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)

Previously, we reported a deficient cloning capacity of the bone marrow (BM) mesenchymal stem cells to give colony-forming unit fibroblast (CFU-F) and an inefficient confluence capacity of BM stromal cells in advanced untreated lung cancer patients (LCP) and breast cancer patients (BCP). Moreover, a decreased level of bFGF at day 7 in the conditioned media from BM CFU-F cultures was found in both cancer groups when compared to the normal range. The current study was specially undertaken, to evaluate the percentage of subconfluent fibroblasts expressing receptors (R) of interleukin-1 (IL-1), platelet-derived growth factor (PDGF), fibroblast growth factor (FGF), transforming growth factor (TGF-beta), epidermal growth factor (EGF), and the proteins c-Fos and c-Myc in BM primary cultures from untreated LCP and BCP. An immunocytochemical study on subconfluent BM fibroblast cultures from 13 healthy patients, 16 LCP, and 8 BCP was performed, using as primary antibodies, anti-type I of IL-1 R (IL-1R-1), anti-alpha, beta chains of PDGF R (PDGFR-alpha, PDGFR-beta), anti-type I of FGF R (FGFR-I), anti-type I, II, and III of TGF-beta R (TGF-betaR-I, TGF- betaR-II, and TGF-betaR-III), anti-EGF R, anti-c-Fos, and anti-c-Myc. A diminished percentage of subconfluent fibroblasts expressing PDGFR-alpha, TGFbetaR-I, II, III, EGFR, and FGFR-I was found in LCP and BCP compared to healthy patients. A diminished percentage of subconfluent fibroblasts expressing c-Fos and c-Myc was found in patients when compared to healthy patients. The alterations we describe could help to explain the deficiency regarding the proliferative and confluence capacity of BM stroma cells in cancer patients.
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PMID:Alteration on the expression of IL-1, PDGF, TGF-beta, EGF, and FGF receptors and c-Fos and c-Myc proteins in bone marrow mesenchymal stroma cells from advanced untreated lung and breast cancer patients. 1630 43

Topoisomerase II inhibitors are widely used in cancer chemotherapy. However, their use is limited by severe adverse effects to normal tissues, including cardiotoxicity. One approach to reduce the cytotoxicity in normal tissues may be to sensitize cancer cells to the toxicity of these agents, allowing them to be administered in a lower and safer dose. A hallmark of many types of cancer is overexpression of c-Myc, and a molecule which targets c-Myc will affect the cancer cells more significantly than the normal tissues. This report demonstrates that pretreatment of cells with a polypeptide, which inhibits c-Myc transcriptional function causes cells to be more susceptible to the topoisomerase II inhibitors doxorubicin and etoposide. Inhibition of c-Myc and Max dimerization by this polypeptide leads to as much as a 2-fold reduction in the doxorubicin and etoposide IC(50) in three different cell lines tested. Furthermore, the c-Myc inhibitor affects the cell cycle distribution of MCF-7 breast cancer cells by enhancing the G(0)/G(1) accumulation induced by doxorubicin and etoposide. We have shown that this effect is not due to enhanced drug accumulation or inhibited drug efflux. Rather, it is likely due to the transcriptional consequences of c-Myc inhibition, specifically reduction in the levels of the polyamine synthesizing enzyme ornithine decarboxylase. In summary, our results suggest that polypeptides, which inhibit c-Myc transcriptional function, may prove to be a useful tool in combination therapy with topoisomerase II inhibiting drugs.
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PMID:Enhancing the antiproliferative effect of topoisomerase II inhibitors using a polypeptide inhibitor of c-Myc. 1631 34

