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)

Determination of estrogen receptor alpha (ER) status in breast cancer is an important predictive factor for clinical response to endocrine therapy. We have recently shown that discrepancies in ER status determined by immunohistochemical assay (ER-IHA) can occur between amino-terminal (1D5) and carboxyl-terminal (AER-311) targeted ER antibodies and that those tumors which demonstrate discordance are associated with increased expression of truncated ER variant mRNAs. In this study, we have explored this observation to examine if ER variant expression can exert a direct effect on ER-IHA or whether this association is attributable to the characteristics of the antibodies. ER negative cos-1 cells were transfected with expression vectors containing wild type ER (wt-ER) and/or a frequently expressed truncated variant, ER-clone-4 variant. We found that ER-IHA performed with the same N- and C-terminal targeting ER antibodies on cos-1 cells expressing wt-ER alone demonstrated no difference in signals by western blot (P > 0.1). However, co-expression of wt-ER and the truncated ER-clone-4 variant, resulted in discordant IHA results with relatively higher ER-IHA H-scores from N-terminal antibodies (P < 0.03). Furthermore, re-examination of a subset of breast tumors previously studied by ER-IHA showed persistent concordance in 4/5 cases and persistent differences in 3/5 cases with a different pair of ER antibodies. We conclude that the presence of truncated ER variant proteins can interfere with the interpretation of ER status determined by IHA and that this may account for some of the inconsistencies between ER status and response to endocrine therapy.
Breast Cancer Res Treat 1999 Dec
PMID:Influence of estrogen receptor variants on the determination of ER status in human breast cancer. 1071 84

The estrogen receptor alpha (ER alpha) is implicated in the development of breast cancer. The immunophilins, cyclophilin 40 (CyP40) and FKBP52, are associated with ER alpha and other steroid receptors in mutually exclusive heterocomplexes and may differentially modulate receptor activity. Since previous studies have not assessed the levels of these immunophilins in breast cancer, we examined 10 breast cancer cell lines for mRNA and protein expression of CyP40 and FKBP52 and for amplification of the CyP40 gene. In addition, 26 breast carcinomas, including seven with matched normal breast tissue, were examined for mRNA expression of both immunophilins. CyP40 and FKBP52 were ubiquitously expressed in breast cancer cell lines, but there were significant differences in their pattern of expression. FKBP52 protein levels were generally an order of magnitude greater than those for CyP40. FKBP52 mRNA expression correlated strongly with protein expression and was significantly higher in ER alpha-positive compared with ER alpha-negative cell lines. However, CyP40 mRNA expression did not correlate with protein expression, nor did expression of this immunophilin correlate with ER alpha status. Relatively high expression of CyP40 in one cell line (BT-20) could be attributed to amplification of the CyP40 gene. Both immunophilins were also ubiquitously expressed in breast carcinomas, and we demonstrate for the first time that both CyP40 and FKBP52 mRNA are overexpressed in breast tumors compared to matched normal breast controls. The overexpression of CyP40 and FKBP52, coupled with relative differences in their expression in tumors, may have important functional implications for ER alpha and other steroid receptors in breast cancer.
Breast Cancer Res Treat 1999 Dec
PMID:Expression of the estrogen receptor-associated immunophilins, cyclophilin 40 and FKBP52, in breast cancer. 1071 88

