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)

Cytotoxic activity of drug conjugates of human chorionic gonadotropin (hCG) and doxorubicin alone was investigated compared to doxorubicin in breast cancer cells with and without expression of hCG receptors. Expression of hCG receptor was determined in MCF-7 and MB231 breast cancer cell line using a multiplex nested rt-PCR approach. The entire sequence of mRNA encoding for hCG receptor was detected in MCF-7 but not in MB231 breast cancer cell line. Cytostatic effect of doxorubicin-hCG conjugates was investigated in these cell lines in comparison to unconjugated doxorubicin. The number of viable cells was determined after 24, 48, 72, 96, and 120h. To exclude non-specific uptake of the carrier hCG from the culture media, a similar experiment was performed with albumin-doxorubicin conjugates. The number of viable cells decreased in a concentration depending manner after doxorubicin and hCG-doxorubicin conjugate treatment. However, the cytotoxic effect of hCG-doxorubicin conjugate was 10-fold increased compared to unconjugated doxorubin in hCG-receptor positive MCF-7 but not in hCG-receptor negative MB231 cells. Albumin-doxorubicin conjugates showed no increased toxicity compared to doxorubicin. We conclude that the cytotoxic effect of hCG-doxorubicin conjugates is mediated specifically via the hCG receptor. By using hCG conjugates, the development of more selective cytostatics can be achieved.
Breast Cancer Res Treat 2003 Jan
PMID:Cytotoxic effect of conjugates of doxorubicin and human chorionic gonadotropin (hCG) in breast cancer cells. 1260 11

Half of the placental genes to which a woman is exposed during pregnancy come from her mating partner. Placental hormones, especially human chorionic gonadotropin and human placental lactogen, are considered to mediate the protective effects of full-term pregnancy and lactation on breast cancer risk. In this paper, variants in a woman's placental human chorionic gonadotropin or human placental lactogen genes, which are easily measurable through her offspring's genotypes, are associated with her breast cancer risk. If this hypothesis is true it would indicate that genotype of a woman's mating partner can affect her breast cancer risk and that offspring's genotype may be useful in predicting such risk. Because the placenta produces a wide range of hormones and enzymes (in addition to human chorionic gonadotropin and human placental lactogen), results supporting this hypothesis could open new dimensions to genetic research for diseases beyond breast cancer (including gynecologic tumors and reproductive and pregnancy-related disorders).
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PMID:Placental genes and breast cancer: can the offspring's or father's genotypes predict mother's risk? 1260 94

Peripheral-type benzodiazepine receptor (PBR) is an 18 kDa high-affinity drug ligand and cholesterol binding protein involved in various cell functions. Antisera for distinct PBR areas identified immunoreactive proteins of 18, 40, and 56 kDa and occasionally 72, 90, and 110 kDa in testicular Leydig and breast cancer cells. These sizes may correspond to PBR polymers and correlated to the levels of reactive oxygen species. Treatment of Leydig cells with human chorionic gonadotropin rapidly induced free radical, PBR polymer, and steroid formation. UV photoirradiation generates ROS species, which increased the size of intramembraneous particles of recombinant PBR reconstituted into proteoliposomes consistent with polymer formation, determined both by SDS-PAGE and by freeze-fracture electron microscopy. Spectroscopic analysis revealed the formation of dityrosines as the covalent cross-linker between PBR monomers. Moreover, photoirradiation increased PK 11195 drug ligand binding and reduced cholesterol binding capacity of proteoliposomes. Further addition of PK 11195 drug ligand to polymers increased the rate of cholesterol binding. These data indicate that reactive oxygen species induce in vivo and in vitro the formation of covalent PBR polymers. We propose that the PBR polymer might be the functional unit responsible for ligand-activated cholesterol binding and that PBR polymerization is a dynamic process modulating the function of this receptor in cholesterol transport and other cell-specific PBR-mediated functions.
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PMID:In vivo and in vitro peripheral-type benzodiazepine receptor polymerization: functional significance in drug ligand and cholesterol binding. 1269 47