alpha-Tocopherol succinate (TS), an analogue of vitamin E, has growth-inhibitory activity in a wide spectrum of in vitro and in vivo cancer models. Here, we report that modulation of oncogenic Ras is associated with TS activity. TS inhibits the proliferation and induces apoptosis of NIH3T3 cells stably transfected with oncogenic K-Ras and H-Ras, but not NIH3T3 cells expressing empty vector. TS treatment resulted in decreased Ras protein levels in oncogenic Ras expressing NIH3T3 cells but not in parental NIH3T3 cells. Treatment with TS suppressed the levels of phospho-Akt and phospho-Erk1/2 in oncogenic Ras expressing NIH3T3 cells. Overexpression of constitutively active phosphoinositide-3-kinase, Akt, and Mek1/2 significantly attenuated TS growth inhibition of oncogenic Ras-transformed NIH3T3 mouse fibroblast cell lines. In addition, transcriptional targets of oncogenic Ras such as c-Myc, cyclin D1, and E2F1 were down-regulated by TS in oncogenic Ras-expressing cells. The above TS effects on oncogenic Ras signaling were also observed in endogenous oncogenic K-Ras expressing HCT 116 (human colon cancer) and MDA-MB-231 (human breast cancer) cells. Taken together, these data show that TS down-regulation of the Ras signaling pathways that are mediated by Mek/Erk and phosphoinositide-3-kinase/Akt plays, at least in part, a critical role in TS inhibition of proliferation and survival of transformed cells. This data supports further investigation of the chemopreventive and therapeutic potential of TS in tumors that are dependent on activated Ras signaling and identifies phosphor-Erk and phosphor-Akt as potential biomarkers of TS activity.
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PMID:RRR-alpha-tocopherol succinate down-regulates oncogenic Ras signaling. 1650 4

One hypothesis for breast cancer development suggests that breast carcinogenesis involves a progression of events leading from benign epithelium to hyperplasia (with or without atypia) to carcinoma in situ and then invasive carcinoma. The MYC gene (alias c-Myc) is a transcriptional regulator whose expression is strongly associated with cell proliferation and cell differentiation. The present study is a descriptive analysis of MYC status throughout the hypothesized stages of invasive ductal carcinoma progression. A tissue microarray (TMA) was constructed including representative selected areas (normal cells, hyperplasia, in situ carcinoma, and invasive carcinoma) from each of 15 patients. Fluorescence in situ hybridization (FISH) with the LSI c-MYC/CEN8/IgH probe was performed. Two cases displayed MYC amplification (13%), showing this amplification only in the invasive carcinoma zones selected. Five cases displayed polysomy of chromosome 8 (33%), detected only in ductal in situ and invasive zones selected. Benign lesions and normal adjacent cells were classified as normal. None of the hyperplasia specimens and normal specimens analyzed showed any alterations in MYC status or any aneusomies of chromosome 8. The presence of MYC amplification only in invasive cells suggests that the finding of MYC amplification could reflect an advanced tumor progression.
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PMID:The MYC oncogene in breast cancer progression: from benign epithelium to invasive carcinoma. 1652 9

Obesity has been recognized as a risk factor for breast cancer. Adipocyte-derived leptin may play as a paracrine regulator on the growth of breast cancer cells. Expression of both leptin and its OB-Rb receptor was detected in human breast cancer ZR-75-1 cells and further induced by leptin, suggesting that both expression and message mediation of leptin were autoregulated by itself. With cell counting and MTT assay, we had observed leptin stimulated ZR-75-1 growth in dose- and time-dependent manners. To study what steps of cell cycle progression leptin may involve in, we analyzed cell-cycle profile with flow cytometric analysis, mRNA and protein expressions of four cell-cycle regulators with RT-PCR and Western blotting analysis. Under the treatment of leptin, the G1 arrest of cells was reduced accompanied with up-regulation of G1 phase-specific cyclin D1 and proto-oncogene c-Myc, but down-regulation of cyclin-dependent kinase inhibitor p21(WAF1/CIP1) and tumor suppressor p53. Furthermore, JAK2 inhibitor AG490, PI3K/Akt inhibitor Wortmannin, and MEK/ERK1/2 inhibitor PD98059 were efficiently prevented leptin-promoted cell growth. Effect of cooperation between leptin and estrogen on ZR-75-1 growth had been observed. Collectively, the results showed that the proliferative effect of leptin on ZR-75-1 was associated with the up-regulation of cyclin D1 and c-Myc and down-regulation of tumor suppressor p53 and p21(WAF1/CIP1) plausibly through a hypothesized JAK2-PI3K/Akt-MEK/ERK pathway. The leptin- and OB-Rb-expressing capability of ZR-75-1 created a possible autocrine control of leptin, in which signal could be effectively amplified by itself, on cell growth.
Breast Cancer Res Treat 2006 Jul
PMID:Leptin-induced growth of human ZR-75-1 breast cancer cells is associated with up-regulation of cyclin D1 and c-Myc and down-regulation of tumor suppressor p53 and p21WAF1/CIP1. 1675 79

