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

Vitamin D derivatives have been shown both to inhibit the proliferation of cultured breast cancer cells and to cause regression of experimental mammary tumours in vivo. We have investigated the ability of several vitamin D analogues to promote the regression of experimental rat mammary tumours. Our results revealed that one vitamin D compound in particular, EB1089 (1(S),3(R)-dihydroxy-20(R)-5'-ethyl- 5'-hydroxy-hepta-1'(E),3'(E)-dien-1'-yl)-9,10-secopregna-5(Z ),7(E) ,10(19)-triene), was highly effective at inhibiting tumour progression, without causing a significant rise in serum calcium concentration. Tumour regression occurs when the rate of cell death is greater than the rate of cell proliferation. Apoptosis (programmed or active cell death) is an active, energy-dependent process in which a distinct series of biochemical and molecular events leads to the death of cells by specific signals. We have examined effects of 1,25-dihydroxyvitamin D3 (1,25(OH)2(D)3) and the synthetic vitamin D analogue EB1089 on indices of apoptosis in cultured human breast cancer cells. The effects of the vitamin D compounds on the expression of two oncoproteins which may regulate apoptosis, bcl-2 and p53 were examined by Western analysis. In MCF-7 cell cultures treated for six days with 1,25(OH)2(D)3 or EB1089 (1 x 10(-8) M), bcl-2 protein was reduced in comparison to control levels, whereas p53 protein was increased. In addition, the p21 protein, whose gene WAF-1 is induced by wild type p53, was also increased by both vitamin D compounds. Using Northern analysis, it was observed that 24-h treatment of MCF-7 cells with 1 x 10(-8) M 1,25(OH)2(D)3 or EB1089 resulted in an induction of TRPM-2 (clusterin) mRNA, a gene associated with onset of apoptosis in the involuting prostate. Fragmentation of genomic DNA is a characteristic feature of apoptosis. With the terminal deoxynucleotidyl transferase (TdT) assay, 3'-OH DNA breaks indicative of DNA fragmentation were detected histochemically in MCF-7 cells treated with 1 x 10(-8) M 1,25(OH)2(D)3 or EB1089 for four days prior to fixation and TdT reaction. Further evidence of apoptosis was obtained following six days treatment of MCF-7 cell cultures with 5 x 10(-8) M 1,25(OH)2(D)3 or EB1089, utilizing a cell death ELISA assay, which measures the presence of histone-associated oligonucleosome complexes generated from DNA fragmentation. Taken together our findings indicate that vitamin D derivatives may play a role in regulating the expression of genes and protein products implicated in apoptosis.
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PMID:Effects of 1,25 dihydroxyvitamin D3 and its analogues on induction of apoptosis in breast cancer cells. 890 23

We considered of interest to determine the possible interrelationship between the proliferation-related marker MIB-1/Ki-67 and the bcl-2, a protein involved in the blockage of apoptosis, and whether they contributed to the prognosis of breast cancer. For this purpose we carried out a retrospective immunohistochemical study of 238 cases of stage I and II breast carcinomas with a follow up of at least 5 years. The study revealed that high expression of MIB-1 was associated with high nuclear and histological grades (p < 0.001 for both), negative estrogen receptor status (p = 0.009) and progesterone status (p = 0.004), and younger age (p = 0.014). High bcl-2 expression was associated with smaller tumor size (p = 0.001), positive estrogen and progesterone receptors (p < 0.001 for both); low nuclear grade (p < 0.001), low histological grade (p < 0.002), stage I disease (p = 0.01) and low MIB-1 expression (p = 0.025). The univariate Cox regression showed a significant association of high MIB-1 expression (p = 0.002) and low bcl-2 expression (p = 0.04) with shorter OS. Furthermore, MIB-1 expression was a significant independent predictor of OS (p = 0.002) as showed by stepwise Cox regression analysis.
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PMID:[Immunohistochemical detection of bcl-2 and MIB-1/Ki-67 in breast cancer: retrospective analysis of 238 cases]. 903 81

