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

We and others have reported that C-28 methyl ester of 2-cyano-3, 12-dioxoolen-1, 9-dien-28-oic acid (CDDO-Me) effectively inhibits the growth of multiple cancer cell types. Our previous studies indicated that prolonged CDDO-Me treatment inactivated extracellular signal-regulated kinase signaling in acute myelogenous leukemia cells. Whether treatment with CDDO-Me has an earlier effect on other proteins that are important for either signal transduction or oncogenesis is unknown. Constitutively activated signal transducer and activator of transcription 3 (STAT3) is frequently found in human breast cancer samples. Constitutively activated STAT3 was shown to up-regulate c-Myc in several types of cancer and has a feedback effect on Src and Akt. To examine the effects of CDDO-Me on STAT3 signaling in breast cancer, we used the murine 4T1 breast tumor model, which is largely resistant to chemotherapy. In vitro, after treatment of 4T1 cells with 500 nmol/L CDDO-Me for 2 h, we found (a) inactivation of STAT3, (b) inactivation of Src and Akt, (c) 4-fold reduction of c-Myc mRNA levels, (d) accumulation of cells in G(2)-M cell cycle phase, (e) abrogation of invasive growth of 4T1 cells, and (f) lack of apoptosis induction. In in vivo studies, CDDO-Me completely eliminated 4T1 breast cancer growth and lung metastases induced by 4T1 cells in mice when treatment started 1 day after tumor implantation and significantly inhibited tumor growth when started after 5 days. In vivo studies also indicated that splenic mature dendritic cells were restored after CDDO-Me treatment. In summary, these data suggest that CDDO-Me may have therapeutic potential in breast cancer therapy, in part, through inactivation of STAT3.
 ...
PMID:The novel triterpenoid C-28 methyl ester of 2-cyano-3, 12-dioxoolen-1, 9-dien-28-oic acid inhibits metastatic murine breast tumor growth through inactivation of STAT3 signaling. 1748 32

Signal transducer and activator of transcription 3 (Stat3) belongs to a family of latent cytoplasmic transcription factors important for cytokine signaling. Stat3 is constitutively activated in various tumors, and activated Stat3 itself also acts as an oncogene. Transcriptional activity of Stat3 is controlled by Tyr-phosphorylation, followed by dimerization and nuclear translocation. However, phosphorylation on Ser727 is indispensable for its maximal transcriptional activity with unclear mechanism. Here, we report that peptidyl-prolyl cis/trans isomerase 1 (Pin1), which specifically recognizes the pSer/Thr-Pro motifs on its target proteins, interacts with Stat3 upon cytokine/growth factor stimulation. Overexpression of Pin1 promotes Stat3 transcriptional activity and target gene expression, as well as recruitment of transcription coactivator, p300. These effects, however, were compromised in the Pin1-deficient cells, and were totally dependent on the Ser727 phosphorylation site. Finally, we showed that Pin1 enhances Stat3-mediated epithelial-mesenchymal transition in breast cancer cells induced by oncostatin M. Our data reveal a novel, Ser727 phosphorylation-dependent, post-translational regulation mechanism for Stat3.
 ...
PMID:Pin1 is required for the Ser727 phosphorylation-dependent Stat3 activity. 1756 47

Bone is the primary anatomical site of breast cancer metastasis, and bone metastasis is associated with increased morbidity and mortality. Mesenchymal stem cells (MSC) are a predominant fibroblast cell population within the bone marrow, and metastatic breast cancer cells that seed within bone would predictably encounter MSC or their soluble factors. Therefore, we examined the impact of primary human MSC on a panel of estrogen receptor-alpha (ERalpha)-positive (MCF-7, T47D, BT474, and ZR-75-1) and ERalpha-negative (MDA-MB-231 and MDA-MB-468) human breast tumor cell lines. All ERalpha-positive breast tumor cell lines displayed low basal activation of signal transducer and activator of transcription 3 (STAT3) until exposed to MSC, which induced chronic phosphorylation of STAT3 on tyrosine-705. Paracrine IL-6 was found to be the principal mediator of STAT3 phosphorylation in coculture studies, and MSC induction of STAT3 phosphorylation was lost when IL-6 was depleted from MSC conditioned media or the IL-6 receptor was blocked on tumor cells. Enhanced tumor cell growth rates were observed in the ERalpha-positive mammary tumor cell line MCF-7 after paracrine and autocrine IL-6 exposure, where MCF-7 growth rates were enhanced by >2-fold when cocultured with MSC in vitro and even more pronounced in vivo with autocrine IL-6 production.
 ...
PMID:Interleukin-6 is a potent growth factor for ER-alpha-positive human breast cancer. 1758 27

