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Query: UMLS:C0006142 (breast cancer)
 160,383 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Depending on the tissue, progesterone is classified as a proliferative or a differentiative hormone. To explain this paradox, and to simplify analysis of its effects, we used a breast cancer cell line (T47D-YB) that constitutively expresses the B isoform of progesterone receptors. These cells are resistant to the proliferative effects of epidermal growth factor (EGF). Progesterone treatment accelerates T47D-YB cells through the first mitotic cell cycle, but arrests them in late G1 of the second cycle. This arrest is accompanied by decreased levels of cyclins D1, D3, and E, disappearance of cyclins A and B, and sequential induction of the cyclin-dependent kinase (cdk) inhibitors p21 and p27(Kip1). The retinoblastoma protein is hypophosphorylated and extensively down-regulated. The activity of the cell cycle-dependent protein kinase, cdk2, is regulated biphasically by progesterone: it increases initially, then decreases. This is consistent with the biphasic proliferative increase followed by arrest produced by one pulse of progesterone. A second treatment with progesterone cannot restart proliferation despite adequate levels of transcriptionally competent PR. Instead, a second progesterone dose delays the fall of p21 and enhances the rise of p27(Kip1), thereby intensifying the progesterone resistance in an autoinhibitory loop. However, during the progesterone-induced arrest, the cell cycling machinery is poised to restart. The first dose of progesterone increases the levels of EGF receptors and transiently sensitizes the cells to the proliferative effects of EGF. We conclude that progesterone is neither inherently proliferative nor antiproliferative, but that it is capable of stimulating or inhibiting cell growth depending on whether treatment is transient or continuous. We also suggest that the G1 arrest after progesterone treatment is accompanied by cellular changes that permit other, possibly tissue-specific, factors to influence the final proliferative or differentiative state.
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PMID:Biphasic regulation of breast cancer cell growth by progesterone: role of the cyclin-dependent kinase inhibitors, p21 and p27(Kip1). 932 42

1,25-Dihydroxyvitamin D3 (1,25-(OH)2D3), the active form of vitamin D3, and tetradecanoylphorbol acetate (TPA) are potent negative growth regulators of breast cancer cells. In this study, we compared the mechanism of action of these two compounds in MCF-7 cells and a vitamin D3-resistant variant (MCF-7D3Res). In parental MCF-7 cells, 1,25-(OH)2D3 induced morphological and biochemical markers of apoptosis (chromatin and nuclear matrix condensation and DNA fragmentation), whereas TPA induced growth arrest without apoptosis. Both 1,25-(OH)2D3 and TPA independently up-regulated the vitamin D receptor, p21, and the hypophosphorylated form of retinoblastoma (Rb) protein. The growth regulatory effects of 1,25-(OH)2D3 and TPA did not correlate with induction of p53 protein expression. When both compounds were added simultaneously, synergistic effects on MCF-7 cell number were observed, and cell cycle regulatory proteins were down-regulated. The MCF-7D3Res cells, which are not sensitive to 1,25-(OH)2D3, were growth inhibited by TPA, and TPA partially sensitized MCF-7D3Res cells to the growth inhibitory effects of 1,25-(OH)2D3. In MCF-7D3Res cells, 1,25-(OH)2D3 treatment had minimal effects on p21 or Rb protein expression, whereas TPA down-regulated Rb protein and transiently up-regulated p21. These studies indicate dissociation between the pathways triggered by 1,25-(OH)2D3 and TPA, which mediate growth regulation in MCF-7 cells. Because both compounds induce growth arrest, but only 1,25-(OH)2D3 mediates apoptosis, we conclude that cell cycle arrest is not sufficient to trigger cell death of MCF-7 cells, and that 1,25-(OH)2D3 generates distinct signals which lead to induction of apoptosis in breast cancer cells.
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PMID:Differential effects of 1,25-dihydroxyvitamin D3 and tetradecanoylphorbol acetate on cell cycle and apoptosis of MCF-7 cells and a vitamin D3-resistant variant. 934 95

