Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0178874 (tumor progression)
40,807 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Although several lines of epidemiological evidence suggest that estrogen exposure influences the incidence of breast cancer development, the mechanisms by which estrogen may stimulate the formation of breast cancer remain poorly understood. We have explored how alterations in estrogen exposure can influence the development of mammary cancer in the C3(1)/T(AG) transgenic model, where estrogen levels and estrogen receptor alpha (ERalpha) expression do not appear to modify the level of transgene expression. The C3(1)/T(AG) transgene becomes transcriptionally active in mammary ductal target cells at 3 weeks of age after the estrogen-induced differentiation of the mammary epithelial anlage to the ductal outgrowth stage. Complete maturation of the mammary ductal tree, however, is not required for cancer development because tumors arise in animals where ductal branching and terminal end bud formation have been prematurely arrested by ovariectomy. Mammary tumorigenesis in this model is promoted by increased estrogen exposure with the development of significantly more mammary intraepithelial neoplastic lesions and carcinomas associated with accelerated malignant conversion. The promotion of mammary tumors in this model appears to occur through an estrogen-induced proliferation and increase in the number of available target cells for transformation at the terminal ductal lobular units, as has been postulated to occur in women who receive hormone replacement therapy and/or by additional molecular mechanisms. We show, for the first time in a transgenic mouse model, that mammary tumor progression is associated with the loss of ERalpha expression, as has been often observed in human breast cancers with important clinical significance. Estrogen signaling may, therefore, serve different functions, depending upon the stage of tumorigenesis. ERbeta expression is up-regulated during tumor progression, although the functional significance of this remains to be determined.
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PMID:Estrogen promotes mammary tumor development in C3(1)/SV40 large T-antigen transgenic mice: paradoxical loss of estrogen receptoralpha expression during tumor progression. 1115 89

Disturbance in expression of estrogen receptors together with changing influence of growth factor receptors and apoptosis associated proteins plays a role in breast cancer development and progression. However, immunohistochemical detection and relationships among these proteins were not often considered in relation to breast cancer and a few evaluations of expression provided mismatching results and conclusions. Consequently, we examined by immunohistochemistry the expression of the insulin-like growth factor-I receptor (IGF-IR), estrogen receptor alpha (ERalpha) and apoptosis-associated proteins, Bcl-2 and Bax, in human primary breast cancer, as well as analyzing the relationships among these proteins. The positive immunostaining for IGF-IR, ERalpha, Bcl-2 and Bax was noted in 56, 63.8, 82.8 and 50% of tumors, respectively. We observed that IGF-IR negatively correlated with ERalpha in the group of all tumors and in axillary node negative cancer (p<0.03, p<0.05, respectively), but not in the subgroup of node positive cancer. Expression of ERalpha correlated positively with Bcl-2 and negatively with Bax proteins (p<0.0001, p<0.05, respectively). We did not note significant relationships between IGF-IR and Bcl-2, or IGF-IR and Bax proteins. We found that increased Bax expression was associated with positive lymph node status, pT2 stage and G3 grade of tumors. Knowledge about alterations in the IGF-IR expression and relations of the receptor to other biological factors could help in our understanding of breast cancer biology and the importance of the IGF-IR in cancer progression as well as in effective management of breast cancer.
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PMID:Expression of insulin-like growth factor-I receptor, estrogen receptor alpha, Bcl-2 and Bax proteins in human breast cancer. 1594 74

Sex steroid hormone signaling regulates the development, growth, and functioning of the breast and the prostate and plays a role in the development and progression of cancer in these organs. The intracellular concentration of active sex steroid hormones in target tissues is regulated by several enzymes, including 17beta-hydroxysteroid dehydrogenases (17HSDs). Changes in the expression patterns of these enzymes may play a pathophysiological role in malignant transformation. We recently analyzed the mRNA expressions of the 17HSD type 1, 2, and 5 enzymes in about 800 breast carcinoma specimens. Both 17HSD type 1 and 2 mRNAs were detected in normal breast tissue from premenopausal women but not in specimens from postmenopausal women. The patients with tumors expressing 17HSD type 1 mRNA or protein had significantly shorter overall and disease-free survival than the other patients. The expression of 17HSD type 5 was significantly higher in breast tumor specimens than in normal tissue. Cox multivariate analyses showed that 17HSD type 1, tumor size, and estrogen receptor alpha (ERalpha) had independent prognostic significance. We developed, using a LNCaP prostate cancer cell line, a model to study the malignant transformation of prostate cancer and showed that androgen-sensitive LNCaP cells are transformed into neuroendocrine-like cells when cultured without androgens and, eventually into highly proliferating androgen-independent cells. We conducted Northern hybridizations and microarrays to analyze the gene expression during these processes. Substantial changes in the expressions of steroid metabolizing enzymes occurred during the transformation process. The variations in steroid-metabolizing enzymes during cancer progression may be crucial in the regulation of the growth and function of organs.
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PMID:Control of cell proliferation by steroids: the role of 17HSDs. 1640 64