It is very important to examine the influence of inhibition of in situ estrogen production on the pathobiology of human sex steroid-dependent tumors in order to understand the clinical effects of aromatase inhibitors. We have examined the biological changes before and after aromatase inhibitor treatment in vitro (endometrial and ovarian cancer) and in vivo (breast cancer). First, we analyzed these changes using histoculture of 15 human endometrial cancers and 9 ovarian cancers. Five of the fifteen endometrial cancers and four of the nine ovarian cancers demonstrated decreased [3H]thymidine uptake or Ki67 labeling index after 14alpha-hydroxy-4-androstene-3,6,17-trione (NKS01) treatment. In ovarian cancer cases, the responsive cases tended to be associated with higher aromatase and estrogen receptor alpha (ER) expression compared with the other cases but this was not seen in the endometrial cancer cases. There were no changes in ER and aromatase expression before and after NKS01 treatment in either ovarian or endometrial cancer cases. We then studied the same primary human breast tumors before and after aminoglutethimide (AMG, n=3) and 4-hydroxyandrostenedione (4-OHA, n=3) treatment. Tumor aromatase activity increased in 3 cases and decreased or was unchanged in 3 cases but aromatase immunoreactivity in stroma and adipocytes was unaltered in 5 cases. There were no changes in the ER labeling index before or after treatment. Five of the six cases including the responsive cases tended to be associated with decreased cell proliferation or Ki67 expression and increased apoptosis when examined by the TUNEL method. These results indicate that aromatase inhibitors may exert their effects on human breast and other cancers through decreasing proliferation and increasing apoptosis, possibly without altering ER status.
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PMID:Effects of aromatase inhibitors on the pathobiology of the human breast, endometrial and ovarian carcinoma. 1073 Nov 9

We and others have demonstrated that estrogen receptor alpha (ERalpha) and p53, two important regulatory proteins in breast cancer, bind to each other. In this report, using the glutathione S-transferase pull-down methodology, we show the ligand-independent interaction of ERalpha with the NH2-terminal region of p53, a region known to bind the p300 and human double minute-2 (hdm2) regulatory factors. Furthermore, we have demonstrated that ERalpha is capable of binding hdm2 directly. The interaction of ERalpha and p53 does not interfere with the binding between p53 and hdm2; rather, these proteins form a ternary complex. The effect of ERalpha on the p53-hdm2 regulatory loop has been examined. Our results indicate that ERalpha protects p53 from being deactivated by hdm2. It is evident from these investigations that the ligand-independent protection of p53 by ERalpha is a novel role for this protein in addition to its classic regulatory function as a ligand-inducible transcription factor. This study also describes a new mechanism of cellular regulation of p53 activity.
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PMID:Estrogen receptor protects p53 from deactivation by human double minute-2. 1076 63

The orphan receptors COUP-TFI and COUP-TFII play an important role in development and differentiation by activating specific genes and by modulating the activity of nuclear receptors including estrogen receptor alpha (ERalpha) and retinoic acid receptors (RARs). Previously, it was demonstrated that the expression and activity of ERalpha and RARs are lost or impaired in anti-estrogen-resistant breast cancers. Here we show that, similar to ERalpha and RARs, the expression of COUP-TFII but not COUP-TFI is reduced in approximately 30% of breast cancer cell lines. Introduction of COUP-TFII to MDA-MB-435 cells resulted in reduced growth and plating efficiency. Interestingly, COUP-TFII increased the expression of cyclin D1 and p21(WAF1/CIP1) in MDA-MB-435 cells. Although parental and COUP-TFII-transduced cells progressed through the G1-S phase at a similar rate, progression of COUP-TFII cells through the G2/M transition phase was delayed. The activity of cdk2 required for G2/M progression was reduced in COUP-TFII cells compared to parental cells. This property of COUP-TFII is distinct from that of ERalpha and RARs, which usually modulate the G1 phase of breast cancer cells. Furthermore, these results reveal an important physiological function of COUP-TFII, which correlates with its ability to induce gene expression rather than modulation of nuclear receptor activity.
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PMID:The orphan receptor COUP-TFII regulates G2/M progression of breast cancer cells by modulating the expression/activity of p21(WAF1/CIP1), cyclin D1, and cdk2. 1077 65