Interest has been increasingly focused on all-trans-retinoic acid (tRA) and 13-cis-retinoic acid (13cRA) in cancer chemoprevention and treatment. We have examined the in vitro effects of these 2 retinoic acids (RAs) on human breast-cancer cell lines MCF-7 and ZR-75.1 (both estrogen-receptor-positive, ER+) and MDA-MB-231 (estrogen-receptor-negative, ER-), in terms of inhibition of proliferation and induction of apoptosis. Both retinoic acids exerted an evident dose-dependent growth inhibition, although in the ER- cell line the anti-proliferative effect was obtained only with the highest concentration used; the anti-proliferative activity of tRA was more evident than 13cRA on all 3 tested cell lines. tRA and 13cRA induced apoptosis in MCF-7 and MDA-MB-231 cell lines, but not in ZR-75.1. The apoptotic phenomenon was clearly time-dependent, and in our experience it was not related to the arrest in a specific phase of cell cycle. After treatment with RAs the levels of bcl-2 were reduced in MCF-7, while in ZR-75.1 and in MDA-MB-231 no treatment-related modifications were observed. An analysis of estrogen-receptor status, used as a marker of differentiation, demonstrated that after treatment with RAs the levels of estrogen receptor (ER) decreased in ZR-75.1 only. Our study indicates that the anti-proliferative effects of RAs are sustained by induction of apoptosis in MCF-7 and MDA-MB-231 cells, while in ZR-75.1 cells an induction of differentiation without apoptosis was the prevalent mechanism of growth inhibition. Our results encourage further studies on in vivo effects of these retinoids in breast cancer.
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PMID:Effects of all-trans-retinoic acid and 13-cis-retinoic acid on breast-cancer cell lines: growth inhibition and apoptosis induction. 905 65

1,25-dihydroxyvitamin D3 [1,25(OH)2D3], the active metabolite of vitamin D2 inhibits breast cancer cell growth both in vivo and in vitro. In addition to its anti-proliferative effects, 1,25(OH)2D3 induces morphological and biochemical markers of apoptosis in MCF-7 cells. In the studies reported here, we compared the effects of 1,25(OH)2D3 and EB1089, a low calcemic vitamin D analog, on cell cycle kinetics and apoptosis in MCF-7 cells. Both vitamin D compounds reduced viable MCF-7 cell number in a time and dose dependent manner, with EB1089 approximately 50 fold more potent than 1,25(OH)2D3. Flow cytometric analysis indicated that both agents induced cell cycle arrest in G, G1 which was associated with accumulation of the hypophosphorylated form of the retinoblastoma (Rb) protein. MCF-7 cells treated with either 1,25(OH)2D3 or EB1089 for 48 h exhibited characteristics of apoptosis, including cytoplasmic condensation, pyknotic nuclei, condensed chromatin and DNA fragmentation. Cells treated with either agent exhibited up regulation of proteins associated with mammary gland regression (clusterin and cathepsin B) and down regulation of the anti-apoptotic protein bcl-2. These studies demonstrate that, despite its lower calcemic activity in vivo, the vitamin D analog EB1089 induces effects that are indistinguishable from those of 1,25(OH)2D3 on cell number, cell cycle and indices of apoptosis in MCF-7 cells in vitro. In addition, since both agents rapidly down regulate estrogen receptor, disruption of estrogen dependent signalling may play a role in the induction of apoptosis by vitamin D compounds in MCF-7 cells.
Breast Cancer Res Treat 1997 Jan
PMID:Comparative effects of 1,25(OH)2D3 and EB1089 on cell cycle kinetics and apoptosis in MCF-7 breast cancer cells. 911 16

