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)

To investigate whether estrogen treatment of hormone-responsive human breast cancer cells was associated with activation of members of the jun family of immediate early response genes, the expression of these oncogenes in human breast cancer cells was examined. 17 beta-Estradiol had little effect on expression of c-jun, jun B, jun D, or c-fos mRNA by MCF-7 cells over 12 h, although it stimulated c-myc expression 4-fold within 30 min. In contrast, several peptide growth factors, including transforming growth factor-alpha (TGF-alpha), rapidly and transiently induced expression of c-jun, jun B, and c-fos mRNA 4- to 10-fold over control. A similar pattern of expression was seen in two other estrogen-responsive human breast cancer cell lines, ZR-75-1 and T47D. Inhibition of protein synthesis by cycloheximide did not abrogate induction of c-jun or jun B mRNA by TGF-alpha in MCF-7 cells, suggesting that new protein synthesis was not required. In addition, nuclear runoff transcription analysis demonstrated that increased expression of c-jun and jun B mRNA after TGF-alpha treatment of MCF-7 cells was regulated at least in part at the transcriptional level. Chronic exposure of MCF-7 cells to 17 beta-estradiol for 24-48 h was associated with decreased expression of jun B mRNA only, while similar treatment with TGF-alpha did not change mRNA expression of any jun family member. Thus, expression of jun family members is induced by peptide growth factors like TGF-alpha but not 17 beta-estradiol in human breast cancer cells. These results suggest that these nuclear protooncogenes play different roles in modulating gene expression by MCF-7 cells after exposure to TGF-alpha or 17 beta-estradiol.
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PMID:Induction of jun gene family members by transforming growth factor alpha but not 17 beta-estradiol in human breast cancer cells. 841 22

In order to assess the specificity of biotinylated anti-c-erbB-3 antibody, screening was performed on a series of tumour cell lines and lymphocytes. Staining was found to be consistent, with good reproducibility. Twenty-nine consecutive breast cancer samples were obtained from women treated with tamoxifen and undergoing elective mastectomy. Twenty-eight invasive ductal carcinomas and 1 DCIS were stained for c-erbB-3 expression: 2 were grade I (Bloom and Richardson), 15 grade II, and 11 grade III tumours, 1 being unclassified; 16 were axillary node positive and 10 node negative; in 2 cases no nodes were sampled. Tumours examined by flow cytometry were stained with cytokeratin FITC antibody and the cytokeratin-positive population gated. Using Mann-Whitney analysis no association was seen between c-erbB-3 expression and Bloom and Richardson grade or axillary node status. In the tumour samples c-erbB-3 expression was found to show as association with EGF-R (P = 0.021 r2 = 0.16), PgR (P = 0.02, r2 = 0.16), c-myc (P < 0.0001, r2 = 0.5), c-jun (P = 0.001, r2 = 0.4) and c-fos (P = 0.001, r2 = 0.5) but not with c-erbB-2 (P = 0.2, r2 = 0.06), ER (P = 0.4, r2 = 0.02) or p53 1801 (P = 0.05, r2 = 0.2). Expression of c-erbB-3 may not be an independent marker of prognosis, but it is associated with other markers of poor prognosis and early cellular events linked with aberrant growth and differentiation.
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PMID:A flow cytometric study of c-erbB-3 expression in breast cancer. 853 73