Oncogenic and anti-apoptotic Bcl-2 is expressed much less in estrogen receptor alpha (ERalpha) negative breast cancers, which show more malignant phenotypes, than ERalpha-positive, indicating that some other Bcl-2 family member(s) are involved in the apoptotic balance of the cancer cells. We first analyzed mRNA expression of pro-apoptotic Bak and Bax along with that of anti-apoptotic Bcl-2 and Bcl-xL, using breast cancer specimens of 27 patients. Bak mRNA was expressed much less in ERalpha negative breast cancers, along with reduced expression of Bcl-2. Immunostaining of sections of 108 patients confirmed the observation. Next, stable transformants of MCF-7 cells with sense Bak expression vector showed fewer colonies in soft agar compared with the parental cells, while stable introduction of antisense Bak vector enhanced colony formation at lower estradiol concentrations. The reduction of Bak may play important roles in malignant development of breast cancer to acquire estrogen independency, counteracting the reduced Bcl-2.
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PMID:Different expression patterns of Bcl-2 family genes in breast cancer by estrogen receptor status with special reference to pro-apoptotic Bak gene. 1080 77

17 beta-hydroxysteroid dehydrogenases (17 beta-HSDs) are involved in the interconversion of biologically active and inactive sex steroids and are considered to play important roles in the in situ metabolism of estrogen in various estrogen dependent tissues. 17 beta-HSD type 1 catalyzes primarily the reduction of estrone (E1) to estradiol (E2), whereas 17 beta-HSD type 2 catalyzes primarily the oxidation of E2 to E1. However, the possible biological roles of these estrogen metabolizing isozymes in human breast cancer, especially in carcinogenesis of the human breast, have not been examined in detail. Because of the potential roles of estrogens in the early stages of human breast carcinogenesis, we have examined the immunolocalization of 17 beta-HSD type 1 and type 2 isozymes and estrogen receptor alpha(ER alpha) in both normal human breast tissue and in breast cancers, including ductal carcinoma in situ (DCIS), proliferative disease without atypia (PDWA) or fibrocystic disease and atypical ductal hyperplasia (ADH). We also correlated these findings with clinicopathological findings, Ki67 antigen, progesterone receptor (PR), c-erbB-2, and p53. 17 beta-HSD type 2 immunoreactivity was sporadically detected in non-proliferative or Ki67 negative ductal epithelia of normal breast, but rarely in breast carcinoma cells. 17 beta-HSD type 1 immunoreactivity was detected in 12/22 (54.5%) PDWA cases, 8/26 (30.8%) ADH cases, and 25/40 (62.5%) DCIS cases, respectively. 17 beta-HSD type 1 immunoreactivity was not statistically correlated with the age of the patients, Ki67 labeling index (LI), and PR LI, p-53 and c-erbB-2 immunoreactivity. There was no significant correlation between ER alpha LI and 17 beta-HSD type 1 immunoreactivity. There was a positive correlation between ER alpha and Ki67 LI in PDWA, whereas a negative correlation was detected between ER alpha and Ki67 LI in DCIS. There was no correlation between ER alpha and Ki67 LI in ADH. These results suggest that in human breast epithelial cells, development of ADH and DCIS may be associated with the loss and/or deviation of oestrogen dependent regulation of cell proliferation.
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PMID:17 beta-Hydroxysteroid dehydrogenase type 1 and type 2 in ductal carcinoma in situ and intraductal proliferative lesions of the human breast. 1081 Apr 3

