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)

c-Myc is a nuclear protein with important roles in cell transformation, cell proliferation, and gene transcription. It has been previously shown that a 14-amino acid (aa) modified peptide (H1-S6A,F8A) derived from the helix 1 (H1) carboxylic region of c-Myc can interfere in vitro with specific c-Myc DNA binding. Here, we have linked the above Myc-derived 14-aa peptide to a 16-aa sequence from the third helix of Antennapedia (Int). It has been repeatedly reported that this 16-aa Antennapedia peptide is able to cross mammalian cell membranes and to work as a vector for short peptides. Using fluorescent (dansylated or rhodaminated) peptides, we have shown that the fusion peptide with the Antennapedia fragment (Int-H1-S6A,F8A) but not the c-Myc derived fragment alone (H1-S6A,F8A) was capable of internalization inside MCF-7 human breast cancer cells. Int-H1-S6A,F8A and H1-S6A,F8A were the only two peptides capable of inhibiting coimmunoprecipitation of the c-Myc/Max heterodimer in vitro. We have treated (continuously for 10-11 days) MCF-7 cells with four different peptides: Int, H1-S6A,F8A, Int-H1-S6A,F8A, and Int-H1wt [a peptide differing from Int-H1-S6A,F8A by 2 aa (S6 and F8) in the H1 region]. In intact MCF-7 cells, Int-H1-S6A,F8A was the only active peptide capable of inducing the following biological effects: (a) inhibition of cloning efficiency on plates; (b) inhibition of cell growth and induction of apoptosis in subconfluent/confluent cells; and (c) inhibition of transcription of two c-Myc-regulated genes (ODC and p53). Int-H1-S6A,F8A was active in the 1-10 microM range. Int-H1-S6A,F8A may represent a lead molecule for peptidomimetic compounds that have a similar three-dimensional structure but are more resistant to peptidases and, therefore, suitable for in vivo treatment of experimentally induced tumors.
 ...
PMID:Inhibition of cancer cell growth and c-Myc transcriptional activity by a c-Myc helix 1-type peptide fused to an internalization sequence. 972 75

The molecular signaling events involved in the inhibition of breast cancer cell growth by retinoic acid and interferon-alpha were investigated. All-trans-retinoic acid and interferon-alpha acted synergistically to inhibit growth of both the estrogen receptor-positive breast cancer cell line MCF-7 and the estrogen receptor-negative line BT-20. In MCF-7 cells, all-trans-retinoic acid potentiated the effects of interferon-alpha by up-regulating the expression of the RNA-dependent protein kinase (PKR). Consequently, the synergism between all-trans-retinoic acid and interferon-alpha down-regulated the expression of c-Myc, but not its functional partner, Max. Transfection of MCF-7 cells with a dominant-negative mutant of PKR relieved c-Myc down-regulation and cell growth inhibition, indicating that PKR is directly involved in c-Myc down-regulation and that c-Myc down-regulation is responsible for the inhibition of cell growth. Corresponding with c-Myc down-regulation, c-Myc.Max heterodimers bound to their consensus DNA sequence were undetectable in cells treated with all-trans-retinoic acid and interferon-alpha, indicating diminished c-Myc functionality. When c-Myc was overexpressed ectopically via a c-Myc expression vector, MCF-7 cells became resistant to growth inhibition by all-trans-retinoic acid plus interferon-alpha. These experiments define the following pathway as a major pathway in the synergistic growth inhibition of MCF-7 cells by all-trans-retinoic acid plus interferon-alpha: all-trans-retinoic acid + interferon-alpha --> upward arrow double-stranded RNA-dependent protein kinase --> downward arrow c-Myc --> cell growth inhibition.
 ...
PMID:c-Myc is a major mediator of the synergistic growth inhibitory effects of retinoic acid and interferon in breast cancer cells. 980 32