Recent studies have demonstrated that following estrogen ablation, estrogen responsive breast cancer cells undergo apoptosis. In addition, estrogen receptor (ER) expression has been strongly correlated with the expression of the bcl-2 gene product, p26Bcl-2 protein, which is known to inhibit apoptosis. In the present studies, we investigated whether estrogen affects the intracellular levels of p26Bcl-2 and thereby modulates taxol-induced apoptosis of estrogen responsive human breast cancer MCF-7 cells. Transfer of MCF-7 cells to a culture-medium without estrogens reduced their intracellular p26Bcl-2 levels by 50%. Inclusion of 0.1 microM estradiol in the medium produced approximately a four-fold increase in p26Bcl-2, but not p29Bcl-x1, or p21Bax levels; the expression of the c-myc and mdr-1 genes remained unchanged. Estradiol-induced four-fold increase in the ratio of the p26Bcl-2 to p21Bax levels caused a significant decline in the lethal, kilobase size DNA fragments of apoptosis, which had resulted when MCF-7 cells were cultured in a medium without estrogen. In addition, in MCF-7 cells, estradiol-induced increase in the intracellular p26Bcl-2 to p21Bax ratios was associated with a significant reduction in the large-sized DNA fragmentation induced by treatment with taxol. The increased ratios also protected MCF-7 cells against taxol-mediated cytotoxicity as assessed by the MTT assay. These results suggest that by modulating p26Bcl-2 levels, estrogens may affect the antitumor activity of taxol and potentially of other anti-breast cancer drugs against estrogen responsive human breast cancer cells.
Breast Cancer Res Treat 1997 Jan
PMID:Estrogen increases intracellular p26Bcl-2 to p21Bax ratios and inhibits taxol-induced apoptosis of human breast cancer MCF-7 cells. 911 21

The recent highlighted points in prognostic factors after breast cancer operation include: 1) the emergence of many genetic and biochemical markers, including c-erbB-2, int-2, EGFR, p53, nm23, LOH, E cadherin, s-phase fraction. The prognostic value of these factors is related to their role in cell cycle regulation, invasion/metastasis mechanisms, etc. The agents related to therapeutic effectiveness, namely p-glycoprotein, pS2, and bcl-2 may become important stratification factors when conducting clinical trials. Pathologic factors, like nodal status, however, are the most useful prognostic factors at the moment. Many newly developed prognostic factors should be examined by multivariate analysis and validated prospectively before clinical use.
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PMID:[Recent prognostic factors for breast cancer]. 912 98

The expression of estrogen receptor (ER) and bcl-2 (Bcl-2), an apoptosis protective oncogene, in normal and cancerous breast duct epithelia was immunohistochemically examined in fresh frozen tumor tissues from 142 Japanese breast cancer patients. The clinico-pathological characteristics and the disease free survival of the patients were analyzed. The expression of both the proteins was also observed in intraductal components of breast cancer. Although less than 1% of normal duct epithelia expressed ER, Bcl-2 was diffusely expressed. The expression of both these proteins in breast cancer significantly correlated with each other. Their expression significantly correlated negatively with tumor size but not with lymph node status. The papillo-tubular sub-type of invasive ductal carcinoma expressed Bcl-2 significantly more frequently than the solid-tubular sub-type. Patients with Bcl-2 expressing tumors survived without recurrence significantly more than those with tumors exhibiting reduced expression. Papillary-cribriform type intraductal components expressed both those proteins more often than the solid-comedo type.
Breast Cancer Res Treat 1997 Jan
PMID:Clinical significance of bcl-2 gene expression in human breast cancer tissues. 913 6