p21/waf1/cip1 and mdm-2 are downstream effectors of p53. p21 plays a major role in negatively regulating cell-cycle progression, while mdm-2 inhibits p53 effects, and its role has been implicated in oncogenesis. In this study, we investigated the expression profiles of p21, mdm-2 and p53 in human breast-carcinoma tissues. The aim was to determine whether a correlation exists between the expression profiles of these markers and tumor differentiation, ER status and prognosis. We studied tumor specimens obtained from 106 patients and found a highly significant association among low histology grade, p53 over-expression, high mdm-2 expression and lack of p21 expression. Our studies also demonstrate that, in human breast cancer, low levels of p21 and higher mdm-2 levels directly correlate with the onset of lymph-node metastases and shortened patient survival. Furthermore, the expression profiles of p21, mdm-2 and p53 were independently correlated with patient survival.
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PMID:p21/waf1/cip1 and mdm-2 expression in breast carcinoma patients as related to prognosis. 935 76

Examination of a panel of ER positive breast cancer cell lines showed that they were differentially growth inhibited by vitamin D3 and its analogue EB1089. EB1089 treatment of the breast cancer cell lines MCF-7 E, BT20, T47D, and ZR75 demonstrated a correlation between a reduction in Cdk2 kinase activity towards phosphorylation of histone H1 and a decrease in DNA synthesis, while no modulation of Cdk2 activity was observed in the vitamin D3 and EB1089 resistant cell line MCF-7 L. This was accompanied by a time dependent decrease in the percentage of S phase cells in the responsive lines. Characterization of the expression levels of Cdk2 and its related cell cycle proteins in MCF-7 E cells showed that after EB1089 treatment, there was a concentration and time dependent up-regulation of p21 as well as a decrease in cyclin A proteins. Paradoxically, cyclin E levels were increased as a function of treatment. Analysis of cyclin-Cdk2-Cdki complex formation showed that in EB1089 treated MCF-7 E cells, Cdk2, cyclin A and cyclin E immunoprecipitates contained an increased abundance of p21. In contrast to MCF-7 E cells, increases in both p21 and p27 as well as their complex formation with Cdk2 were observed in BT20 and ZR75 cells. These findings indicate that up-regulation of p21 as well as p27 in some cell types may account for the inactivation of Cdk2 activity and a G1 block of the cell cycle following EB1089 treatment.
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PMID:Modulation of cell cycle control by vitamin D3 and its analogue, EB1089, in human breast cancer cells. 938 Apr 7

Genetic alterations, such as p53 mutations, may affect a tumour's response to chemotherapy. We have treated two human breast cancer cell lines that differ in p53 status with epirubicin in order to study if there are differences in cell cycle kinetic response. MCF-7 cells express wild-type p53, while SK-BR-3 cells express only a mutated form of p53. The transition of cells from one cell cycle stage to another was studied by a bromodeoxyuridine (BrdUrd)-flow cytometry (FCM) method. MCF-7 cells showed a block in the G1 phase after treatment with 50 nM epirubicin for 24 hours, in agreement with the actions of p53 at the G1 checkpoint. SK-BR-3 cells, on the other hand, progressed through the G1 checkpoint and were blocked in late S and G2 phases, presumably due to the activation of a later checkpoint. In addition, studies of the mRNA levels of p53 and its effector gene p21 revealed that although both cell lines expressed p53 mRNA, a marked difference in the mRNA levels of p21 was seen. A dramatic increase in the level of p21 mRNA was seen in epirubicin-treated MCF-7 cells, while no such increase was seen in SK-BR-3 cells.
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PMID:Activated cell cycle checkpoints in epirubicin-treated breast cancer cells studied by BrdUrd-flow cytometry. 941 15