Telomerase underpins stem cell renewal and proliferation and is required for most neoplasia. Recent studies suggest that hormones and growth factors play physiological roles in regulating telomerase activity. In this report we show a rapid repression of the telomerase reverse transcriptase (TERT) gene by transforming growth factor beta (TGF-beta) in normal and neoplastic cells by a mechanism depending on the intracellular signaling protein Smad3. In human breast cancer cells TGF-beta induces rapid entry of Smad3 into the nucleus where it binds to the TERT gene promoter and represses TERT gene transcription. Silencing Smad3 gene expression or genetically deleting the Smad3 gene disrupts TGF-beta repression of TERT gene expression. Expression of the Smad3 antagonist, Smad7, also interrupts TGF-beta-mediated Smad3-induced repression of the TERT gene. Mutational analysis identified the Smad3 site on the TERT gene promoter, mediating TERT repression. In response to TGF-beta, Smad3 binds to c-Myc; knocking down c-Myc, Smad3 does not bind to the TERT gene, suggesting that c-Myc recruits Smad3 to the TERT promoter. Thus, TGF-beta negatively regulates telomerase activity via Smad3 interactions with c-Myc and the TERT gene promoter. Modifying the interaction between Smad3 and TERT gene may, thus, lead to novel strategies to regulate telomerase.
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PMID:Transforming growth factor beta suppresses human telomerase reverse transcriptase (hTERT) by Smad3 interactions with c-Myc and the hTERT gene. 1678 37

In this study, we first report the chemopreventive effect of rugosin E in human breast cancer cell line, MDA-MB-231. Treatment with rugosin E decreased the cell proliferation of MDA-MB-231 cells in a dose-dependent manner. Rugosin E treatment arrested MDA-MB-231 cells at G0/G1 phase. This effect was strongly associated with concomitant decrease in the level of cyclin D1, cyclin D2, cyclin E, cdk2, cdk4, and cdk6, and increase of p21/WAF1. In addition, rugosin E also induced apoptotic cell death. Rugosin E increased in the expression of Bax, Bak, and Bcl-Xs, but decreased the levels of Bcl-2 and Bcl-X(L), and subsequently triggered mitochondria apoptotic pathway (release of cytochrome c, activation of caspase-9, and caspase-3). In addition, pre-treatment of cells with caspase-9 inhibitor blocked rugosin E-induced cell proliferation and apoptosis, indicating caspase-9 activation was involved in rugosin E-mediated MDA-MB-231 cells apoptosis. Rugosin E inhibited the constitutively activated and inducible NF-kappaB in both its DNA-binding activity and transcriptional activity. Furthermore, rugosin E also inhibited the TNF-alpha-activated NF-kappaB-dependent reporter gene expression of cyclin D1, c-Myc, XIAP, Bcl-2, and Bcl-X(L) were all downregulated by rugosin E. Our results indicated that rugosin E inhibits the activation of NF-kappaB, and this may provide a molecular basis for drug development in the prevention and treatment of cancer by rugosin E.
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PMID:Rugosin E, an ellagitannin, inhibits MDA-MB-231 human breast cancer cell proliferation and induces apoptosis by inhibiting nuclear factor-kappaB signaling pathway. 1696 81

