Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0178874 (tumor progression)
 40,807 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Interference with autocrine or paracrine loops offers a potential means of treatment of tumors which currently lack effective therapies. Hormonally responsive breast cancers generally respond to treatment with antiestrogens but a frequent occurrence is an outgrowth of populations of tumor cells that are no longer dependent on estrogen for growth. If the acquisition of the ability to constitutively express growth factors or growth factor receptors is associated with this form of tumor progression, identification of the growth factors and their receptors having the capability of reducing the dependence on estrogen for growth is an important first step in the design of strategies aimed at interfering with their function. Experimental systems employing transfection with eukaryotic expression vectors are described that are designed to test the hypothesis that overexpression of epidermal growth factor receptor or the related protein C-ERB-B2 may confer an increased growth rate under conditions of estrogen deprivation. The transfected cells are also being used to explore the molecular mechanisms underlying the regulation of epidermal growth factor receptor expression by estrogen.
 ...
PMID:Growth factor receptors and the progression of breast cancer. 196 91

Protein tyrosine kinases have been implicated in tumor initiation and progression. Here we used Northern blotting to study expression of their genes in cultured normal melanocytes and 19 melanoma cell lines from different stages of tumor progression. We detected transcripts for 2 cytoplasmic (ABL and FES) and 6 receptor (ECK, ERB-B2, FGF-R4, IGFI-R, KDR and TIE) kinases but not for receptors RET or TRK-A. Genes for ECK, FGF-R4 and TIE were expressed ectopically in melanomas (not in normal melanocytes). Similarly, ECK protein was detected by immunoblotting in metastatic melanomas but not in normal melanocytes. ECK mRNA levels tended to increase again during late melanoma progression. ECK and TIE mRNAs were also detected in highly metastatic variant cells but not in the corresponding poorly metastatic parental lines. Conversely, FES and KDR gene expression was lost in most advanced primary and metastatic melanomas. These findings suggest positive and negative roles for specific tyrosine kinases during progression.
 ...
PMID:Abnormal protein tyrosine kinase gene expression during melanoma progression and metastasis. 781 45

Although estrogen receptor (ER)-alpha is expressed in both benign and malignant ovarian tumors, the role of ER in ovarian carcinogenesis of epithelial tumors is still unknown. In view of the recent characterization of ER-beta, a second form of ER that seems to be highly expressed in ovaries, we reexamined this issue by studying the relative expression of ER-alpha and -beta in human ovarian tumor progression. We developed a competitive PCR assay based on coamplification of the two ERs in target nucleotide sequences displaying a high homology (exons 3 and 4). Coamplification experiments with varying amounts of plasmids containing ER-alpha and -beta cDNAs showed that this assay was reliable for discriminating as little as a 2-fold difference in the initial ER-alpha:ER-beta cDNA ratio. The relative expression of ER-alpha compared with ER-beta mRNAs was studied in human ovarian cancer cell lines (n = 5) and in normal ovaries (n = 6), then in human benign and malignant tumor samples including ovarian cysts (n = 24), borderline tumors (n = 3), and cancers (n = 10). In normal ovaries, ER-beta mRNA was the predominant ER form, whereas in ovarian cancer cell lines ER-alpha mRNA was markedly increased as compared with ER-beta. In benign and borderline tumors, ER-beta mRNA was detected in 78% of tumors, whereas ER-alpha mRNA was detected in 29%. In ovarian carcinomas, both ER-alpha and -beta mRNAs were expressed in 80% of tumors. The ER-alpha:ER-beta mRNA ratio was >1 in only one cyst sample (4%). In contrast, the ER-alpha:ER-beta mRNA ratio was markedly increased in ovarian cancers because 60% showed an ER-alpha:ER-beta mRNA >1. In situ hybridization experiments showed overlapping tissular distribution of ER-beta and -alpha expression in cancers and cysts, with a main localization in the epithelium and only a low level of expression in stromal cells. In summary, we found an increase in the ER-alpha:ER-beta mRNA ratio in ovarian carcinomas as compared with normal ovaries and cysts. These data suggest that overexpression of ER-alpha relative to ER-beta mRNA may be a marker of ovarian carcinogenesis.
 ...
PMID:Differential expression of estrogen receptor-alpha and -beta messenger RNAs as a potential marker of ovarian carcinogenesis. 985 67

