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

The RNA polymerase II (Pol II) holoenzyme in yeast is an essential transcriptional regulatory complex which has been defined by genetic and biochemical approaches. The mammalian counterpart to this complex, however, is less well defined. Experiments herein demonstrate that, along with Pol II and SRB proteins, proteins associated with transcriptional regulation as cofactors are associated with the Pol II holoenzyme. Earlier experiments have demonstrated that the breast cancer-associated tumor suppressor BRCA1 and the CREB binding protein (CBP) were associated with the holoenzyme complex. The protein related to CBP, the E1A-associated p300 protein, is shown in these experiments to be associated with the holoenzyme complex as well as the BRG1 subunit of the chromatin remodeling SWI/SNF complex. Importantly, the Pol II holoenzyme complex does not contain some factors previously reported as stoichiometric components of the holoenzyme complex, most notably the proteins which function in repair of damaged DNA, such as PCNA, RFC and RPA. The presence of the p300 coactivator and the chromatin-modifying BRG1 protein support a role for the Pol II holoenzyme as a key target for regulation by enhancer binding proteins.
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PMID:Factors associated with the mammalian RNA polymerase II holoenzyme. 944 79

Progesterone has biphasic effects on proliferation of breast cancer cells; it stimulates growth in the first cell cycle, then arrests cells at G1/S of the second cycle accompanied by up-regulation of the cyclin-dependent kinase inhibitor, p21. We now show that progesterone regulates transcription of the p21 promoter by an unusual mechanism. This promoter lacks a canonical progesterone response element. Instead, progesterone receptors (PRs) interact with the promoter through the transcription factor Sp1 at the third and fourth of six Sp1 binding sites located downstream of nucleotide 154. Mutation of Sp1 site 3 eliminates basal transcription, and mutation of sites 3 and 4 eliminates transcriptional up-regulation by progesterone. Progesterone-mediated transcription is further prevented by overexpression of E1A, suggesting that CBP/p300 is required. Indeed, in HeLa cells, Sp1 and CBP/p300 associate with stably integrated flag-tagged PRs in a multiprotein complex. Since many signals converge on p21, cross-talk between PRs and other factors co-localized on the p21 promoter, may explain how progesterone can be either proliferative or differentiative in different target cells.
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PMID:Progesterone regulates transcription of the p21(WAF1) cyclin- dependent kinase inhibitor gene through Sp1 and CBP/p300. 955 33

Nuclear receptors regulate transcription by binding to specific DNA response elements of target genes. Herein, we report the molecular cloning and characterization of a novel Xenopus cDNA encoding a transcription coactivator xSRC-3 by using retinoid X receptor (RXR) as a bait in the yeast two-hybrid screening. It belongs to a growing coactivator family that includes a steroid receptor coactivator amplified in breast cancer (AIB1), p300/ CREB-binding protein (CBP)-interacting protein (p/ CIP), and transcriptional intermediate factor 2 (TIF2). It also interacts with a series of nuclear receptors including retinoic acid receptor (RAR), thyroid hormone receptor (TR), and orphan nuclear receptors [hepatocyte nuclear receptor 4 (HNF4) and constitutive androstane receptor (CAR)]. However, it does not interact with small heterodimer partner (SHP), an orphan nuclear receptor known to antagonize ligand-dependent transactivation of other nuclear receptors. In CV-1 cells, cotransfection of xSRC-3 differentially stimulates ligand-induced transactivation of RXR, TR, and RAR in a dose-dependent manner. Interestingly, xSRC-3 is highly expressed in adult liver and early stages of oocyte development, suggesting that studies of xSRC-3 may lead to better understanding of the roles nuclear receptors play in oocyte development as well as liver-specific gene expression.
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PMID:Molecular cloning of xSRC-3, a novel transcription coactivator from Xenopus, that is related to AIB1, p/CIP, and TIF2. 965 7