Differences in gene expression are likely to explain the phenotypic differences between hormone-responsive and hormone-unresponsive breast cancer. We have identified differentially expressed cDNAs in the estrogen receptor (ER)-positive MCF7 breast carcinoma cell line compared with the ER-negative MDA-MB-231 breast carcinoma cell line. Differential screening isolated four differentially expressed genes: cytokeratin 8, cytokeratin 18, Hsp27 and GPCR -Br. To identify differentially expressed genes of lower abundance, suppression subtractive hybridization was utilized and 29 differentially expressed clones were isolated. Sequence analysis revealed that 11 clones were from previously described genes: HEK8, neuropeptide Y receptor Y1, p21 WAF-1, p55 PIK, cytokeratin 18 (cloned twice), fructose-1,6-biphosphatase, cytokeratin 8, TGFbeta1 binding protein, elongation factor 1alpha2 and pS2. The remaining 18 clones did not match sequences in the GenBank/EMBL database, indicating that they may be novel genes. Expression of pS2, neuropeptide Y receptor Y1 and three novel clones was induced by estradiol, indicating estrogen-responsiveness. The expression pattern of one novel gene, DEME -6, correlated with expression of ER and ERF -1/ AP -2gamma in a panel of breast carcinoma cell lines. A 2.6 kb cDNA of DEME -6 was sequenced and contains an open reading frame of 574 amino acids that demonstrates 62.4% similarity with a gene from Caenorhabditis elegans chromosome III. Expression of DEME -6 was also detected in primary breast carcinomas but not in normal breast tissue, as determined by RT-PCR. These findings support the hypothesis that a set of genes coordinately regulated with ER , but not necessarily estradiol-responsive, are characteristic of the hormone-responsive breast cancer phenotype.
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PMID:Differential screening and suppression subtractive hybridization identified genes differentially expressed in an estrogen receptor-positive breast carcinoma cell line. 946 76

Indole-3-carbinol (I3C), a naturally occurring component of Brassica vegetables such as cabbage, broccoli, and Brussels sprouts, has been shown to reduce the incidence of spontaneous and carcinogen-induced mammary tumors. Treatment of cultured human MCF7 breast cancer cells with I3C reversibly suppresses the incorporation of [3H]thymidine without affecting cell viability or estrogen receptor (ER) responsiveness. Flow cytometry of propidium iodide-stained cells revealed that I3C induces a G1 cell cycle arrest. Concurrent with the I3C-induced growth inhibition, Northern blot and Western blot analyses demonstrated that I3C selectively abolished the expression of cyclin-dependent kinase 6 (CDK6) in a dose- and time-dependent manner. Furthermore, I3C inhibited the endogenous retinoblastoma protein phosphorylation and CDK6 phosphorylation of retinoblastoma in vitro to the same extent. After the MCF7 cells reached their maximal growth arrest, the levels of the p21 and p27 CDK inhibitors increased by 50%. The antiestrogen tamoxifen also suppressed MCF7 cell DNA synthesis but had no effect on CDK6 expression, while a combination of I3C and tamoxifen inhibited MCF7 cell growth more stringently than either agent alone. The I3C-mediated cell cycle arrest and repression of CDK6 production were also observed in estrogen receptor-deficient MDA-MB-231 human breast cancer cells, which demonstrates that this indole can suppress the growth of mammary tumor cells independent of estrogen receptor signaling. Thus, our observations have uncovered a previously undefined antiproliferative pathway for I3C that implicates CDK6 as a target for cell cycle control in human breast cancer cells. Moreover, our results establish for the first time that CDK6 gene expression can be inhibited in response to an extracellular antiproliferative signal.
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PMID:Indole-3-carbinol inhibits the expression of cyclin-dependent kinase-6 and induces a G1 cell cycle arrest of human breast cancer cells independent of estrogen receptor signaling. 946 64