Metastatic breast cancer is an incurable disease, often characterized by poor response to standard chemotherapy, which is mainly based on anthracyclines and taxanes. Thus, increasing tumor cell sensitivity to these agents is an attractive goal towards improving the clinical management of this disease. The present study investigates the effects of signal transducer and activator of transcription 3 (Stat3) inhibition on the response of the highly metastatic MDA-MB-231 human breast adenocarcinoma cell line to doxorubicin (DOX). Stat3 is a transcription factor often constitutively activated in breast tumors and cancer cell lines, and is thought to contribute to malignant transformation and progression by transactivation of a host of target genes involved in cell proliferation and survival, angiogenesis and invasiveness. Our results indicate that (a) untreated MDA-MB-231 cells express higher baseline levels of (activated) pTyr(705)Stat3, that are further upregulated following exposure to DOX, than the non-metastatic MCF-7 cell line; (b) inhibiting the Stat3 signaling pathway, by exposure to the tyrphostin AG490 (an inhibitor of the upstream activating Janus kinases), by transfection with a dominant-negative form of Stat3 or by treatment with satraplatin (a tetravalent platinum derivative that inhibits Stat3 activation), increases breast cancer cell response to the proapoptotic effect of DOX (to different extents). In addition, the latter two approaches have been shown to interfere with expression of one or more antiapoptotic proteins. Overall, these observations suggest that suppression of Stat3 signaling may provide a potential therapeutic approach to overcoming DOX resistance in metastatic breast cancer cells.
 ...
PMID:Inhibition of Stat3 increases doxorubicin sensitivity in a human metastatic breast cancer cell line. 1792 Jul 63

Activation of the signal transducer and activator of transcription 3 (STAT3) is frequently detected in many cancer types. Activated STAT3 may participate in oncogenesis by stimulating cell proliferation and resisting apoptosis, as well as promoting tumor angiogenesis, invasion, and migration. Many STAT3-dependent cellular responses are mediated through interactions with other proteins, and the amino-terminal domain (N-domain) of STAT3 was proposed to be responsible for this. Our NMR studies revealed that synthetic analogs of the STAT4 second alpha-helix bind to the N-domain and perturb its structure. Structural data available for the STAT4 N-domain was used for the rational design of STAT3 helix 2 analogs with enhanced biological activity. Cell-permeable derivatives of the STAT3 second helix were found to directly and specifically bind to STAT3 but not STAT1 as determined by FRET analysis in cells expressing GFP-STAT3 and GFP-STAT1. Furthermore, they potently induced apoptotic death in breast cancer cells but not normal breast cells or STAT3-deficient fibroblasts. The inhibitors caused significant changes in the mitochondrial potential of cancer cells, leading to cell death. These compounds not only are promising drug candidates but also offer a convenient tool for studying the mechanisms of action of STAT transcription factors and have facilitated our understanding of the crucial role of the N-domain in STAT3 function.
 ...
PMID:Rationally designed inhibitors identify STAT3 N-domain as a promising anticancer drug target. 1815 67

De novo or acquired resistance to tamoxifen is a major clinical challenge for the management of estrogen receptor (ER)-positive breast cancers. Although cyclin D1 overexpression is associated with a better outcome for breast cancer patients, its overexpression is also linked to tamoxifen resistance. We previously reported that the beneficial effect of cyclin D1 correlates with its ability to repress the antiapoptotic transcription factor signal transducer and activator of transcription 3 (STAT3). In contrast, molecular pathways linking overexpression of cyclin D1 to tamoxifen resistance have not been established. In the current study, the effect of tamoxifen on the growth of genetically matched high or low cyclin D1-expressing breast cancer cells was characterized and the interactions between cyclin D1, ER, and STAT3 in response to tamoxifen treatment were determined. We show that repression of STAT3 by cyclin D1 inhibits cell growth on Matrigel and in tumors in vivo; however, treatment with tamoxifen abolishes cyclin D1-mediated repression of STAT3 and growth suppression. We show that tamoxifen induces a redistribution of cyclin D1 from STAT3 to the ER, which results in the activation of both STAT3 and the ER. These results offer a molecular mechanism for the dual effect of cyclin D1 overexpression in breast cancer and support the notion that the level of cyclin D1 expression and activated STAT3 are important markers to predict response to tamoxifen treatment.
 ...
PMID:Tamoxifen stimulates the growth of cyclin D1-overexpressing breast cancer cells by promoting the activation of signal transducer and activator of transcription 3. 1824 87