Loss of p53 function by mutational inactivation is the most common marker of the cancerous phenotype. Previous studies from our laboratory have demonstrated 17 beta estradiol (E2) induction of p53 protein expression in breast cancer cells. Although direct effects of E2 on the expression of p53 gene are not known, the steroid is a potent regulator of c-Myc transcription. In the present studies, we have examined the ability of E2 and antiestrogens to regulate the P1 promoter of the p53 gene which contains a c-Myc responsive element. Estrogen receptor (ER)-positive T47D and MCF-7 cells were transiently transfected with the P1CAT reporter plasmid and levels of CAT activity in response to serum, E2 and antiestrogens were monitored. Factors in serum were noted to be the dominant inducers of chloramphenicol acetyltransferase (CAT) expression in MCF-7 cells. The levels of CAT were drastically reduced when cells were maintained in serum free medium (SFM). However, a subtle ER-mediated induction of CAT expression was detectable when MCF-7 cells, cultured in SFM, were treated with E2. In serum-stimulated T47D cells, the CAT expression was minimal. The full ER antagonist, ICI 182 780 (ICI) had no effect. Treatment with E2 or 4-hydroxy tamoxifen (OHT) resulted in P1CAT induction; OHT was more effective than E2. Consistent with c-Myc regulation of the P1 promoter, E2 stimulated endogenous c-Myc in both cell lines. Two forms of c-Myc were expressed independent of E2 stimuli. The expression of a third more rapidly migrating form was E2-dependent and ER-mediated since it was blocked by the full ER antagonist, ICI, but not by the ER agonist/antagonist OHT. These data demonstrate both ER-mediated and ER-independent regulation of c-Myc and the P1 promoter of the p53 gene, and show differential effects of the two classes of antiestrogens in their ability to induce the P1 promoter of the p53 gene in breast cancer cells.
 ...
PMID:Estrogen-dependent and independent activation of the P1 promoter of the p53 gene in transiently transfected breast cancer cells. 1002 83

The c-Myc oncoprotein is a transcription factor involved in cellular transformation. We previously found (M. V. Blagosklonny, et al., Cancer Res., 57: 320-325, 1997) that exposure of human SkBr3 breast cancer and LNCaP prostate cancer cells to 12-O-tetradecanoylphorbol-13-acetate (TPA) led to a growth arrest associated with the up-regulation of the cyclin-dependent kinase inhibitor p21(WAF1/cIP1) and the inhibition of c-Myc expression. We show here that exogenous c-Myc inhibits p21 expression in SkBr3 and LNCaP cells induced to enter into S-phase. p27 expression was not increased from basal levels in TPA-treated growth-arrested cells. A time course after infection of TPA-arrested cells using a c-Myc-expressing adenovirus revealed that the inhibition of p21 expression preceded entry into S-phase. In contrast, after infection by E2F-1-expressing adenovirus, p21 expression was reduced after the cells entered S-phase. Overexpression of c-Myc reduced the levels of endogenous p21 mRNA, and transfection of c-Myc repressed p21-promoter luciferase-reporter gene expression. The results suggest that the down-regulation of p21 expression may contribute to c-Myc-dependent entry into S-phase, possibly in situations in which growth arrest is associated with increased p21 expression.
 ...
PMID:Overexpression of c-Myc inhibits p21WAF1/CIP1 expression and induces S-phase entry in 12-O-tetradecanoylphorbol-13-acetate (TPA)-sensitive human cancer cells. 1031 92

The overexpression of Bcl-2, an anti-apoptotic oncogene, identifies human T1 breast cancer patients who have an increased risk of lymph-node metastasis. We examined in these patients (n = 142) whether the c-Myc oncogene influences metastatic progression in conjunction or not with Bcl-2 expression and the loss of apoptosis in tumors. The association between Bcl-2 and lymph-node metastasis was only significant when c-Myc was concomitantly expressed (chi2 test, p = 0.008). Moreover, very large associations (pOR = 6.4) between c-Myc and lymph-node metastasis were observed among Bcl-2 positive tumors and tumors with loss of apoptosis (pOR = 8.4). In contrast, the metastatic advantage linked to Bcl-2 was decreased (pOR = 2) when c-Myc was not coexpressed. It is concluded that the synergism between Bcl-2 and c-Myc oncogenes may promote metastasis in breast tumors, linked to loss of apoptosis.
Breast Cancer Res Treat 1999 Mar
PMID:Synergistic cooperation between c-Myc and Bcl-2 in lymph node progression of T1 human breast carcinomas. 1036 79

