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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Peroxisome proliferator-activated receptor binding protein (PBP), a nuclear receptor coactivator, interacts with estrogen receptor alpha (ERalpha) in the absence of estrogen. This interaction was enhanced in the presence of estrogen but was reduced in the presence of antiestrogen, tamoxifen. Transfection of PBP in CV-1 cells resulted in enhancement of estrogen-dependent transcription, indicating that PBP serves as a coactivator in ER signaling. To examine whether overexpression of PBP plays a role in breast cancer because of its coactivator function in ER signaling, we determined the levels of PBP expression in breast tumors. High levels of PBP expression were detected in approximately 50% of primary breast cancers and breast cancer cell lines by ribonuclease protection analysis, in situ hybridization, and immunoperoxidase staining. Fluorescence in situ hybridization of human chromosomes revealed that the PBP gene is located on chromosome 17q12, a region that is amplified in some breast cancers. We found PBP gene amplification in approximately 24% (6/25) of breast tumors and approximately 30% (2/6) of breast cancer cell lines, implying that PBP gene overexpression can occur independent of gene amplification. This gene comprises 17 exons that, together, span >37 kilobases. The 5'-flanking region of 2.5 kilobase pairs inserted into a luciferase reporter vector revealed that the promoter activity in CV-1 cells increased by deletion of nucleotides from -2,500 to -273. The -273 to +1 region, which exhibited high promoter activity, contains a typical CCAT box and multiple cis-elements such as C/EBPbeta, YY1, c-Ets-1, AP1, AP2, and NFkappaB binding sites. These observations, in particular PBP gene amplification, suggest that PBP, by its ability to function as ERalpha coactivator, might play a role in mammary epithelial differentiation and in breast carcinogenesis.
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PMID:Amplification and overexpression of peroxisome proliferator-activated receptor binding protein (PBP/PPARBP) gene in breast cancer. 1048 14

Hormone-related cancers, namely breast, endometrium, ovary, prostate, testis, thyroid and osteosarcoma, share a unique mechanism of carcinogenesis. Endogenous and exogenous hormones drive cell proliferation, and thus the opportunity for the accumulation of random genetic errors. The emergence of a malignant phenotype depends on a series of somatic mutations that occur during cell division, but the specific genes involved in progression of hormone-related cancers are currently unknown. In this review, the epidemiology of endometrial cancer and breast cancer are used to illustrate the paradigms of hormonal carcinogenesis. Then, new strategies for early detection and prevention of hormonal carcinogenesis are discussed. This includes developing polygenic models of cancer predisposition and the further development of safe and effective chemopreventives that block target sequence activity. We developed polygenic models for breast and prostate cancer after hypothesizing that functionally relevant sequence variants in genes involved in steroid hormone metabolism and transport would act together, and also interact with well-known hormonally related risk factors, to define a high-risk profile for cancer. A combination of genes each with minor variation in expressed activity could provide a degree of separation of risk that would be clinically useful as they could yield a large cumulative difference after several decades. The genes included in the breast cancer model are the 17beta-hydroxysteroid dehydrogenase 1 (HSD17B1) gene, the cytochrome P459c17alpha (CYP17) gene, the aromatase (CYP19) gene, and the estrogen receptor alpha (ER) gene. The prostate cancer model includes the androgen receptor gene (AR), steroid 5alpha-reductase type II (SRD5A2), CYP17 and the 3beta hydroxysteroid dehydrogenase (HSD3B2) gene. We present data from our multi-ethnic cohort to support these models.
Carcinogenesis 2000 Mar
PMID:Hormonal carcinogenesis. 1123 97

Since the estrogen receptor alpha (ER) is an important mediator of hormonal responses such as proliferation in estrogen-sensitive tissues, we hypothesized that polymorphisms in the ER gene could be functional and associated with endometrial cancer risk. We performed a population-based case-control study in Sweden, focusing on restriction fragment length polymorphisms for XbaI and PvuII and an upstream TA repeat polymorphism. In the main analysis, 154 cases and 205 controls who never used hormone replacement therapy took part and we calculated age-adjusted and multivariate odds ratios (OR) and 95% confidence intervals (CI) using unconditional logistic regression. The XbaI X allele appeared to confer a reduced risk for endometrial cancer. The multivariate OR for the XX genotype was 0.52 (95% CI 0.21-1.29) compared to the xx genotype and there were suggestions of decreasing risk with increasing number of X alleles (P for trend = 0.07). The PvuII PP genotype was also associated with a non-significantly decreased risk for endometrial cancer (multivariate OR 0.70, 95% CI 0.34-1.44) compared with the pp genotype (P for trend = 0.43). The multivariate OR for two short TA (<19 repeats) alleles versus two long alleles was 1.54 (95% CI 0. 73-3.27) and there were suggestions of increasing risk with increasing number of short alleles (P for trend = 0.26). We observed the same pattern of results in an expanded group of subjects, which included women who had used hormone replacement (in total 288 cases and 392 controls). Our data suggest that variants of the ER gene may be associated with an altered risk of endometrial cancer.
Carcinogenesis 2000 Apr
PMID:Estrogen receptor alpha gene polymorphisms and endometrial cancer risk. 1075 95