The role of estrogen receptor alpha (ER-alpha) in melanoma is unknown. ER-alpha expression may be regulated in melanoma via hypermethylation of promoter CpG islands. We assessed ER-alpha hypermethylation in primary and metastatic melanomas and sera as a potential tumor progression marker. ER-alpha methylation status in tumor (n = 107) and sera (n = 109) from American Joint Committee on Cancer (AJCC) stage I to IV melanoma patients was examined by methylation-specific PCR. The clinical significance of serum methylated ER-alpha was assessed among AJCC stage IV melanoma patients receiving biochemotherapy with tamoxifen. Rates of ER-alpha methylation in AJCC stage I, II, and III primary melanomas were 36% (4 of 11), 26% (5 of 19), and 35% (8 of 23), respectively. Methylated ER-alpha was detected in 42% (8 of 19) of stage III and 86% (30 of 35) of stage IV metastatic melanomas. ER-alpha was methylated more frequently in metastatic than primary melanomas (P = 0.0003). Of 109 melanoma patients' sera in AJCC stage I, II, III, and IV, methylated ER-alpha was detected in 10% (2 of 20), 15% (3 of 20), 26% (5 of 19), and 32% (16 of 50), respectively. Serum methylated ER-alpha was detected more frequently in advanced than localized melanomas (P = 0.03) and was the only factor predicting progression-free [risk ratio (RR), 2.64; 95% confidence interval (95% CI), 1.36-5.13; P = 0.004] and overall survival (RR, 2.31; 95% CI, 1.41-5.58; P = 0.003) in biochemotherapy patients. Hypermethylated ER-alpha is a significant factor in melanoma progression. Serum methylated ER-alpha is an unfavorable prognostic factor.
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PMID:Estrogen receptor-alpha methylation predicts melanoma progression. 1681 43

Clinical trials and laboratory-based studies indicate that the growth hormone/insulin-like growth factor-I axis may affect the development of breast cancer. The purpose of the present investigation was to develop a genetic model of mammary cancer to test the hypothesis that downregulation of GH signaling can substantially retard mammary cancer progression. We crossed the Laron mouse, in which the gene for the GH receptor/binding protein has been disrupted, with the C3(1)/TAg mouse, which develops estrogen receptor alpha negative mammary cancers. All mice used in our experiments were heterozygous for the large T antigen (TAg) and either homozygous wild-type for GHR (Ghr+/+) or null for GHR (Ghr-/-). Compared with the TAg/Ghr+/+ mice, the TAg/Ghr-/- mice showed delayed mammary cancer latency with significantly decreased multiplicity (9.8 +/- 1.4 versus 3.2 +/- 1.2) and volume (776.1 +/- 284.4 versus 50.5 +/- 8.9 mm3). Furthermore, the frequency of mammary hyperplasias was significantly reduced in the TAg/Ghr-/- mice (15.0 +/- 1.7 versus 6.8 +/- 1.7). To establish that these mammary cancers were estrogen-independent, 12-week-old TAg/Ghr+/+ mice, which lack visible hyperplasia, were either ovariectomized (ovx) or sham operated (sham). Compared with the sham group, ovariectomy resulted in no difference in the frequency of mammary hyperplasia, mammary tumor latency, incidence, multiplicity or tumor size. Together, these data demonstrate that the disruption of GH signaling significantly retards TAg-driven mammary carcinogenesis, and suggest that disrupting GH signaling may be an effective strategy to inhibit the progression of estrogen-independent breast cancer.
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PMID:Inhibition of estrogen-independent mammary carcinogenesis by disruption of growth hormone signaling. 1691 63