We have developed four new mammary adenocarcinoma cell lines from the C3(1)/SV40 Large T-antigen (Tag) transgenic mouse model: M28N2 and M27H4 (weakly tumorigenic), M6 (carcinoma), and M6C (metastatic). The C3(1) promoter directs Tag expression to the mammary epithelium and 100% of female C3(1)/Tag transgenic mice develop mammary adenocarcinoma in a predictable and progressive manner. The cell lines we developed from this model are demonstrated to be of epithelial origin and display growth rates, both in vitro and following subcutaneous inoculation into nude mice, that are consistent with their representative stage of tumor progression. The more tumorigenic cell lines, M6 and M6C, both express the sodium/iodide symporter, a mammary carcinoma cell marker with potential therapeutic and diagnostic applications. All of the cell lines express estrogen receptor (ER) alpha and ER beta mRNA, and Western blot analysis demonstrates that the ER alpha protein is down-regulated in the M6 and M6C cell lines. M28N2 cells also express progesterone receptor (PgR), which is very unusual in a mouse mammary carcinoma cell line. In addition, all of the cell lines display growth inhibition when plated in media supplemented with charcoal-stripped fetal calf serum (CS FBS). When CS FBS is supplemented with beta estradiol or the progestin MPA, no significant difference in growth rates is observed relative to growth in CS FBS. The development and characterization of a progressive series of new mammary carcinoma cell lines will aid in the study of mammary carcinoma progression both in vitro and in vivo.
 ...
PMID:Development and characterization of a progressive series of mammary adenocarcinoma cell lines derived from the C3(1)/SV40 Large T-antigen transgenic mouse model. 1260 5

Knockout and expression studies suggest that estrogen receptor beta (ERbeta) plays a prominent role in ovarian function and pathology. Moreover, ovarian cancers are characterized by high morbidity and low responsiveness to anti-estrogens. Here we demonstrate, using quantitative PCR to measure ERalpha and ERbeta levels in 58 ovarian cancer patients, that ERbeta expression decreased in cysts and ovarian carcinomas as compared with normal ovaries and that this decrease is attributable only to a selective loss in ERbeta expression during cancer progression. To address the question of a possible involvement of ERbeta in ovarian cancers, we restored ERalpha and ERbeta expression in two human ovarian cancer cell lines PEO14 (ERalpha-negative) and BG1 (ERalpha-positive) using adenoviral delivery. ERalpha, but not ERbeta, could induce progesterone receptor and fibulin-1C. Moreover, ERalpha and ERbeta had opposite actions on cyclin D1 gene regulation, because ERbeta down-regulated cyclin D1 gene expression, whereas ERalpha increased cyclin D1 levels. Interestingly, ERbeta expression strongly inhibited PEO14 and BG1 cell proliferation and cell motility in a ligand-independent manner, whereas ERalpha had no marked effect. Induction of apoptosis by ERbeta also contributed to the decreased proliferation of ovarian cancer cells, as shown by Annexin V staining. This study shows that ERbeta is an important regulator of proliferation and motility of ovarian cancer and provides the first evidence for a proapoptotic role of ERbeta. The loss of ERbeta expression may thus be an important event leading to the development of ovarian cancer.
 ...
PMID:Involvement of estrogen receptor beta in ovarian carcinogenesis. 1596 30

The characterization of estrogen receptor beta (ERbeta) brought new insight into the mechanisms underlying estrogen signaling. Estrogen induction of cell proliferation is a crucial step in carcinogenesis of gynecologic target tissues, and the mitogenic effects of estrogen in these tissues (such as breast, endometrium and ovary) are well documented both in vitro and in vivo. There is also an emerging body of evidence that colon and prostate cancer growth is influenced by estrogens. In all of these tissues, most studies have shown decreased ERbeta expression in cancer as compared with benign tumors or normal tissues, whereas ERalpha expression persists. The loss of ERbeta expression in cancer cells could reflect tumor cell dedifferentiation but may also represent a critical stage in estrogen-dependent tumor progression. Modulation of the expression of ERalpha target genes by ERbeta or ERbeta-specific gene induction could explain that ERbeta has a differential effect on proliferation as compared with ERalpha. ERbeta may exert a protective effect and thus constitute a new target for hormone therapy, such as ligand specific activation. The potential distinct roles of ERalpha and ERbeta expression in carcinogenesis, as suggested by experimental and clinical data, are discussed in this review.
 ...
PMID:Loss of ERbeta expression as a common step in estrogen-dependent tumor progression. 1536 53

Normal human diploid cells have a limited life span and undergo replicative senescence after various limited population doublings. Cells must pass the senescence barrier to become immortal. The exact mechanisms of immortalization are not clear, although inactivation of the RB pathway, and/or the p53 pathway and activation of telomerase has been shown to be necessary for immortalization of certain cell types with DNA viruses or hTERT. Methylation-associated inactivation of tumor suppressor genes plays an important role in tumor progression. To test if gene-specific methylation contributes to the immortalized and transformed phenotype, we analyzed the methylation status of 17 genes in normal cells immortalized with SV40, hTERT, Ad5, Ad12-SV40 or HPV-18. Some of these immortalized lines were progressively transformed and tumorigenic in nude mice. We observed gene-specific methylation in the in vitro immortalized and transformed cells. SV40 and HPV18 immortalization resulted in different methylation spectra. In SV40- and h-TERT-immortalized prostate epithelial cells, the most frequently methylated gene was RASSF1A, while in HPV18-immortalized cell lines, the RAR-beta2 gene was universally methylated. Immortalization with SV40 resulted in methylation of a greater number of genes than immortalization with HPV. Furthermore, in SV40-immortalized cell lines, methylation affected different genes in fibroblasts compared with epithelial cells, suggesting that different mechanisms may be used by SV40 to immortalize cell lines of different origins. In HPV18-immortalized and subsequently transformed cell lines, the most commonly methylated genes were hormone responsive genes, such as AR, ER-beta and RAR-beta2. In general, more genes were methylated in neoplastically-transformed cell lines than in only immortalized cell lines, indicating that accumulation of epigenetic abnormalities may contribute to oncogenesis.
 ...
PMID:A methylation profile of in vitro immortalized human cell lines. 1558 50