Estrogen receptor (ER)-negative breast carcinomas are often difficult to treat as they do not respond to hormone therapy. In an attempt to determine if expressing the human estrogen receptor in an ectopic manner could restore the hormone responsiveness of these cells, we have expressed the human ER in ER-negative MDA-MB 231 breast cancer cells using a recombinant adenovirus gene delivery system that allows high level expression of ER in essentially all cells. In these cells, the ER was correctly translated, had a wild type hormone binding affinity (Kd = 0.6 nM), bound well to estrogen response element-containing DNA, and showed an activation pattern of estrogen response element-reporter gene activity by estrogen and antiestrogens very similar to that observed in MCF-7 breast cancer cells containing endogenous ER (stimulation by estrogen, no stimulation by the antiestrogens trans-hydroxytamoxifen or ICI 164384, and blockade of estradiol stimulation by trans-hydroxytamoxifen or ICI 164384). Intriguingly, estradiol stimulation of these cells was also able to induce expression of pS2, an estrogen regulated gene considered to be a favorable prognostic marker for endocrine therapy in ER-positive breast cancer cells. Expression of the ER had no effect by itself on the proliferation rate of MDA-MB 231 cells. However, treatment of the ER-containing cells with estradiol or with the pure antiestrogen ICI 164 384 suppressed proliferation of the cells while the antiestrogen trans-hydroxytamoxifen had little effect on proliferation; and cotreatment with trans-hydroxytamoxifen reversed the estradiol- or ICI 164 384-evoked suppression of proliferation. To understand the mechanism underlying the inhibition of proliferation by estradiol, we examined the expression of several growth related endogenous genes. c-Myc protooncogene expression was strongly inhibited by treatment with estradiol as was expression of BRCA1 and BRCA2 genes, which is in agreement with their mitogenic-dependent expression, while expression of beta-actin, a housekeeping gene, was not affected by hormone treatment. Together, these data suggest that reexpressing the human ER in breast cancer cells that no longer express this protein renders them sensitive to hormone treatment. The ability of the antiestrogen ICI 164 384 to suppress the proliferation of ER-negative breast cancer cells that reexpress ER might be useful ultimately as an endocrine gene therapy approach for controlling the growth of ER-negative breast cancer cells. The application of recombinant adenoviruses expressing the human ER presents interesting features which might be used as a basis for designing more powerful and effective treatments for ER-negative breast cancers.
 ...
PMID:Expression of human estrogen receptor using an efficient adenoviral gene delivery system is able to restore hormone-dependent features to estrogen receptor-negative breast carcinoma cells. 1037 22

USF is a family of transcription factors that are structurally related to the Myc oncoproteins and also share with Myc a common DNA-binding specificity. USF overexpression can prevent c-Myc-dependent cellular transformation and also inhibit the proliferation of certain transformed cells. These antiproliferative activities suggest that USF inactivation could be implicated in carcinogenesis. To explore this possibility, we compared the activities of the ubiquitous USF1 and USF2 proteins in several cell lines derived from either normal breast epithelium or breast tumors. The DNA-binding activities of USF1 and USF2 were present at similar levels in all cell lines. In the non-tumorigenic MCF-10A cells, USF in general, and USF2 in particular, exhibited strong transcriptional activities. In contrast, USF1 and USF2 were completely inactive in three out of six transformed breast cell lines investigated, while the other three transformed cell lines exhibited loss of USF2 activity. Analyses in cells cultured from healthy tissue confirmed the transcriptional activity of USF in normal human mammary epithelial cells. These results demonstrate that a partial or complete loss of USF function is a common event in breast cancer cell lines, perhaps because, like Myc overexpression, it favors rapid proliferation.
 ...
PMID:Loss of USF transcriptional activity in breast cancer cell lines. 1052 35