In addition to breast and ovarian cancer in women, recent evidence suggests that germ-line mutations of the breast cancer susceptibility gene-1 (BRCA1) also confer an increased life-time risk for prostate cancer in male probands. However, it is not known if and how BRCA1 functions in prostate cancer. We stably expressed wild-type (wt) and tumor-associated mutant BRCA1 transgenes in DU-145, a human prostate cancer cell line with low endogenous expression of BRCA1. As compared with parental cells and vector transfected clones, wtBRCA1 clones exhibited: (1) a slightly decreased proliferation rate (doubling time = 25 h as compared with 22 h for control cells); (2) a (3-6)-fold increase in sensitivity to chemotherapy drugs (adriamycin, camptothecin, and taxol); (3) increased susceptibility to drug-induced apoptosis; (4) reduced repair of single-strand DNA strand breaks; and (5) alterations in expression of key cellular regulatory proteins (including BRCA2, p300, Mdm-2, p21(WAF1/CIP1), Bcl-2 and Bax). Clones transfected with the 5677insA breast cancer-associated mutant BRCA1 (insBRCA1) displayed a similar phenotype to wtBRCA1 clones, except that insBRCA1 clones had a significantly decreased proliferation rate (doubling time = 42 h). On the other hand, cells transfected with with 185delAG mutant BRCA1 showed no obvious phenotype as compared with parental or vector transfected cells. These findings suggest that BRCA1 may function as a human prostate tumor suppressor by virtue of its ability to modulate proliferation and various components of the cellular damage response. They also suggest several potential target gene products for a BRCA1 prostate tumor suppressor function.
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PMID:BRCA1 as a potential human prostate tumor suppressor: modulation of proliferation, damage responses and expression of cell regulatory proteins. 966 40

Previously, we have shown that phorbol ester (PMA) induces p21(WAF1/CIP1)-dependent growth arrest in SKBr3 breast cancer and LNCaP prostate cancer cells. Here, I demonstrate that inhibition of Raf-1 kinase by dominant-negative Raf-1 or pharmacological depletion of Raf-1 prevented PMA-mediated induction of p21(WAF1/CIP1). Similarly, PD98059, a specific inhibitor of MEK, abolished p21(WAF1/CIP1) induction and PMA-induced growth arrest. Like PMA, the H-ras oncogene, another activator of the Raf-1/MEK/MAPK pathway, transactivated p21(WAF1/CIP1) in SKBr3 cells. I further investigated PMA-induced growth arrest following infection of SKBr3 cells with 12S E1A-expressing adenovirus. Although high levels of E1A oncoprotein prevented both PMA-induced p21(WAF1/CIP1) and growth arrest, smaller amounts of E1A abrogated growth arrest without down-regulation of p21(WAF1/CIP1). Therefore, E1A can stimulate proliferation downstream of p21(WAF1/CIP1). Albeit less effective than full activity, either Rb- or p300-binding activity of E1A was sufficient for the abrogation of PMA-mediated growth arrest. E1A-driven proliferation of PMA-treated SKBr3 cells was accompanied by apoptosis. New therapeutic approaches can be envisioned that would utilize stimulation of the Raf-1/MEK/MAPK pathway to inhibit growth of PMA-sensitive cancer cells.
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PMID:The mitogen-activated protein kinase pathway mediates growth arrest or E1A-dependent apoptosis in SKBR3 human breast cancer cells. 979 42

The tumor suppressor protein p53 exerts its cell cycle-regulatory effects through its ability to function as a sequence-specific DNA-binding transcription factor. Herein, we show that p53 physically interacts with specific subregions of steroid receptor coactivator-1 (SRC-1) and its family members, p/CIP (p300/CBP interacting protein), xSRC-3, and AIB1 (amplified in breast cancer), originally isolated as transcription coactivators of nuclear receptors, as demonstrated by the yeast and mammalian two-hybrid tests as well as glutathione S-transferase pull-down assays. Interestingly, cotransfection of HeLa cells with SRC-1- or p/CIP expression vector potentiated the p53-mediated transactivation, whereas AIB1 and xSRC-3 were repressive. All of these SRC-1 members, however, similarly stimulated transactivation mediated by nuclear receptors and AP-1, as previously described. These results suggest that SRC-1 and its family members may differentially modulate the p53 transactivation in vivo.
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PMID:Steroid receptor coactivator-1 and its family members differentially regulate transactivation by the tumor suppressor protein p53. 1055 85