The use of the antiestrogen tamoxifen for breast cancer management, although generally well tolerated, is linked to an increase in uterine pathologies in a high number of postmenopausal women receiving the drug. This effect is thought to be due to estrogenic stimulation of the uterine endometrium by the antiestrogen; however, the molecular mechanism underlying the uterotrophic activity of tamoxifen and the uterine cellular compartments that respond to the drug have not been clearly established. In this study, we determined which of the several uterine tissues (myometrium, stroma, and luminal and glandular epithelium) demonstrated chronic overexpression of c-fos and the jun proto-oncogenes in response to tamoxifen. Uteri from tamoxifen-treated, castrated rats were examined histologically, and cell type-specific expression of c-fos, c-jun, jun-B, and jun-D was assessed using in situ hybridization. Treatment with tamoxifen resulted in uterine luminal and glandular epithelial hypertrophy and basally located nuclei by 36 h. Extreme uterine glandular and luminal epithelial cell hypertrophy persisted 7 days after administration of the drug. Expression of c-fos and jun-B messenger RNA was first detected in the luminal and glandular epithelial at 12-36 h post tamoxifen injection. Seven days after tamoxifen treatment, c-fos and jun-B messenger RNA levels were lower but still evident in the uterine endometrial epithelium. Tamoxifen completely repressed constitutive expression of c-jun in the uterine luminal epithelial cells by 12 h but, unlike estrogen, did not induce c-jun expression in the uterine myometrium. Expression of jun-D in the uterine glandular and luminal epithelia was observed at 12 h but not at 24 h post tamoxifen. These results support our working hypothesis that persistent overexpression of cellular oncogenes c-fos and jun-B in the uterine endometrial epithelium may contribute to the molecular mechanism underlying the uterine toxicity associated with chronic tamoxifen treatment.
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PMID:Tamoxifen-induced proto-oncogene expression persists in uterine endometrial epithelium. 853 16

HMG-CoA reductase inhibitors, such as Lovastatin and Simvastatin, cause cell cycle arrest by interfering with the mitogenic activity of mitogens present in culture media. Cells are induced to pause in G1 and can readily resume growth upon removal of the enzymatic block. Estrogens, acting via their nuclear receptor, are mitogens for different normal and transformed cell types, where they foster cell cycle progression and cell division. In estrogen-responsive MCF-7 human breast cancer cells, but not in non responsive cells, 17 beta-estradiol (E2) induces cells arrested with Lovastatin or Simvastatin to proliferate in the presence of inhibitor, without restoring HMG-CoA reductase activity or affecting the protein prenylation pattern. Mitogenic stimulation of G1-arrested MCF-7 cells with E2 includes primary transcriptional activation of c-fos, accompanied by transient binding in vivo of the estrogen receptor and/or other factors to the ERE and the estrogen-responsive DNA region of this proto-oncogene, as detected by dimethylsulphate genomic footprinting analysis. Mitogenic stimulation of growth-arrested MCF-7 cells by E2 occurs, under these conditions, without evident activation of ERK-1 and -2 kinases, and thus independently from the mitogen-responsive signal transduction pathways that converge on these enzymes.
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PMID:17 beta-Estradiol overcomes a G1 block induced by HMG-CoA reductase inhibitors and fosters cell cycle progression without inducing ERK-1 and -2 MAP kinases activation. 863 97

The c-fos proto-oncogene has been implicated as a regulator of estrogen-mediated cell proliferation. We have tested the tissue specificity and antitumor efficacy of a mouse mammary tumor virus-regulated antisense c-fos retroviral vector. Systemically administered vector could be detected in several tissues but was only expressed in breast epithelium, thus supporting targeting to mouse mammary tumor virus-regulated tissues. Ex vivo transduction of 30-70% of MCF-7 human breast cancer cells produced expression of antifos RNA, decreased expression of the c-fos target mRNA, induction of differentiation, and inhibition of s.c. tumor growth and invasiveness. In vivo transduction of established i.p. MCF-7 tumors with a single injection of XM6:antifos inhibited tumor growth in athymic mice with a corresponding inhibition of c-fos, transforming growth factor beta1 and transforming growth factor alpha expression. Four daily injections with the antifos RNA induced a much larger MCF-7 i.p. tumor inhibition, with a marked prolongation of survival in the absence of any host tissue toxicity. These results indicate that inhibition of key nuclear genes such as c-fos may lead to disruption of paracrine factors and an antitumor effect, providing a strategy for cancer gene therapy.
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PMID:Tissue-targeted antisense c-fos retroviral vector inhibits established breast cancer xenografts in nude mice. 864 Jul 67