Studies aimed at elucidating the immunological and prognostic significance of HLA-DR expression on breast carcinoma cells have yielded contradictory results. To expand on previous studies, we have investigated the associations of tumor cell expression of HLA-DR and its related co-chaperones, invariant chain (Ii) and HLA-DM, with infiltrating inflammatory cells, in situ cytokine mRNA levels and prognosis and outcome in 112 breast carcinoma patients with a median follow-up of 59 months. While the majority of HLA-DR+ tumors co-express Ii, only a minority express HLA-DM. Tumor cell expression of HLA-DR and co-chaperones positively associated with both infiltrating CD4+ and CD8+ T-cell subsets (P < 0.01). Expression of HLA-DR and Ii associated with decreased estrogen receptor alpha levels and younger age at diagnosis, suggesting a role for hormones in the control of HLA class II expression in breast carcinoma. Patients with DR+Ii+DM- tumors had markedly decreased recurrence-free and disease-specific survival as compared with patients with DR+Ii+DM+ tumors (P < 0.05) and HLA-DR/co-chaperone expression was an independent predictor of survival by multivariate Cox regression analysis, controlling for standard prognostic indicators. Tumors that co-express HLA-DR, Ii and HLA-DM have increased levels of IFN-gamma, IL-2 and IL-12 mRNA, suggesting improved survival of patients with DR+Ii+DM+ tumors may be attributable to Th1-dominated immunity. We conclude that expression of determinants of the immune response by tumor cells may influence breast tumor progression and patient outcome.
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PMID:Tumor cell expression of HLA-DM associates with a Th1 profile and predicts improved survival in breast carcinoma patients. 1698 35

It has long been appreciated that estrogenic signaling contributes to breast cancer progression. c-Src is also required for a number of processes involved in tumor progression and metastasis. We have previously identified the K303R mutant estrogen receptor alpha (ERalpha) that confers hypersensitivity to low levels of estrogen. Because ERalpha and c-Src have been shown to interact in a number of different systems, we wanted to evaluate the role of c-Src kinase in estrogen-stimulated growth and survival of ERalpha-positive breast cancer cells. MCF-7 cells stably expressing the mutant receptor showed increased c-Src kinase activity and c-Src tyrosine phosphorylation when compared with wild-type ERalpha-expressing cells. A c-Src inhibitor, AZD0530, was used to analyze the biological effects of pharmacologically inhibiting c-Src kinase activity. MCF-7 cells showed an anchorage-dependent growth IC50 of 0.47 micromol/L, which was increased 4-fold in the presence of estrogen. In contrast, cells stably expressing the mutant ERalpha had an elevated IC50 that was only increased 1.4-fold by estrogen stimulation. The c-Src inhibitor effectively inhibited the anchorage-independent growth of both of these cells, and estrogen was able to reverse these effects. When cells were treated with suboptimal concentrations of c-Src inhibitor and tamoxifen, synergistic inhibition was observed, suggesting a cooperative interaction between c-Src and ERalpha. These data clearly show an important role for ERalpha and estrogen signaling in c-Src-mediated breast cancer cell growth and survival. Here, we show that c-Src inhibition is blocked by estrogen signaling; thus, the therapeutic use of c-Src inhibitors may require inhibition of ERalpha in estrogen-dependent breast cancer.
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PMID:Cooperative action of tamoxifen and c-Src inhibition in preventing the growth of estrogen receptor-positive human breast cancer cells. 1717 5

Although there is growing evidence that estrogens promote tumor progression in epithelial ovarian cancer, the molecular mechanisms accounting for this are still unclear. Selective estrogen receptor modulators (SERMs) mimic estrogen action in certain tissues while opposing it in others. The molecular mechanisms of the effects of SERMs such as raloxifene on the tumor progression of epithelial ovarian cancer are also still unclear. Here, we show that various genomic actions of estrogen differ from those of raloxifene in human ovarian cancer cell lines expressing estrogen receptor alpha (ERalpha). 17beta-Estradiol (E2) induced the gene expression of c-Myc and IGF-1 and increased the binding of ERalpha to the AP1 site of the promoters of c-Myc and IGF-1. ERalpha silencing abolished the E2-stimulated c-Myc expression. E2 induced the recruitment of co-activators such as SRC-1, SRC-3 and CBP to the promoters of c-Myc and IGF-1, and SRC-1 silencing abolished both the E2-stimulated c-Myc expression and cell-cycle progression. In contrast, although raloxifene increased the binding of ERalpha to the AP1 site of the promoters of c-Myc and IGF-1, raloxifene had no effect on the gene expression of c-Myc or IGF-1. Raloxifene induced the recruitment of co-repressors such as HDAC2, N-CoR and SMRT to the promoter of IGF-1. Thus, the difference between the genomic actions exerted by estrogen and raloxifene in human ovarian cancer cell lines expressing ERalpha appear to be dependent on the recruitment of co-regulators.
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PMID:Difference between genomic actions of estrogen versus raloxifene in human ovarian cancer cell lines. 1819 94