The recent report highlighted a significant association between signal transducer and activator of transcription 3 (STAT3) and Snail and LIV-1 (SLC39A6 or ZIP6), the breast cancer-associated protein that belongs to a new subfamily of zinc transporters. LIV-1 is a downstream target of STAT3, both in zebrafish and mammalian cells and provides control over epithelial-mesenchymal transition (EMT). Crucially, these observations link LIV-1, previously demonstrated to be associated with lymph node metastasis in breast cancer, to genes with a proven role in development. A putative role of LIV-1 as a regulator of E-cadherin that modulates the cell-cell adhesion is thus inferred. In present study, the correlation of LIV-1 and E-cadherin expression in human breast cancer cell MCF-7 and the effect of LIV-1 expression on the cell growth were assessed to explore the possible mechanisms associated with this observation in breast cancer. It was shown that the silencing of LIV-1 would induce the down-expression of E-cadherin. There was opposite results if the cells were overexpressed with LIV-1. In addition, the results showed that promotion effect after silencing of LIV-1 and inhibition effect after overexpression of LIV-1 in transfected cells. To our knowledge, this is the first evidence that the expression of E-cadherin could be regulated by the zinc transporter LIV-1. The results suggest that there is an association of LIV-1 expression with less aggressive tumors due to high E-cadherin expression because of high LIV-1 expression. LIV-1 may be a regulator of E-cadherin.
 ...
PMID:Concordant correlation of LIV-1 and E-cadherin expression in human breast cancer cell MCF-7. 1833 Jul 19

Common sites of breast cancer metastasis include the lung, liver, and bone, and of these secondary metastatic sites, estrogen receptor alpha (ERalpha)-positive breast cancer often favors bone. Within secondary organs, cancer cells would predictably encounter tissue-specific fibroblasts or their soluble factors, yet our understanding of how tissue-specific fibroblasts directly affect cancer cell growth rates and survival remains largely unknown. Therefore, we tested the hypothesis that mesenchymal fibroblasts isolated from common sites of breast cancer metastasis provide a more favorable microenvironment with respect to tumor growth rates. We found a direct correlation between the ability of breast, lung, and bone fibroblasts to enhance ERalpha-positive breast cancer cell growth and the level of soluble interleukin-6 (IL-6) produced by each organ-specific fibroblast, and fibroblast-mediated growth enhancement was inhibited by the removal or inhibition of IL-6. Interestingly, mice coinjected with MCF-7 breast tumor cells and senescent skin fibroblasts, which secrete IL-6, developed tumors, whereas mice coinjected with presenescent skin fibroblasts that produce little to no IL-6 failed to form xenograft tumors. We subsequently determined that IL-6 promoted growth and invasion of breast cancer cells through signal transducer and activator of transcription 3-dependent up-regulation of Notch-3, Jagged-1, and carbonic anhydrase IX. These data suggest that tissue-specific fibroblasts and the factors they produce can promote breast cancer disease progression and may represent attractive targets for development of new therapeutics.
 ...
PMID:Fibroblasts isolated from common sites of breast cancer metastasis enhance cancer cell growth rates and invasiveness in an interleukin-6-dependent manner. 1897 55

Cross talk between the steroid hormone receptors for estrogen and progesterone (PR) and the ErbB family of receptor tyrosine kinases appears to be a hallmark of breast cancer growth, but its underlying mechanism remains poorly explored. Here we have highlighted signal transducer and activator of transcription 3 (Stat3) as a key protein activated by heregulin (HRG), a ligand of the ErbB receptors, through co-opted, ligand-independent PR function as a signaling molecule. Stat3 activation was an absolute requirement in HRG-induced mammary tumor growth, and targeting Stat3 effectively inhibited growth of breast cancer cells with activated HRG/ErbB-2 and PR. Our findings unravel a novel potential therapeutic intervention in PR- and ErbB-2-positive breast tumors, involving the specific blockage of PR signaling activity.
 ...
PMID:Activation of Stat3 by heregulin/ErbB-2 through the co-option of progesterone receptor signaling drives breast cancer growth. 1910 53

Overexpression of the ErbB2 receptor tyrosine kinase is prevalent in approximately 30% of human breast cancers and confers Taxol resistance. Our previous work has shown that ErbB2 inhibits Taxol-induced apoptosis in breast cancer cells by transcriptionally up-regulating p21(Cip1). However, the mechanism of ErbB2-mediated p21(Cip1) up-regulation is unclear. Here, we show that ErbB2 up-regulates p21(Cip1) transcription through increased Src activity in ErbB2-overexpressing cells. Src activation further activated signal transducer and activator of transcription 3 (STAT3) that recognizes a SIE binding site on the p21(Cip1) promoter required for ErbB2-mediated p21(Cip1) transcriptional up-regulation. Both Src and STAT3 inhibitors restored Taxol sensitivity in resistant ErbB2-overexpressing breast cancer cells. Our data suggest that ErbB2 overexpression can activate STAT3 through Src leading to transcriptional up-regulation of p21(Cip1) that confers Taxol resistance of breast cancer cells. Our study suggests a potential clinical application of Src and STAT3 inhibitors in Taxol sensitization of ErbB2-overexpressing breast cancers.
 ...
PMID:ErbB2-mediated Src and signal transducer and activator of transcription 3 activation leads to transcriptional up-regulation of p21Cip1 and chemoresistance in breast cancer cells. 1937 87


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>