17 beta-hydroxysteroid dehydrogenases (17 beta-HSDs) are involved in the interconversion of biologically active and inactive sex steroids and are considered to play important roles in the in situ metabolism of estrogen in various estrogen dependent tissues. 17 beta-HSD type 1 catalyzes primarily the reduction of estrone (E1) to estradiol (E2), whereas 17 beta-HSD type 2 catalyzes primarily the oxidation of E2 to E1. However, the possible biological roles of these estrogen metabolizing isozymes in human breast cancer, especially in carcinogenesis of the human breast, have not been examined in detail. Because of the potential roles of estrogens in the early stages of human breast carcinogenesis, we have examined the immunolocalization of 17 beta-HSD type 1 and type 2 isozymes and estrogen receptor alpha(ER alpha) in both normal human breast tissue and in breast cancers, including ductal carcinoma in situ (DCIS), proliferative disease without atypia (PDWA) or fibrocystic disease and atypical ductal hyperplasia (ADH). We also correlated these findings with clinicopathological findings, Ki67 antigen, progesterone receptor (PR), c-erbB-2, and p53. 17 beta-HSD type 2 immunoreactivity was sporadically detected in non-proliferative or Ki67 negative ductal epithelia of normal breast, but rarely in breast carcinoma cells. 17 beta-HSD type 1 immunoreactivity was detected in 12/22 (54.5%) PDWA cases, 8/26 (30.8%) ADH cases, and 25/40 (62.5%) DCIS cases, respectively. 17 beta-HSD type 1 immunoreactivity was not statistically correlated with the age of the patients, Ki67 labeling index (LI), and PR LI, p-53 and c-erbB-2 immunoreactivity. There was no significant correlation between ER alpha LI and 17 beta-HSD type 1 immunoreactivity. There was a positive correlation between ER alpha and Ki67 LI in PDWA, whereas a negative correlation was detected between ER alpha and Ki67 LI in DCIS. There was no correlation between ER alpha and Ki67 LI in ADH. These results suggest that in human breast epithelial cells, development of ADH and DCIS may be associated with the loss and/or deviation of oestrogen dependent regulation of cell proliferation.
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PMID:17 beta-Hydroxysteroid dehydrogenase type 1 and type 2 in ductal carcinoma in situ and intraductal proliferative lesions of the human breast. 1081 Apr 3

The role of estrogen as a promoter agent of sporadic breast cancer has been considered by assaying, in benign breast disease (BBD) and in situ carcinomas (CIS), 2 markers, the estrogen receptor alpha (ERalpha) and cathepsin D (cath-D) involved in estrogen action on mammary tissue. ERalpha and cath-D were assayed by quantitative immunohistochemistry using an image analyzer in 170 lesions of varying histological risk (94 BBD and 76 CIS), and in "normal" glands close to these lesions. The ERalpha level increased significantly in proliferative BBD with atypia (P < .001), in non-high-grade CIS (P < .001), and in adjacent "normal" glands. ERalpha level was decreased in high-grade ductal CIS (DCIS) and also in adjacent "normal" glands. Cath-D level increased in ductal proliferative BBD (P < or = .01) and in high-grade DCIS (P < or = .003), but not in the other lesions. After menopause, ERalpha level was increased (P = .012) but not cath-D level. According to Mac Neman test, the high-grade DCIS were predominantly ERalpha negative and cath-D positive (P = .0017), and the other CIS were predominantly ERalpha positive and cath-D negative (P = .0002). The 2 markers are overexpressed early in premalignant lesions, but independently. This dissociation suggests a branched model of mammary carcinogenesis involving 1 estrogen-independent pathway with high cath-D and low ERalpha levels (including high-grade DCIS) and 1 estrogen-dependent pathway, with high ERalpha level (including proliferative BBD with atypia and low-grade DCIS). We propose that ERalpha-negative breast cancers may develop directly from high-grade DCIS and that ERalpha assay in preinvasive lesions should be considered in prevention trials with antiestrogens.
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PMID:Dissociated overexpression of cathepsin D and estrogen receptor alpha in preinvasive mammary tumors. 1083 99