Insulin stimulated proliferation of MCF-7 human breast cancer cells in serum-free medium, whereas 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and 2,3,7,8-tetrachlorodibenzofuran (TCDF) did not affect cell growth. In cells cotreated with insulin plus TCDD or TCDF, insulin-induced cell proliferation and [3H]thymidine incorporation were inhibited. In contrast, alpha-naphthoflavone, a partial aryl hydrocarbon (Ah) receptor antagonist, blocked the inhibitory effects of TCDD, suggesting that the Ah receptor was involved in TCDD-induced responses in MCF-7 cells. TCDD alone did not affect Kd and Bmax values for binding of [125I]insulin to the insulin receptor (IR); however, in MCF-7 cells cotreated with insulin plus TCDD, the insulin-induced Kd value for IR-ligand binding was decreased and the Bmax value was increased. TCDD induced IR mRNA levels and inhibited several other insulin-induced responses including c-fos protooncogene expression, phosphorylation of the insulin receptor, and a 185-kDa protein in MCF-7 cells.
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PMID:Effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on insulin-induced responses in MCF-7 human breast cancer cells. 865 25

Breast cancer vasoactive intestinal peptide (VIP) receptors were characterized. Using in vitro autoradiographic techniques, 125I-labeled VIP bound with high affinity to breast biopsy sections. 125I-labeled VIP bound specifically to give breast cancer cell lines examined using receptor-binding techniques. Specific 125I-labeled VIP binding to MDA-MB-231 cells was inhibited with high affinity by VIP and pituitary adenylate cyclase-activating polypeptide (IC50, = 2 nM) and with moderate affinity by the VIP hybrid (IC50 = 0.5 microM). VIP elevated the cAMP in a dose-dependent manner, and VIP hybrid (10 microM) inhibited the increase in cAMP caused by VIP. Using Northern blot analysis, VIP (10 nM) stimulated c-fos and c-myc mRNA, and the increase caused by VIP was reversed by the VIP hybrid. The VIP hybrid inhibited breast cancer growth in vitro and in vivo using nude mice bearing breast cancer xenografts. These data suggest that the VIP hybrid is a breast cancer VIP receptor antagonist.
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PMID:Breast cancer growth is inhibited by vasoactive intestinal peptide (VIP) hybrid, a synthetic VIP receptor antagonist. 875 16

In human breast cancer cell lines, an inverse relationship exists between the basal levels of oestrogen receptor (ER) and epidermal growth factor receptor (EGF-R) gene expression. In addition, the tumour-promoting phorbol ester 12-O-tetradecanoyl-phorbol-13-acetate (TPA) inhibits ER and stimulates EGF-R expression in MCF-7 breast cancer cells. This study aimed to define further the potential mechanisms involved in the modulation of ER and EGF-R gene expression by TPA. ER mRNA levels were reduced after 3 h and declined to 30% of control between 12 and 72 h after exposure to 10 nM TPA. This decrease in mRNA levels was preceded by an apparent fall in ER transcription rate. There was no effect on the stability of ER mRNA following pretreatment for 3-24 h with TPA, supporting the conclusion that the fall in ER mRNA levels was predominantly due to a decrease in ER transcription rate. Levels of EGF-R mRNA increased 10-fold by 12 h due predominantly to an increased transcription rate. The TPA-induced decrease in ER mRNA was unaffected by the simultaneous administration of the protein synthesis inhibitor cycloheximide, whereas the increase in EGF-R mRNA was inhibited by co-incubation with cycloheximide. These data indicate a requirement for continuing protein synthesis for the TPA effect on EGF-R but not on ER mRNA levels. Because the modulation of ER and EGF-R gene expression by TPA is likely to involve the protein kinase C (PKC) signal transduction pathway, the effects of other known activators of PKC were investigated. The non-phorboid tumour promoter mezerein modulated ER (an 80% decrease) and EGF-R (a 20-fold increase) mRNA levels in a similar manner to TPA. In contrast, neither 1,2-dioctanoyl-sn-glycerol (DiC8) nor 1-oleoyl-2-acetyl-sn-glycerol (OAG), both permeant analogues of the endogenous physiological activators of PKC, affected ER and EGF-R mRNA levels. These latter results were not due to a lack of efficacy because a single administration of DiC8 was as effective as TPA in inducing c-fos mRNA at 30 min. However DiC8 was less active in the later induction of c-myc mRNA. These data demonstrate reciprocal regulation of ER and EGF-R gene expression by TPA, involving effects on transcriptional events, which appear to be mediated by sustained activation of PKC.
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PMID:Inverse regulation of oestrogen receptor and epidermal growth factor receptor gene expression in MCF-7 breast cancer cells treated with phorbol ester. 883 62

