (VDR). Regulation of VDR is under the influence of several factors which include the functional ligand for this receptor (1,25(OH)2-vitamin D3) as well as heterologous steroid hormones. We evaluated the nature of homologous regulation in T-47D human breast cancer cells with a radiolabelled ligand binding assay and a ribonuclease protection assay for VDR. Significant VDR up-regulation, as measured by hormone binding assays, occurred with pre-incubations with 10(-9)M through 10(-6)M 1,25(OH)2-vitamin D3 (P < 0.05). A 7-fold VDR up-regulation with 10(-8)M 1,25(OH)2-vitamin D3 occurred at 4 h treatment and was not associated with an increase in VDR mRNA expression on ribonuclease protection assay. This supports the hypothesis that up-regulation of VDR is probably the result of ligand-induced stabilization of pre-existing receptor. All-trans-retinoic acid, the progesterone analog R-5020, and prednisone were found to induce heterologous up-regulation of the VDR. We then determined with ligand binding assays whether 1,25(OH)2-vitamin D3 could influence receptor levels for another hormone in a manner analogous to the heterologous regulation of VDR. Regulation of estrogen receptor (ER) by 1,25(OH)2-vitamin D3 was studied in T-47D and MDA-MB-231 breast cancer cells. Incubation of T-47D cells, which are ER (+), with 10(-8)M 1,25(OH)2-vitamin D3 did not result in up-regulation of ER. Yet estrogen binding was significantly up-regulated in a cell line that is ER(-), MDA-MB-231. The increased estrogen binding was associated with a shift in binding affinity and ribonuclease protection assay showed absence of ER mRNA in these cells, suggesting an up-regulation of estrogen binding proteins and not of the ER itself.
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PMID:Modulation of vitamin D receptor and estrogen receptor by 1,25(OH)2-vitamin D3 in T-47D human breast cancer cells. 766 88

The co-transfection assay is a novel functional assay using cells transiently transfected with plasmids encoding intracellular receptors and corresponding reporter genes. Using this assay, natural product extracts were tested to identify compounds that modulate intracellular receptor activity, measured as changes in reporter gene activity. A crude extract of the marine alga Cymopolia barbata was found to inhibit progesterone-stimulated reporter gene expression in cells transfected with the human progesterone receptor (hPR) and an appropriate reporter construct. Purification of the active constituents of the extract, guided by the co-transfection assay, yielded two diastereomers of cyclocymopol monomethyl ether, possessing opposing pharmacological activities with the hPR. The antagonist (3R)-cyclocymopol monomethyl ether (LG100127) blocked 1 nM progesterone-stimulated reporter gene expression with an IC50 value of 549 +/- 55 nM in the co-transfection assay. The agonist (3S)-cyclocymopol monomethyl ether (LG100128) had efficacy similar to that of progesterone and an EC50 value of 35 +/- 2 nM. Stimulation by progesterone of the hPR in the human breast cancer cell line T-47D results in enhanced expression of alkaline phosphatase; LG100127 blocked alkaline phosphatase expression stimulated either by progesterone or by LG100128, and LG100128 mimicked progesterone in this assay. Both diastereomers displaced [3H]progesterone from baculovirus-expressed hPR. LG100127 and LG100128 each interacted with the human androgen receptor but did not interact with the human glucocorticoid receptor, estrogen receptor, vitamin D receptor, or retinoid receptors. In summary, these in vitro studies describe the first nonsteroidal pharmacophores for the hPR and demonstrate the use of the co-transfection assay in their discovery.
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PMID:Nonsteroidal human progesterone receptor modulators from the marine alga Cymopolia barbata. 770 Feb 60