Environmental chemicals may affect human health by disrupting endocrine function. Their possible role in the mammary gland and breast tumors is still unknown. Previous studies have demonstrated that vascular endothelial growth factor (VEGF), a key factor in angiogenesis and tumor progression, is an estrogen-regulated gene. We analyzed whether VEGF expression is regulated by different xenoestrogens in several breast cancer cells, MELN (derived from MCF-7) and MELP (derived from MDA-MB-231) and stably expressing estrogen receptor alpha (ERalpha); these cell lines stably express estrogen response element (beta-globin)-luciferase. Genistein, bisphenol A (BPA), 4-(tert-octyl)phenol (OP), dieldrin, and several phthalates, including benzyl butyl phthalate (BBP) and di-ethyl-2-hexyle phthalate (DEHP), were first shown to be estrogenic. These compounds induced a dose-dependent increase of VEGF secretion in MELN and MCF-7 cells; maximal effect was observed at 1-10 microM non-cytotoxic concentrations and was inhibited by the antiestrogen ICI 182 780. VEGF increase was not observed in ERalpha-negative MDA-MB-231 cells. Most substances increased VEGF transcript levels in MELN cells. In contrast, gamma-hexachlorocyclohexane, vinclozolin, and the phthalates (mono-n-butyl ester phthalic acid, di-isononyle phthalate, and di-isodecyle phthalate) were ineffective on both VEGF secretion and estrogenic luciferase induction in these cell lines. Specific kinase inhibitors PD98059, SB203580, or LY294002 suppressed the xenoestrogen-induced VEGF response, suggesting activation of MEK, p38 kinase, and phosphatidylinositol-3-kinase pathways. Our in vitro results show for the first time that genistein and xenoestrogens (BPA, OP, dieldrin, BBP, and DEHP at high concentrations) up-regulate VEGF expression in MELN cells by an ER-dependent mechanism. Since VEGF increases capillary permeability and breast tumor angiogenesis in vivo, the physiological relevance of these findings is discussed.
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PMID:Xenoestrogens modulate vascular endothelial growth factor secretion in breast cancer cells through an estrogen receptor-dependent mechanism. 1825 63

Emerging evidence indicates that chronic inflammation plays an important role in prostate carcinogenesis. Yet to date the precise molecular and cellular mechanisms linking inflammation to carcinogenesis remains unclear. The purpose of this study was to determine the local contribution of prostate epithelial cells to the inflammatory process. We characterized the inflammatory response elicited directly by prostate epithelial cells using an in vitro culture system in which androgen-dependent LNCaP prostate cancer epithelial cells were exposed to conditioned media from LPS-activated THP-1 macrophages. Upon exposure to activated macrophage conditioned media, LNCaP cells elicited a local proinflammatory response, as evidenced by NFkappaB activation, and the production of proinflammatory cytokines TNFalpha, IL-1beta, and IL-6. Furthermore, we observed a significant upregulation of the adhesion molecule VCAM-1 and nuclear estrogen receptor alpha (ERalpha) two biomarkers that correlate with tumor immune evasion and tumor progression. Our results suggest that prostate epithelial cells may play a significant role in sustaining and amplifying the inflammation process through NFkappaB activation and local production of proinflammatory cytokines that results in the recruitment and activation of additional immune cells in the prostate. At the same time, increased expression of VCAM-1 and ERalpha in prostate epithelial cells upon exposure to inflammatory conditions highlights the potential link between chronic inflammation and its involvement in promoting prostate cancer carcinogenesis.
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PMID:Induction of proinflammatory response in prostate cancer epithelial cells by activated macrophages. 1904 Nov 75


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