1,25 Dihydroxyvitamin D3 (1,25-(OH)2D3) and a number of synthetic vitamin D3 analogues with low calcaemic activity, have been shown to inhibit breast cancer cell growth in vitro as well as in vivo. The purpose of the present study was to investigate a possible interaction of 1,25-(OH)2D3 and the vitamin D3 analogue EB1089 with the insulin-IGF-I regulatory system. The oestrogen receptor-positive MCF-7 human breast cancer cells used in this study are able to grow autonomously and their growth is stimulated by insulin. In order to avoid interference of IGF-binding proteins (IGF-BPs), we used an analogue of IGF-I, long R3 IGF-I, which stimulated MCF-7 cell growth similar to insulin. The growth stimulation by insulin and by long R3 IGF-I was completely inhibited by 1,25-(OH)2D3 and EB1089. Autonomous growth was also inhibited by 1,25-(OH)2D3 and EB1089. The analogue EB1089 was active at 50 times lower concentrations than 1,25-(OH)2D3. It was shown that growth inhibition was not achieved through downregulation of insulin and IGF-I binding after 48 h. Paradoxically, after prolonged treatment (8 days), an upregulation of insulin and IGF-I binding was observed. Two possible intracellular mediators of the insulin-IGF mitogenic signal are C-FOS and mitogen-activated protein (MAP) kinase. Insulin-induced C-FOS mRNA was inhibited by 1,25-(OH)2D3, suggesting that it could be involved in the growth inhibition by 1,25-(OH)2D3. MAP kinase activation appeared not to be involved in growth stimulation by both insulin and IGF-I. Together, the present study demonstrates that vitamin D3 compounds can block the mitogenic activity of insulin and IGF-I, which may contribute to their tumour suppressive activity observed in vivo.
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PMID:Inhibition of insulin- and insulin-like growth factor-I-stimulated growth of human breast cancer cells by 1,25-dihydroxyvitamin D3 and the vitamin D3 analogue EB1089. 908 64

Breast cancer cells (BCC) have calcitonin (CT) receptors, yet the action of the hormone on these cells is largely unknown. We found that CT produced a strong and transient time- and dose-dependent increase in c-fos mRNA in BCC lines. This event was prevented by a protein kinase A (PKA) inhibitor, H89. CT alone did not influence the expression of c-jun and of the tissue inhibitors of metalloproteases (timp) -1 and -2 mRNAs; however, it reduced the induction of these mRNAs by the protein kinase C (PKC) activator phorbol 12-myristate 13-acetate (PMA), without apparent changes in the half-life of the mRNA (measured for c-jun). Along the same line, CT reduced the c-jun induction and T-47D growth stimulation by epidermal growth factor (EGF) and insulin. These effects were mimicked by forskolin and/or prevented by H89, suggesting that PKA activation was involved. These results indicate that CT modulates in BCC the mRNA levels of two important growth-related early response genes (c-fos and c-jun) and of two other genes (timp-1 and -2) involved in the control of metastatic events.
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PMID:Regulation of c-fos and c-jun expression by calcitonin in human breast cancer cells. 916 25


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