We analyzed the antiproliferative effect of 1,25-dihydroxyvitamin D3 and four vitamin D analogs on MCF-7, a human breast cancer cell line known to express the vitamin D receptor. Growth curve studies and [3H]thymidine incorporation assays were used to assess the antiproliferative effect of 1,25-dihydroxyvitamin D3 (vitamin D), Ro 23-7553, Ro 24-5531, Ro 25-5317, and Ro 24-5583. Growth of MCF-7 cells was significantly inhibited by 1,25-dihydroxyvitamin D3 and all four analogs at 10(-8) M (P < 0.05). MCF-7 cells treated with analog had significantly less [3H]thymidine incorporation than cells treated with 1,25-dihydroxyvitamin D3 (P < 0.05). The affinity of the analogs for the vitamin D receptor was similar to that of 1,25-dihydroxyvitamin D3. These results demonstrate that analogs of 1,25-dihydroxyvitamin D3 are potent antiproliferative agents on human breast cancer cells and that this activity is likely mediated through the vitamin D receptor.
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PMID:The antiproliferative effect of vitamin D analogs on MCF-7 human breast cancer cells. 775 62

1,25-(OH)2-Vitamin D3, the active metabolite of vitamin D, is a secosteroid hormone with known differentiating activity in leukemic cells. Studies have demonstrated the presence of vitamin D receptors (VDR) in a wide range of tissues and cell types. Antiproliferative activity of 1,25-(OH)2-vitamin D3 has been documented in osteosarcoma, melanoma, colon carcinoma, and breast carcinoma cells. This study was designed to analyze vitamin D receptor level in breast cancer cells as a marker of differentiation and as a predictor of growth inhibition by 1,25-(OH)2-vitamin D3. VDR messenger RNA was found to be present in relatively high levels in well-differentiated cells and in low levels in poorly differentiated cells. All cell lines had detectable VDR mRNA. Radiolabeled ligand binding assay showed a similar pattern. MCF-7 and T47D cells, which express VDR at moderate levels, showed significant growth inhibition by 10(-9) M1,25-(OH)2-vitamin D3 (p < 0.05). MDA-MB-231 cells, which have very low levels of VDR, demonstrated no growth inhibition by 1,25-(OH)2-vitamin D3 at concentrations up to 10(-6) M. Based on these results it can be stated that VDR expression is lost with de-differentiation and that receptor is essential for the antiproliferative response to 1,25-(OH)2-vitamin D3.
Breast Cancer Res Treat 1994
PMID:Vitamin D receptors in breast cancer cells. 788 Oct 99

The biological activity of 16-epoxy side-chain analogs of 1 alpha,25-dihydroxyvitamin D3, (1 alpha,25(OH)2D3) was evaluated in vitro and in vivo. Compared to 1 alpha,25(0H)2D3, all analogs had lower affinities for the pig duodenal vitamin D receptor and also for the human serum vitamin D binding protein. The in vitro effects on cell proliferation or differentiation of human promyeloid leukemia (induction of superoxide production in HL-60 cells), human osteosarcoma MG-63 cells (osteocalcin secretion), or human breast cancer cells (incorporation of thymidine in MCF-7 cells), was markedly inhibited by several epoxy analogs, compared to 1 alpha,25(OH)2D3, but the rank order of their activity widely varied among different cancer cells. The most potent analogs (24S,25S-24-hydroxy-25,26-epoxy-22-ene-1 alpha-OHD3, 25,26-epoxy-23-yne-1 alpha-OHD3, and 25,26-epoxy-23-yne-20-epi-1 alpha-OHD3 or compounds, 16, 5, and 7, respectively) were equipotent (16 and 5) or 30-fold (compound 7 on MG-63 cells) to 40-fold (compound 7 on MCF-7 cells) more active than 1 alpha,25-(OH)2D3. These analogs were nevertheless poorly antirachitic (< 3%) when tested in vitamin D-deficient chicks (using serum and bone calcium, serum osteocalcin and duodenal calbindin D-28K, as end points). Compound 7 was also 100-fold more active than 1 alpha,25-(OH)2D3 in inhibition of proliferation of human foreskin keratinocytes. Some epoxy analogs of 1 alpha,25-(OH)2D3 thus display interesting dissociations between their receptor affinity and their potency to induce cell differentiation, whereas their effect on cell proliferation/differentiation exceed their calcemic effects more than 100- to 1000-fold.
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PMID:Biological evaluation of epoxy analogs of 1 alpha,25-dihydroxyvitamin D3. 853 86