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

Growth factor modulation of estrogen receptor (ER) activity plays an important role in both normal estrogen physiology and the pathogenesis of breast cancer. Growth factors are known to stimulate the ligand-independent activity of ER through the activation of mitogen-activated protein kinase (MAPK) and the direct phosphorylation of ER. We found that the transcriptional activity of AIB1, a ligand-dependent ER coactivator and a gene amplified preferentially in ER-positive breast cancers, is enhanced by MAPK phosphorylation. We demonstrate that AIB1 is a phosphoprotein in vivo and can be phosphorylated in vitro by MAPK. Finally, we observed that MAPK activation of AIB1 stimulates the recruitment of p300 and associated histone acetyltransferase activity. These results suggest that the ability of growth factors to modulate estrogen action may be mediated through MAPK activation of the nuclear receptor coactivator AIB1.
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PMID:AIB1 is a conduit for kinase-mediated growth factor signaling to the estrogen receptor. 1086 61

The acetyltransferase p300 was first identified associated with the adenoviral transforming protein E1A, suggesting a potential role for p300 in the regulation of cell proliferation. Direct evidence demonstrating a role for p300 in human tumours was lacking until the recently publication by Gayther et al, which strongly supports a role for p300 as a tumour suppressor. The authors identify truncating mutations associated with the loss or mutation of the second allele in both tumour samples and cell lines, suggesting that loss of p300 may play a role in the development of a subset of human cancers.
Breast Cancer Res 2000
PMID:Acetyltransferases and tumour suppression. 1125 Jul 15

The natural polyamines -putrescine, spermidine, and spermine- are essential for cell growth and differentiation. Polyamines are involved in several gene regulatory functions, although their mechanism(s) of action has not been elucidated. We investigated the role of polyamines in the function of NF-kappa B and estrogen receptor-alpha (ER alpha), two transcription factors implicated in breast cancer cell proliferation and cell survival, using MCF-7 breast cancer cells. We found that spermine facilitated the binding of ER alpha and NF-kappa B to estrogen response element (ERE)- and NF-kappa B response element (NRE), respectively, and enhanced ER alpha-mediated transcriptional activation in transient transfection experiments. We also found that the association of the co-regulatory protein CBP/p300 with ER alpha and NF-kappa B was increased by spermine treatment of MCF-7 cells. Spermine also increased the nuclear translocation of NF-kappa B compared to the control. In contrast, treatment of MCF-7 cells with polyamine analogs, BE-3-4-3 and BE-3-3-3, resulted in transcriptional inhibition of both ERE- and NRE-driven reporter plasmids. In addition, polyamine analogs inhibited the association of ER alpha and NF-kappa B with CBP/p300 and were unable to facilitate nuclear translocation of NF-kappa B. APO-BRDU assay demonstrated that polyamine analogs induced apoptosis, with a loss of the anti-apoptotic protein Bcl-2. These data show a gene regulatory function of polyamines involving transcriptional activation of ER alpha and NF-kappa B, potentially leading to the up-regulation of genes involved in breast cancer cell proliferation. Our results with BE-3-4-3 and BE-3-3-3 suggest that down-regulation of ER alpha- and NF-kappa B-regulated genes is a possible mechanism for the action of polyamine analogs in inducing apoptosis of breast cancer cells.
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PMID:Regulation of estrogenic and nuclear factor kappa B functions by polyamines and their role in polyamine analog-induced apoptosis of breast cancer cells. 1131 19


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