There is a growing body of evidence that disturbed circadian clock gene expression is associated with tumor development and tumor progression. Based on our initial experiments demonstrating decreased period 1 (Per1) expression in colon cancer, we evaluated clock gene and estrogen receptor (ER) alpha/beta expression in colon cancer cells of primary colorectal tumors and adjacent normal colon mucosa (NM) by real-time RT-PCR. Analysis of gene expression in G(2) and G(3) colorectal tumors revealed a decrease of Per1 mRNA compared with paired NM (G(2): 0.52-fold; P = n.s. and G(3): 0.48-fold; P = 0.03). A significant gender specific difference of Per1 expression was observed in G(2) tumors as compared with NM (female: 0.38-fold; P = 0.004 vs. male: 0.73-fold; P = n.s.). Expression of CLOCK was significantly elevated in G(2) tumors of male patients (1.63-fold, P = 0.01). The expression of ER-beta was significantly decreased in G(2) and G(3) tumors (G(2): 0.32-fold; P = 0.003 and 0.27; P = 0.001). No significant gender specific differences of ER-beta reduction in tumors were observed. A significant correlation between the decrease of Per1 and ER-beta in colorectal tumors (r = 0.61; P < 0.001) was found. No changes in gene expression were detected for ER-alpha and Per2. Our data demonstrate a correlated decrease of Per1 and ER-beta in colorectal tumors, mediated probably by epigenetic mechanisms. The observed gender differences in the expression of CLOCK and Per1 in G(2) tumors might suggest a gender-specific, distinctive role of the cellular clock in colorectal tumorigenesis.
 ...
PMID:Correlated downregulation of estrogen receptor beta and the circadian clock gene Per1 in human colorectal cancer. 1914 95

In order to evaluate the importance of estrogen production in tumor and surrounding tissues, we measured mRNA expression levels of 5 enzymes participating to estrogen synthesis in situ and 4 breast cancer-related proteins in 27 pairs of tumor and non-malignant tissues. Steroid sulfatase (STS) mRNA was more frequently detected in tumor tissues rather than in their non-malignant counterparts. Estrogen sulfotransferase (EST) was constantly expressed with high level not only in tumor tissues but also in their surrounding non-malignant counterparts. In contrast, mRNA expression levels of aromatase, and 17beta-hydroxysteroid dehydrogenase type I and II were relatively low and detected only in small proportion of the patients. We also measured the mRNA expression levels of the same nine genes in tumor tissues of 197 breast cancer patients, and analyzed relationship between the mRNA expression level and the clinicopathological parameters. The mRNA expression levels of STS, aromatase and erbB2 in tumor tissues increased as breast cancer progressed. The tumoral mRNA expression levels of STS, estrogen receptor beta, and erbB2 in patients with recurrence were higher than those in patients without recurrence. Upregulation of STS expression plays an important role in tumor progression of human breast cancer and is considered to be responsible for estrogen production in tumor and surrounding tissues.
 ...
PMID:Expression level of enzymes related to in situ estrogen synthesis and clinicopathological parameters in breast cancer patients. 1915 87

Most types of prostate cancer (PCa) are usually initially responsive to androgenic regulation and, therefore, to androgen ablation therapy. However, in several patients tumors may progress to androgen resistance and be poorly responsive to any therapy. Many factors may account for this progression to androgen independence, including increased responsiveness to estrogens and peptide growth factors. The role of estrogens in androgen independence has been suggested by the observation that both primary and metastatic PCa express the estrogen receptor (ER-beta), a recently discovered ER subtype. On the other hand, peptide growth factors, like IGF-1, IGF-2, and the insulin-like growth factor receptor (IGF-1R), may play a role in regulating growth, survival, and invasion of PCa cells. Here, we show that both androgens and estrogens markedly upregulate the IGF-1R expression in PCa cells by activating a nongenotropic pathway and sensitizing cells to the biological effects of IGF-1. This effect is specific for IGF-1R because it does not involve the highly homologous insulin receptor. IGF-1R upregulation is caused by increased mRNA transcription. However, it does not require steroid receptor binding to DNA, but involves AR and ER binding to c-Src and subsequent activation of ERK1/2 and other cytoplasmatic kinases, which eventually stimulate IGF-1R promoter activity. In conclusion, our data indicate that both androgens and estrogens contribute to IGF system deregulation in PCa and may play a role in tumor progression to androgen independence. Inhibition of the IGF-1R or the Src-ERK pathway should be considered, therefore, as an adjuvant therapy in PCa.
 ...
PMID:Sex steroids upregulate the IGF-1R in prostate cancer cells through a nongenotropic pathway. 1925 Feb 14


1 2 Next >>