The variability of different primary tumors in the susceptibility to metastatic bone disease is poorly understood. Factors that determine the viability of metastatic cells are also poorly understood, but may depend in part upon gene expression of PTHrP and the vitamin D receptor. In contrast, much more is known of the manner in which metastatic disease affects bone remodeling to induce osteolytic bone disease. Mechanisms include a generalized increase in activation frequency at sites close to metastatic tissue, an imbalance between the amount of bone formed and that resorbed within resorption cavities, and uncoupling of bone formation from bone resorption. The greatest morbidity from metastatic bone disease arises from osteolytic disease and gives rise to hypercalcemia, bone pain, and fractures. Because osteolysis is primarily mediated by the activation of osteoclasts, there has been a great deal of interest in the use of agents which primarily affect bone metabolism to alter the natural history of metastatic bone disease. Nonsteroidal antiinflammatory agents and cytotoxic agents are capable of inducing responses in bone, but are limited by their toxicity when effective doses are utilized. The use of calcitonin in the long-term suppression of osteolysis has also been disappointing. The bisphosphonates are, however, capable of inducing sustained decreases in osteoclast activity and numbers in patients with osteolytic bone disease. There are now several studies which have examined the effects of the bisphosphonates on skeletal morbidity in breast cancer. Both clodronate and pamidronate decrease the incidence of hypercalcemia, bone pain, and pathological fractures, but do not significantly alter mortality.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Bone and cancer: pathophysiology and treatment of metastases. 857 90

1,25-Dihydroxyvitamin D3 [1,25-(OH)2D3], the active metabolite of vitamin D3, is a potent inhibitor of breast cancer cell growth both in vivo and in vitro. We have previously demonstrated that 1,25-(OH)2D3 induces morphology (pyknotic nuclei, chromatin and cytoplasmic condensation, and nuclear matrix protein reorganization) consistent with the activation of apoptosis in MCF-7 cells. These morphological changes in 1,25-(OH)2D3-treated cells are associated with up-regulation of TRPM-2/clusterin and cathepsin B (genes associated with mammary gland apoptosis) and down-regulation of bcl-2, an antiapoptotic gene. Thus, the inhibitory effects of 1,25-(OH)2D3 on MCF-7 cell growth involve activation of apoptosis. To investigate the mechanisms by which vitamin D3 activates apoptosis, we have selected a vitamin D3-resistant variant (MCF-7D3Res cells) by continuous culture of MCF-7 cells in 100 nM 1,25-(OH)2D3. The MCF-7D3Res cells represent a stably selected phenotype that grows equally well with or without 100 nM 1,25-(OH)2D3. In contrast to the MCF-7 cells from which they were derived (MCF-7WT cells), MCF-7D3Res cells do not exhibit apoptotic morphology, DNA fragmentation, or up-regulation of apoptosis-related proteins after treatment with 1,25-(OH)2D3. MCF-7D3Res cells exhibit cross-resistance to several vitamin D3 analogs that are potent growth regulators of MCF-7WT cells. MCF-7WT and MCF-7D3Res cells exhibit comparable sensitivity to induction of apoptosis and up-regulation of clusterin in response to the antiestrogen 4-hydroxytamoxifen. MCF-7D3Res cells express comparable levels of the vitamin D receptor (VDR), as assessed by Western blotting or ligand binding, as MCF-7WT cells. In both sensitive and resistant cell lines, 1,25-(OH)2D3 up-regulates whereas 4-hydroxytamoxifen down-regulates VDR protein expression, indicating appropriate homologous and heterologous VDR regulation in MCF-7D3Ras cells. Gel shift analyses indicate that nuclear extracts from MCF-7WT and MCF-7D3Res cells bind equally well to the DR3 consensus vitamin D3 response element. These data suggest that MCF-7D3Res cells have a functional VDR that is uncoupled from a functional apoptotic pathway. MCF-7D3Res cells offer a unique model system for identification of the mechanisms by which vitamin D3 regulates the cell death pathway in breast cancer cells.
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PMID:Characterization of a vitamin D3-resistant MCF-7 cell line. 859 82