Chronically elevated luteinizing hormone (LH) induces significant pathology in the LHbetaCTP transgenic mouse model, which uses the bovine gonadotropin alpha (alpha)-subunit promoter to direct transgene expression specifically to gonadotropes in the anterior pituitary. Previously, it was shown that female LHbetaCTP mice are infertile due to anovulation, develop granulosa cell tumors, and undergo precocious puberty from elevated LH and steroid hormones that fail to completely repress the alpha-subunit promoter. This chapter will discuss recent studies that further elucidate the impact of chronically elevated LH on diverse physiological systems. Granulosa cell tumors induced by elevated LH are strain dependent and prevented when transgenics are treated with human chorionic gonadotropin (hCG) surges. A granulosa cell tumor-associated transcriptome is generated, revealing several possible gene candidates for ovarian granulosa cell tumorigenesis. Primordial follicles in LHbetaCTP transgenics become depleted and oocytes exhibit increased rates of meiotic segregation defects, although meiotic competency is acquired normally. Anovulation can be rescued in transgenics by superovulation, though pregnancy fails at midgestation due to maternal factors. Uterine receptivity defects prevent implantation of normal embryos following induction of pseuodpregnancy. Transgenics develop Cushing-like adrenocortical hyperfunction with increased corticosterone production following induction of adrenal LH receptor expression. Elevated LH acts as a tumor promoter in the gonads and the adrenal gland, when expressed in conjunction with the inhibin-alpha SV40 transgene. Finally, chronic elevated LH promotes mammary tumorigenesis. The understanding of multiple clinical pathologies--including ovarian cancer, perimenopausal reproductive aging, premature ovarian failure, polycystic ovarian syndrome, Cushing's syndrome, and breast cancer--may be enhanced through further study of this useful transgenic mouse model.
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PMID:Consequences of elevated luteinizing hormone on diverse physiological systems: use of the LHbetaCTP transgenic mouse as a model of ovarian hyperstimulation-induced pathophysiology. 1279 27

The cysteine protease cathepsin L exhibits hormone-regulated expression during ovulation. In situ hybridization analyses of immature and pregnant mare serum gonadotropin-treated mouse and rat ovaries showed that cathepsin L expression in granulosa cells of small, growing follicles increased in periovulatory follicles after human chorionic gonadotropin stimulation. In the rat ovary, cathepsin L was also expressed in follicles with signs of atresia. To determine the molecular mechanisms that mediate the diverse regulation of this gene in granulosa cells, rat cathepsin L promoter-reporter constructs were analyzed by transient transfection assays in rat granulosa cells and EMSAs. A construct containing the transcriptional start site and -244 bp of upstream promoter sequence (-244/+33 bp) exhibited inducibility by forskolin, the phorbol ester phorbol myristate acetate, and an additive effect of both. Within this region, three functional specificity protein 1 (Sp1) sites, an overlapping early growth response protein-1 site, and a cAMP regulatory element-binding protein site were identified. Single or double mutants of the above-mentioned sites did not alter forskolin/phorbol myristate acetate inducibility of the promoter. Mutation of all three Sp1/specificity protein 3 (Sp3) sites, which also mutated the early growth response protein-1 site, reduced the promoter activation. Mutation of the cAMP regulatory element-binding protein site in the triple Sp1 mutant construct completely blocked the inducibility of the promoter. When these same constructs were transfected into MCF-7 human breast cancer cells or were cotransfected with an Sp1 expression vector in Drosophila SL2 cells, similar results were obtained. Collectively, the data document that three Sp1/specificity protein 3 binding GC-rich regions and a functional cAMP regulatory element constitute an important transcriptional regulatory complex for expression of the cathepsin L gene in rat granulosa cells.
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PMID:Cathepsin L gene expression and promoter activation in rodent granulosa cells. 1456 3

The preventive effect of human chorionic gonadotropin (hCG)-induced differentiation on experimental mammary carcinogenesis has been reported to be due to the inhibition of cell proliferation, increased DNA repair capabilities of the mammary epithelium, decreased binding of the carcinogen to the DNA and activation of programmed cell death genes leading to apoptosis. To further our understanding of the molecular pathway of the hCG action on mammary epithelial cells we have analyzed gene expression profiles of MCF-7 cells treated with hCG for 24, 48, and 96 h, using a DNA microarray consisting of 1176 genes. Comparison of expression between the treated and not treated cells enabled us to identify 48 genes that are affected by this hormone. Importantly, there is a cluster of genes that are overexpressed during the first 24 h and level off thereafter, whereas other genes are maximally expressed at 96 h of treatment. The results obtained in this study demonstrated that genes regulating cell proliferation, apoptosis, cell trafficking, and DNA repair are significantly affected by hCG in human breast cancer cells in vitro.
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PMID:Effect of human chorionic gonadotropin in the gene expression profile of MCF-7 cells. 1471 17