We have previously shown that the distal promoter (promoter B) of the estrogen receptor alpha (ER alpha) gene is responsible for the enhanced expression of the ER alpha gene seen in human breast cancer and that a novel trans-acting factor, estrogen receptor promoter B associated factor 1 (ERBF-1), is required for transcription from promoter B in breast cancer cells. In development of breast cancer, loss of ER alpha gene expression is one of the most important steps in acquiring hormone resistance, though the mechanisms are poorly understood. Recent studies have reported that methylation of the ER alpha gene promoter A and exon 1 was inversely associated with ER alpha gene expression in human breast cancer and cell lines. The methylation status of the promoter B region, which is responsible for overexpression of ER alpha protein in cancer tissue, has not been investigated. In this report, we found that the methylation status of promoter B, as well as that of promoter A, was inversely associated with ER alpha gene expression in human breast cancer and cell lines. Specific methylation of ER alpha gene promoters in vitro directly decreased transcription of the ER alpha gene in a reporter assay. Demethylating treatment induced transcription of ER alpha mRNA from promoter B in ZR-75-1 cells, which showed no transcription from promoter B, despite weak ERBF-1 expression, but not in ER alpha-negative MDA-MB-231 and BT-20 cells, which lack ERBF-1. ZR-75-1 cells showed promoter activity equal to that of MCF-7 cells in a reporter assay. Our results indicate that methylation of promoter B of the ER alpha gene is important for loss of ER alpha gene expression in human breast cancer, and methylation of the promoters can directly modulate ER alpha gene expression. However, loss of critical transcriptional factors such as ERBF-1 may also be involved in some ER alpha-negative cases.
Carcinogenesis 2000 Dec
PMID:Distinct mechanisms of loss of estrogen receptor alpha gene expression in human breast cancer: methylation of the gene and alteration of trans-acting factors. 1113 8

Little is known of the function and clinical significance of the androgen receptor (AR) in human breast cancer. Paradoxically, synthetic progestins, such as medroxyprogesterone acetate, are used for second line hormone therapy of breast cancer following tamoxifen failure. A sensitive and accurate assay for AR expression in breast tumors is thus required. Here we have developed and validated a real-time RT-PCR assay to quantify AR gene expression at the mRNA level in a series of 131 patients with unilateral invasive primary breast tumors. AR expression varied widely in tumor tissues (by at least 3 orders of magnitude), being underexpressed in 24/131 (18.3%) and overexpressed in 45/131 (34.4%) relative to normal breast tissues. We observed links (or trends) between AR status and age, menopausal status, Scarff-Bloom-Richardson histopathological grade, lymph node status and estrogen receptor alpha and progesterone receptor status. High AR mRNA levels were negatively linked to MYC gene overexpression (P = 8 x 10(-6)), confirming previous in vitro studies. Our results also suggest a role of the ARA70 gene (which encodes a major AR co-activator) in the AR pathway dysregulation observed in breast cancer. This simple, rapid and semi-automated method will be useful for screening cancer patients for altered AR expression and for predicting the response to androgen therapy in AR-related cancer patients.
Carcinogenesis 2001 Sep
PMID:Quantitation of androgen receptor gene expression in sporadic breast tumors by real-time RT-PCR: evidence that MYC is an AR-regulated gene. 1153 75