Retinoids and vitamin D are important factors that regulate cellular growth and differentiation. An additive growth-inhibitory effect of retinoids and vitamin D analogues has been demonstrated for human myeloma, leukaemic and breast cancer cells. We set out to study the effects of the vitamin D analogue EB1089 and the retinoids all-trans- and 9-cis-retinoic acid on the human pancreatic adenocarcinoma cell lines Capan 1 and Capan 2 and the undifferentiated pancreatic carcinoma cell line Hs766T. The cell lines investigated expressed vitamin D receptor, retinoic acid receptor (RAR)-alpha and gamma as determined by polymerase chain reaction after reverse transcription. RAR-beta was expressed only in Hs766T cells. Addition of all-trans-retinoic acid increased the amount of RAR-alpha mRNA in the three cell lines and induced RAR-beta mRNA in Capan 1 and Capan 2 cells. All-trans-retinoic acid at a concentration of 10 nM inhibited the growth of Capan 1 and Capan 2 cells by 40% relative to controls. 9-cis-Retinoic acid was less effective. Neither all-trans-retinoic acid nor 9-cis-retinoic acid affected the growth of Hs766T cells. EB1089, if added alone to the cells, did not significantly inhibit growth. However, the combination of 1 nM EB1089 with 10 nM all-trans-retinoic acid exerted a growth-inhibitory effect of 90% in Capan 1 cells and of 70% in Capan 2 cells. Our data suggest that vitamin D analogues together with retinoids inhibit the growth of human pancreatic cancer cells. However, in vivo studies are necessary to examine the potential use of retinoids and vitamin D analogues on pancreatic cancer.
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PMID:Growth-inhibitory effects of vitamin D analogues and retinoids on human pancreatic cancer cells. 864 77

[3H]thymidine incorporation and DNA content were used to investigate the antiproliferative effects of 1,25(OH)2D3 and four analogues [16-ene-1,25(OH)2D3 (16-ene)]; 16-ene,23-yne-1,25(0H)2,D3; EB1089; and 22 oxa-1,25(OH)2D3] on MCF-7, BT-474, and MDA-MB-453 breast cancer cell lines. 1,25(OH)2D3 and the analogues elicited a biphasic response from MCF-7 and BT-474 estrogen receptor (ER)-positive cells, in the presence of estradiol (E2), with lower doses (between 10(-12) and 10(-10) M) tending to stimulate proliferation and higher doses (between 10(-9) and 10(-6) M) inhibiting proliferation by as much as 65%. In the absence of E2, the stimulatory effect was abrogated. Proliferation of MDA-MB-453, estrogen receptor-negative (ER-) cells, was stimulated by these compounds only at 10(-12) M, and inhibited by all higher doses, by as much as 83%. All three cell lines were shown to be vitamin D receptor (VDR) positive, and 1,25(OH)2D3 and all four analogues bound to the VDR with high affinities in each cell line. The antiestrogen ICI 164,384 inhibited the proliferation of all three cell lines. ICI 164,384 at 10(-8) M in combination with 1,25(OH)2D, or EB1089 converted biphasic response of the ER+ cells to one resembling the response of the ER- cells, by eliminating the stimulatory response elicited by 1,25(OH)2D3 at low doses and enhancing the antiproliferative effects of higher doses by as much as 1000-fold. These data are consistent with the hypothesis that E2 in the ER+ cells blocks the antiproliferative effects of the analogues and suggest the potential usefulness of combined antiestrogen and 1,25(OH)2D3 analogues in ER+ breast tumors, whereas 1,25(OH)2D3 analogues alone might suffice in ER- breast tumors.
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PMID:Antiestrogen potentiation of antiproliferative effects of vitamin D3 analogues in breast cancer cells. 866 15


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