The aim of this study was to identify molecules involved in the proliferation and survival of recurrent estrogen receptor (ER)-positive breast cancer at the site of metastasis. Most studies of biomarkers are done using the initial primary breast tumor whereas pathological studies of breast cancer lesions after distant recurrence are scarce. Here we evaluated the expression of the oncogenes c-Myc and Bcl-2, mediators of estrogen-dependent proliferation and survival, during breast cancer progression and relapse after adjuvant hormonal therapy. Using a preclinical model of tamoxifen-resistant growth, we found overexpression of c-Myc in all (3/3) and of Bcl-2 in most (2/3) tamoxifen resistant-breast cancer variants. To determine whether c-Myc and Bcl-2 are expressed during breast cancer progression in the clinics we identified breast cancer patients who had received adjuvant hormonal therapy for the treatment of their localized disease and had later experienced relapse. From 583 patients who had received adjuvant hormonal therapy a total of 82 experienced recurrence. Nevertheless, only 22 patients had had a biopsy of their metastatic lesion done after relapse. Twenty-one biopsies were useful for this biomarker study. These biopsies were obtained mostly (20) from breast cancer patients who had received tamoxifen as their adjuvant hormonal therapy. One patient had received an aromatase inhibitor instead. Our results showed that almost all (20) metastatic recurrences expressed ER. Expression of c-Myc was observed in 18 out of 19 metastatic lesions scored while expression of Bcl-2 was detected in 17 out of 21 metastatic tumors. A correlation between ER expression and Bcl-2, but not with c-Myc, was found in these recurrent metastatic lesions. In addition, c-Myc expression was correlated with the nuclear grade of the metastatic lesion. Thus, the frequent expression of c-Myc and Bcl-2 in metastatic breast cancer recurrences suggests that combining hormonal therapy with strategies to block c-Myc and Bcl-2 may prevent growth of ER-positive breast cancer at the site of metastasis.
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PMID:Overexpression of c-Myc and Bcl-2 during progression and distant metastasis of hormone-treated breast cancer. 1704 47

The oncoprotein c-Myc is frequently overexpressed in breast cancer and ectopic expression in breast cancer cell lines attenuates responses to antiestrogen treatment. Here, we review preliminary data aimed at further elucidating a potential role for c-Myc in clinical endocrine resistance in breast cancer. Immunohistochemical and semi-quantitative PCR revealed that c-Myc protein and c-myc mRNA were frequently overexpressed in both ER-positive and ER-negative breast carcinoma. Furthermore, both constitutive and inducible c-Myc overexpression in MCF-7 breast cancer cell lines markedly reduced their sensitivity to the growth inhibitory effects of the pure antiestrogen ICI 182,780. In order to identify potential downstream targets of c-Myc that mediate this effect, Affymetrix microarrays were employed to examine the patterns of gene expression shared by MCF-7 cells stimulated by estrogen, or by induction of c-Myc. Approximately 50% of estrogen target genes identified 6h after treatment were also regulated by c-Myc. One novel target, EMU4, was transcriptionally regulated by c-Myc. In addition, there was a strong correlation between c-myc and EMU4 mRNA expression in a battery of breast cancer cell lines. These data confirm that c-Myc overexpression is a common event in breast cancer, and that this is associated with resistance to antiestrogens in vitro. Furthermore, the development of an experimental paradigm for the discovery of c-Myc and estrogen target genes associated with endocrine resistance provides a framework for the discovery and validation of genes involved in estrogen signalling, and c-Myc-mediated-antiestrogen resistance.
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PMID:c-Myc overexpression and endocrine resistance in breast cancer. 1705 4

Amplification of HER2, C-MYC and CCND1 oncogenes is a hallmark of breast cancer (BC); however, its involvement in the bilateral form of this disease has not been investigated yet. In this study, 50 bilateral BC (biBC) pairs (100 tumors) and 72 control unilateral BC were examined using real-time PCR analysis of microdissected archival tissues. In biBC, the frequency of >3-fold oncogene amplification was 6/100 (6%) for HER2, 6/100 (6%) for C-MYC and 7/100 (7%) for CCND1. Altogether, 18/100 (18%) biBC tumors had increased gene dosage of at least one oncogene. Tumors forming synchronous biBC pairs had amplification in 11/46 cases (24%). In 3 of 8 patients with amplification-positive carcinomas, the amplification was detected in both neoplasms: 2 biBC had concordant activation of the same oncogene (HER2 and CCND1, respectively), and in the remaining case distinct oncogenes were affected (HER2 and C-MYC). In contrast, amplifications in metachronous biBC were strongly discordant: none of 27 first carcinomas carried this abnormality, while the frequency of amplification in second tumors (7/27; 26%) was similar to the one observed in unilateral BC (20/72; 28%). The trend toward concordance of oncogene amplification status in synchronous but not in metachronous biBC pairs can be explained by the nearly identical natural history of the disease in simultaneously arising tumors. The skewed pattern of amplifications in metachronous biBC might be attributed to their association with adverse BC prognosis; it appears that only patients with amplification-negative first BC have sufficient chances to survive until the development of the contralateral carcinoma.
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PMID:Nonrandom distribution of oncogene amplifications in bilateral breast carcinomas: Possible role of host factors and survival bias. 1706 26


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