Recent studies by our laboratory indicate that the p16(INK4a) gene is frequently methylated in lung tumors induced by genotoxic carcinogens and that the frequency for methylation of the estrogen receptor alpha (ER) gene varies as a function of carcinogenic exposure. The purpose of the current investigation was to define the role of these two genes in lung tumors induced by the particulate carcinogens carbon black (CB), diesel exhaust (DE) or beryllium metal. Methylation of p16 was observed in 59 and 46% of DE and CB tumors, respectively. In contrast, the ER gene was inactivated in only 15% of DE or CB tumors. Methylation of the p16 and ER genes was very common (80 and 50%, respectively) in beryllium-induced lung tumors; both genes were methylated in 40% of the tumors. Bisulfite sequencing revealed dense methylation throughout exon 1 of the ER gene. The inhibitory effect of methylation on gene transcription was confirmed through RT-PCR expression studies in which p16 gene expression was 30-60-fold lower in methylated than unmethylated tumors. Residual expression in methylated tumors was consistent with contamination by stromal and inflammatory cells. Results indicate that tumors induced by these particulate carcinogens arise, in part, through inactivation of the p16 and ER genes. Furthermore, the inactivation of the p16 gene by these carcinogenic exposures supports a possible role for oxidative stress and inflammation in the etiology of human lung cancer.
Carcinogenesis 2002 Feb
PMID:Aberrant CpG island methylation of the p16(INK4a) and estrogen receptor genes in rat lung tumors induced by particulate carcinogens. 1187 42

Lung cancer is becoming increasingly common in women and in the United States accounts for more female cancer deaths annually than breast cancer. Many epidemiological studies have provided evidence that women are more susceptible than men to the adverse effects of tobacco smoke. These observations suggest the possible role of estrogens in lung carcinogenesis. We report here the expression of mRNA for estrogen receptor alpha (ERalpha) and beta (ERbeta) in cultured human non-small cell lung cancer cells, cultured lung fibroblasts, and primary cultures of normal bronchial epithelium. Western analysis of ERalpha suggested that the main protein expressed in lung tumor cells is a variant, probably attributable to alternative splicing. Protein for ERbeta was found to be a mixture of full-length as well as alternatively spliced variants. beta-Estradiol produced a proliferative response in vitro in both normal lung fibroblasts and cultured non-small cell lung tumor cells. This effect was also observed in vivo. In this regard, beta-estradiol stimulated growth of the non-small cell lung tumor line, H23, grown as tumor xenografts in SCID mice. This effect was blocked by fluvestrant (ICI 182,780). In paraffin sections of non-small cell lung tumors, ERbeta immunoreactivity was localized to the nucleus, whereas ERalpha immunoreactivity was mainly localized to the cytoplasm, suggesting that both nuclear and cytoplasmic signaling may be involved in estrogenic responses in the lung. To show that the ERs found in the lung are functional, we demonstrated that beta-estradiol stimulated transcription of an estrogen response element-luciferase construct transfected in non-small cell lung tumor cell lines. Antiestrogens blocked this effect. Treatment of lung fibroblasts with beta-estradiol also increased secretion of hepatocyte growth factor by 2-fold. These results suggest that estrogen signaling plays a biological role in both the epithelium and the mesenchyme in the lung and that estrogens could potentially promote lung cancer, either through direct actions on preneoplastic or neoplastic cells or through indirect actions on lung fibroblasts. Additionally, it is possible that antiestrogens may have therapeutic value to treat or prevent lung cancer.
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PMID:Human non-small cell lung tumors and cells derived from normal lung express both estrogen receptor alpha and beta and show biological responses to estrogen. 1192 36

WNT family of secreted-type glycoproteins play key roles in carcinogenesis and embryogenesis. We have cloned and characterized human WNT2B/WNT13, WNT3, WNT3A, WNT5B, WNT6, WNT7B, WNT8A, WNT8B, WNT10A, WNT10B, WNT11, WNT14 and WNT14B/WNT15 using bioinformatics and cDNA-PCR, and also reported frequent up-regulation of WNT2 in primary gastric cancer. Here, expression and regulation of WNT1 in human cancer were investigated using cDNA-PCR. WNT1 mRNA was relatively highly expressed in OKAJIMA cells (gastric cancer) and BxPC-3 cells (pancreatic cancer). Expression of WNT1 mRNA was up-regulated in 5 out of 10 cases of primary gastric cancer. Effects of beta-estradiol on expression of human WNT1 in MCF-7 cells (breast cancer) was next investigated, because mouse Wnt-1 induces mammary carcinogenesis even in estrogen receptor alpha (ERalpha) knockout mice. Expression of WNT1 mRNA was significantly up-regulated by beta-estradiol in MCF-7 cells. WNT1 was found to be one of estrogen target genes in human MCF-7 cells, which in part explains Wnt1-induced mammary carcinogenesis in ERalpha knockout mice.
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PMID:Expression and regulation of WNT1 in human cancer: up-regulation of WNT1 by beta-estradiol in MCF-7 cells. 1246 6


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