The association of increased metallothionein (MT) gene expression in breast cancer with metastasis and poor prognosis has led us to investigate the hypothesis that inhibition of MT gene expression may elicit antiproliferative effects in breast carcinoma MCF7 cells. To monitor the effect of downregulation of MT protein on growth, MCF7 cells were transiently transfected by electroporation with an 18-mer MT antisense phosphorothioate oligomer (AO) or an 18-mer random oligomer (RO). The MT-AO is complementary to the region 7 bases downstream from the AUG translational start site of the hMT-IIA gene. Transfection of MCE7 cells with the AO inhibited cell growth by 50-60% at 72 hours when compared to control cells or the cells transfected with RO. The AO-induced growth inhibition was associated with alterations in morphology suggestive of apoptotic cell death. This was further confirmed by DNA linker cleavage into oligonucleosomal fragments and decreased bcl-2 protein levels in AO-transfected cells as opposed to the RO-transfected cells. Reverse transcriptase polymerase chain reaction analysis showed that AO induced a 2-fold increase in the levels of c-fos and p53 transcripts in comparison to RO which had no significant effect. Conversely, c-myc transcripts were decreased by 2.5-fold in the AO-transfected cells when compared to the controls. Furthermore, MCF7 cells transfected with an expression plasmid pBAcNEO-sMT-IIA encompassing human MT-IIA cDNA, constitutively driven by beta-actin promotor, caused a 2.5-fold increase in intracellular levels of MT, as judged by PCR and western blot analysis, in comparison to the cells transfected with pBAcNEO plasmid. In contrast to the AO-induced growth inhibition, overexpression of cytoplasmic MT increased the cell multiplication by 2-fold compared with control cells or the cells transfected with the control plasmid 72 hours post-transfection. Moreover, the effects of AO on oncogene expression were reversed on increased expression of MT. These data suggest that overexpression of MT potentiates the growth of MCF7 cells, whereas downregulation of MT elicits antiproliferative effects.
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PMID:Antisense down-regulation of metallothionein induces growth arrest and apoptosis in human breast carcinoma cells. 917 39

Ki-S1, a marker of proliferation, and bcl-2, the gene product of which is an antagonist of apoptosis, have been measured in 51 ER-positive primary breast cancers before and during tamoxifen treatment and then related to clinical response. Both markers were detected in the majority of tumours before treatment and, quantitatively, initial expression of Bcl-2 protein, but not Ki-S1, was significantly related to the percentage reduction in tumour volume as assessed by ultrasound. Staining for both markers was lower in post treatment samples than in those taken prior to treatments, but concordant decreases in staining indices were seen in only 11 of the 51 tumours. The results demonstrate, using clinical material, that the response to tamoxifen may involve changes in proliferation and/or susceptibility to cell-death.
Breast Cancer Res Treat 1997 Jun
PMID:The expression of Ki-S1 and BCL-2 and the response to primary tamoxifen therapy in elderly patients with breast cancer. 923 71

Tissue homeostasis and the maintenance of cell populations depend on a delicate balance between the rates of cell proliferation and cell death. Programmed cell death or apoptosis is believed to play a major role in physiological processes which, when defective, could contribute to the pathogenesis and progression of tumors. A role for altered programmed cell death in cancer stems from the description of alterations on tumor-associated genes involved in the regulation of apoptosis such as p53 and bcl-2. The p53 gene promotes apoptosis in cells with genetic damage, while bcl-2 is an antiapoptotic gene. It is therefore possible that the balance between p53 and bcl-2 may have significant implications for the pathobiology of breast cancer. This study was therefore undertaken to evaluate the expression of these two proteins with opposite functions and their relation to the total growth fraction of the tumor as measured by PCNA immunoreactivity. A significant correlation was observed between expression of p53 and PCNA. In contrast, bcl-2 expression did not correlate with the expression of p53. There was also no correlation observed between expression of bcl-2 and PCNA. A significant correlation was observed between expression of p53 and the grade of the tumor and stage of the disease. Our results thus support the hypothesis that accumulation of p53 is associated with a high tumor proliferation rate, an association that might be expected in view of the role of wild-type p53 as a negative regulator of cell proliferation. Another important observation was the lack of relationship between bcl-2 expression and PCNA immunoreactivity, supporting the hypothesis that bcl-2 is not a major regulator of proliferation.
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PMID:Expression of the antiapoptotic protein bcl-2 is not dependent on the tumor suppressor p53 protein in Indian breast carcinoma. 925 35


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