BRCA1 was the first breast cancer susceptibility gene to be identified and cloned. In individuals from high-risk families, mutations in BRCA1 increase the lifetime risk of developing breast cancer eight to tenfold, compared to the general population. How the BRCA1 protein product normally functions to suppress tumor formation and how defects in the gene can ultimately lead to breast cancer have been the focus of intense scrutiny by the scientific and medical communities. BRCA1 has intrinsic transactivation activity and is able to activate the p21 promoter. In addition, BRCA1 is linked to a number of genes involved in transcriptional regulation, including CtIP, c-Myc, the RNA holoenzyme complex, and the histone deacetylase complex. Moreover, BRCA1 is essential for cellular response to DNA damage repair. Inactivation of Brca1 in mouse embryonic stem and fibroblast cells results in increased cell sensitivity to DNA-damaging agents. In human cells, BRCA1 binds to both Rad50 and Rad51 and colocalizes with these proteins at repair foci. Part of BRCA1's response to DNA damage may in fact be corroborated through transcriptional regulation. The expression of GADD45, a DNA damage-responsive gene, is increased immediately after induction of BRCA1. Recently, BRCA1 was shown to repress estradiol (E2)-responsive ER-alpha-mediated transcriptional activity, potentially linking the multiple functions of BRCA1 to specific tissue targets. These recent developments in BRCA1 function are an encouraging step toward understanding the role of BRCA1 in breast cancer formation.
 ...
PMID:Emerging roles of BRCA1 in transcriptional regulation and DNA repair. 1052 24

We have studied the expression of ornithine decarboxylase (ODC) mRNA by in situ hybridization and in situ RT-PCR in human breast cancer MCF-7 cell line. In situ RT-PCR demonstrated the overexpression of ODC mRNA, localized over the cytoplasm, while a very low signal was detected by in situ hybridization. Our findings indicate that in situ RT-PCR could represent a useful tool to study different levels of ODC expression in normal and tumor tissues. Since ODC expression is regulated by c-Myc oncoprotein, this model could be useful to monitor in vivo the effects of new anti-neoplastic molecules, specific inhibitors of c-Myc.
 ...
PMID:Detection of ornithine decarboxylase mRNA in human breast cancer MCF-7 cells by in situ RT-PCR. 1063 65

We have examined whether the extended life span of cells induced by Bcl-2 in T(1) ductal breast carcinomas might favor the acquisition and accumulation of genetic alterations that induce lymph node metastases. We analyzed the expression of c-Myc, c-erbB-2 and epidermal growth factor receptor by immuno-histochemistry in a group of 142 T(1) (<2 cm) ductal breast carcinomas embedded in paraffin, previously studied for p53 mutation and Bcl-2 over-expression. We also measured the apoptotic status and estimated the excess risk (pOR) for lymph node metastasis according to the number of accumulated oncogene alterations and Bcl-2 and p53 expression. The linear relationship between number of oncogene alterations and presence of lymph node metastasis was statistically significant in Bcl-2-positive tumors (trend test, p = 0.03), p53-mutated tumors (trend test, p = 0.08) and tumors with loss of apoptosis (trend test, p = 0.08). Very large associations (pOR > 12) between the number of oncogene alterations and lymph node metastasis were observed among Bcl-2-positive tumors that showed increased loss of apoptosis (trend test, p = 0.03). Furthermore, in p53-negative tumors, a strong linear association was found between the number of oncogene alterations and risk of lymph node metastasis among Bcl-2-positive tumors (trend test, p = 0.03). In human T(1) ductal breast carcinoma, over-expression of Bcl-2 along with loss of apoptosis might render breast cancer cells susceptible to the acquisition of additional genetic lesions related to disease progression among p53-negative tumors. Thus, in breast cancer, there are at least 2 pathways to progression: Bcl-2- and p53-dependent mechanisms.
 ...
PMID:Bcl-2 with loss of apoptosis allows accumulation of genetic alterations: a pathway to metastatic progression in human breast cancer. 1075 91


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