Estrogens stimulate the growth of a majority of estrogen receptor (ER)-positive breast cancer cells. In contrast, estradiol exerted a 75% inhibition of DNA synthesis in the MCF-10AE(wt5) cell line, obtained by the transfection of the ER gene into a normal breast epithelial cell line, MCF-10A. The estradiol-mediated growth inhibitory effect was reversed by ICI 164384, a pure anti-estrogen. Analysis of cell cycle by flow cytometry showed a significant increase of G1 cells by estradiol treatment compared to controls. To understand the mechanism of action of estradiol on MCF-10AE(wt5) cells, we examined the level of a cyclin dependent kinase inhibitor (CKI), p21, by Western blot analysis. Our results showed a 5- to 10-fold increase in the level of p21 in estradiol-treated MCF-10AE(wt5) cells compared to controls. ICI 164384 reversed estradiol-mediated induction of p21. Northern blot analysis of p21 mRNA indicated that estradiol stimulated its message in MCF-10AE(wt5) cells. Analysis of a panel of 6 breast cancer cell lines showed the absence of p21 protein, whereas it was present at a very low level in MCF-10A cells. Comparison of p21 in MCF-10A and MCF-10AE(wt5) cells showed an abundance of p21 in the ER-transfected cells. However, this p21 appears to be inactive in the absence of estradiol. These results suggest a p21-mediated pathway as a possible mechanism for the growth inhibitory effects of estradiol on at least a subset of ER-transfected cell lines.
Breast Cancer Res Treat 1998 Jan
PMID:Induction of p21 (CIP1/WAF1/SID1) by estradiol in a breast epithelial cell line transfected with the recombinant estrogen receptor gene: a possible mechanism for a negative regulatory role of estradiol. 949 6

As a model system for the identification of genes involved in the progression of human breast cancer, differential gene expression in cell lines MCF-7 and MCF-7ADR was investigated. The latter cell line is derived from the former. Cell line MCF-7 is estrogen receptor-positive, vimentin-negative and uninvasive in the Matrigel outgrowth assay and in the nude mouse, while MCF-7ADR is estrogen receptor-negative, hormone-resistant, vimentin-positive, invasive in the Matrigel outgrowth assay and in the nude mouse and resistant to adriamycin due to overexpression of glycoprotein gp170. We have shown that tumor progression in this model system is mediated by transcriptional regulation of mitochondria-related genes, proteases, transmembrane receptors and cell cycle-related gene proteins. Among the genes differentially regulated at the transcriptional level in the cell lines MCF-7 and MCF-7ADR are a new mitochondrial transcript, mitochondrial creatine kinase, matrix metalloproteinase-1, stromelysin-3, urokinase and its receptor, tissue factor, E-cadherin, epidermal growth factor receptor, transmembrane proteins Mat-8 and progression associated protein (PAP), cyclin E, cyclin-dependent kinase-2 and cell cycle inhibitory proteins p16, p21 and p27.
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PMID:Molecular analysis of two mammary carcinoma cell lines at the transcriptional level as a model system for progression of breast cancer. 951 94

The eukaryotic cell cycle is regulated by a highly conserved family of protein kinases, the cyclin-dependent kinases (CDKs). Monomeric free CDKs do not possess enzymatic activity, largely due to the steric hindrance caused by the T-loop at the entrance of the catalytic cleft, making ATP inaccessible to the substrate. Binding of a cyclin, primarily to the NH2-terminal lobe of the CDK that surrounds the PSTAIRE helix, induces a large conformational change in the PSTAIRE helix of the CDK and also causes the T-loop to move out of the way of the catalytic cleft. We identified from breast cancer tissues a novel variant of human CDC2, termed CDC2deltaT, that lacks 171 nucleotides corresponding to 57 amino acids, which compose most of the T-loop. CDC2deltaT was detected in 10 of 14 breast cancer tissues analyzed, whereas it was not detectable in diploid human fibroblast cell lines or in interleukin 2-stimulated normal human lymphocytes. CDC2deltaT protein is unable to complex with cyclin B1 and lacks histone H1 kinase activity. CDC2deltaT also fails to bind to the CDK inhibitor p21. These results indicate that the T-loop not only plays a key role in keeping a free CDK in its inactive state but also in facilitating CDK activation by promoting cyclin binding.
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PMID:T-loop deletion of CDC2 from breast cancer tissues eliminates binding to cyclin B1 and cyclin-dependent kinase inhibitor p21. 951 86


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