Widespread use of MCF-7 human breast cancer cells as a model system for breast cancer has lead to variations in these cells between different laboratories. Although several reports have addressed these differences in terms of proliferation and estrogenic response, differences in sensitivity to apoptosis have just begun to be described. Based on the possible differences in apoptotic sensitivity that may arise due to the existence of MCF-7 cell variants, we determined the relative sensitivity of MCF-7 cell variants from three established laboratories (designated M, L and N) to known inducers of apoptosis. Consistent with our previous studies we demonstrate that differences exist among these variants in regards to tumor necrosis factor alpha (TNF)-induced cell death and inhibition of proliferation in a dose-dependent manner. To establish if the difference in apoptotic susceptibility was specific to TNF, the three MCF-7 cell variants were tested for their response to other known inducers of apoptosis: okadaic acid, staurosporine and 4-hydroxy-tamoxifen. Viability and DNA fragmentation analysis revealed a similar pattern of resistance to apoptosis by all agents in the MCF-7 M variant. The MCF-7 L variant was resistant to okadaic acid and 4-hydroxy-tamoxifen but not staurosporine. In contrast, MCF-7 N cells were sensitive to induction of apoptosis by all agents. The role of both protein kinase C (PKC) and estrogen signaling in the regulation of cell survival prompted investigation of these pathways as a mechanism for differential sensitivity of MCF-7 cell variants to apoptosis. While both estrogen receptor alpha (ERalpha) and ERbeta were expressed in MCF-7 M and N cells, the absence of ERbeta in MCF-7 L cells correlated with decreased estrogen responsiveness of the L variant. Variations in estrogenic responsiveness and PKC isoform expression may account for the enhanced susceptibility of both the L and N variants to staurosporine.
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PMID:Differences in protein kinase C and estrogen receptor alpha, beta expression and signaling correlate with apoptotic sensitivity of MCF-7 breast cancer cell variants. 1081 93

The role of estrogen as a promoter agent of sporadic breast cancer has been considered by assaying, in benign breast disease (BBD) and in situ carcinomas (CIS), 2 markers, the estrogen receptor alpha (ERalpha) and cathepsin D (cath-D) involved in estrogen action on mammary tissue. ERalpha and cath-D were assayed by quantitative immunohistochemistry using an image analyzer in 170 lesions of varying histological risk (94 BBD and 76 CIS), and in "normal" glands close to these lesions. The ERalpha level increased significantly in proliferative BBD with atypia (P < .001), in non-high-grade CIS (P < .001), and in adjacent "normal" glands. ERalpha level was decreased in high-grade ductal CIS (DCIS) and also in adjacent "normal" glands. Cath-D level increased in ductal proliferative BBD (P < or = .01) and in high-grade DCIS (P < or = .003), but not in the other lesions. After menopause, ERalpha level was increased (P = .012) but not cath-D level. According to Mac Neman test, the high-grade DCIS were predominantly ERalpha negative and cath-D positive (P = .0017), and the other CIS were predominantly ERalpha positive and cath-D negative (P = .0002). The 2 markers are overexpressed early in premalignant lesions, but independently. This dissociation suggests a branched model of mammary carcinogenesis involving 1 estrogen-independent pathway with high cath-D and low ERalpha levels (including high-grade DCIS) and 1 estrogen-dependent pathway, with high ERalpha level (including proliferative BBD with atypia and low-grade DCIS). We propose that ERalpha-negative breast cancers may develop directly from high-grade DCIS and that ERalpha assay in preinvasive lesions should be considered in prevention trials with antiestrogens.
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PMID:Dissociated overexpression of cathepsin D and estrogen receptor alpha in preinvasive mammary tumors. 1083 99

Thymidylate synthase (TS) catalyzes methylation of deoxyuridine phosphate to give deoxythymidine phosphate, and 17beta-estradiol (E2) induces TS gene expression in MCF-7 human breast cancer cells. Analysis of the TS gene promoter showed that E2-responsiveness required the -229 to -140 promoter region containing a G-rich sequence and CACCC box. Subsequent mutational analysis of this region indicated that only the G-rich motif (-150 to -142) was required for E2 action. Results of gel mobility shift and in vitro DNA footprinting assays showed that both estrogen receptor alpha (ERalpha) and Sp1 proteins were required for hormone-induced trans-activation that involved ERalpha/Sp1 binding to the G-rich site in which only Sp1 protein bound DNA. Both proteins also interacted in Drosophila cells in functional assays, confirming the transcriptional activation of TS-involved ERalpha/Sp1, and this adds to the increasing number of genes that are activated through this pathway in breast cancer cells.
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PMID:Transcriptional activation of thymidylate synthase by 17beta-estradiol in MCF-7 human breast cancer cells. 1087 44


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