The epidemiological data suggest that breast cancer risk decreases in women who complete full-term pregnancy at a young age. Studies on a rat breast cancer model indicate that human chorionic gonadotropin (hCG), a hormone that is present in very high levels during pregnancy, could be responsible for this decrease. These findings, as well as those demonstrating the presence of functional luteinizing hormone (LH)/hCG receptors in human breast cells, prompted us to investigate the anti-proliferative and anti-invasive effects of hCG in human breast cancer MCF-7 cells by down-regulating NF-kappaB and AP-1 transcription factors. Treatment of MCF-7 cells with highly purified hCG resulted in a modest dose-dependent and hormone-specific decrease in cell proliferation. hCG treatment also decreased cell invasion, which was more dramatic than the decrease in cell proliferation. These hCG actions were abrogated when receptor synthesis was inhibited by treatment with antisense hCG/LH receptor phosphorothioate oligodeoxynucleotide. hCG treatment prevented the tumor necrosis factor-dependent NF-kappaB and AP-1 activation, which paralleled a decrease in the phosphorylation and degradation of IkappaBalpha. The findings that hCG treatment increased cAMP synthesis and activated cAMP-dependent protein kinase, dibutyryl cAMP mimicked hCG in preventing NF-kappaB activation, and dideoxyadenosine, an adenylate cyclase inhibitor, prevented the hCG effect on NF-kappaB suggested that the hCG actions are mediated via the cAMP-dependent protein kinase A signaling pathway. In summary, our results demonstrate that hCG has anti-proliferative and anti-invasive effects in MCF-7 cells by down-regulating NF-kappaB and AP-1. These findings support the premise that hCG could be responsible for the pregnancy-induced protection against breast cancer in women.
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PMID:Human chorionic gonadotropin decreases proliferation and invasion of breast cancer MCF-7 cells by inhibiting NF-kappaB and AP-1 activation. 1504 47

The aim of this study was to use a two-marker assay for the detection of breast cancer cells circulating in patients' blood. We have applied a PCR-based methodology to follow up the possibility of the development of metastatic disease in stage I and II patients who had undergone curative surgery. Since the number of circulating cancer cells in peripheral blood is very low, the technique for their detection needs to be not only highly sensitive, but also very specific. The reverse transcriptase-polymerase chain reaction (RT-PCR) technique may improve the sensitivity of breast cancer cell detection up to only a few cells per one million. The principle of the RT-PCR assay is to amplify a messenger RNA characteristic for breast epithelial cells in a blood sample. Since we do not expect such cells to be circulating in peripheral blood of healthy subjects, detection of the characteristic mRNA should indicate the presence of circulating breast cancer cells. We analyzed the usefulness of three mRNA markers: cytokeratin 19 (CK19), mammaglobin (hMAM) and beta subunit of human chorionic gonadotropin (beta-hCG) for this test. Blood samples (112) were obtained from 55 patients, in stages I and II, with or without metastasis to regional lymph nodes (N0 or N1). We found that a two-marker assay increases the sensitivity of detection of breast cancer cells in comparison with a single-marker one. Combination of two tumor-specific mRNA markers, hMAM/CK19 or beta-hCG/CK19, allowed the detection of circulating breast cancer cells in 65% of N1 patients and 38% of N0 patients. By comparison, the combination hMAM/beta-hCG allowed the detection of circulating breast cancer cells in the blood of 68% of N1 patients and 46% of N0 patients. Addition of the third marker did not significantly increase the detection sensitivity.
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PMID:Detection of circulating breast cancer cells in peripheral blood by a two-marker reverse transcriptase-polymerase chain reaction assay. 1544 36

Protein biomarkers suitable for the prevention of breast cancer must be extremely sensitive, easily detectable and highly correlated with the disease. They should be expressed in the reversible phase of carcinogenesis. Among the large number of candidate tumour-associated proteins, those related to the oestrogen/chorionic gonadotropin/insulin pathway seem to be of most interest because these can be causally implicated. They presumably are the first to express differently and are open to hormonal treatments. The biomarkers that give information on membrane receptor-modulated signal transduction should be considered as well. Up to now, only tamoxifen has shown some preventive activity, suggesting that the oestrogen pathway is useful indeed. Fenretinide and recombinant human chorionic gonatotropin (hCG) are also promising. But the financial requirements and the very long assessment periods largely prevent current research. This is precisely why we badly need to give priority to molecular biology research, in particular in the protein compartment There is widespread belief that advanced proteomics together with increased informatics can provide specific combinations of disease-related expression profiles that could identify high-risk groups with much more reliability and allow us to monitor preventive strategies.
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PMID:Protein biomarkers for breast cancer prevention. 1555 59

Sporadic breast cancer is a fatal disease most frequently diagnosed in American women from all ethnic groups, suggesting that primary prevention should be the ultimate goal for breast cancer control. We have developed a novel paradigm for breast cancer prevention arising from the well-established knowledge that an early first full-term pregnancy protects the breast against neoplastic transformation, as well as from our studies of the biological principle underlying this protection. We have shown experimentally that the first pregnancy induces the expression of a specific genomic signature in the breast that results from the completion of a cycle in this organ's differentiation driven by the reproductive process. This signature, in turn, is a biomarker associated with a possible overall lifetime decrease in breast cancer risk. We have shown in an experimental model that a short treatment with human chorionic gonadotropin, a placental hormone secreted during pregnancy, induces the same genomic signature that occurs in pregnancy, inhibiting not only the initiation but also the progression of mammary carcinomas, and stopping the development of early lesions such as intraductal proliferations and carcinoma in situ. These observations indicate that human chorionic gonadotropin given for a very short period, only until this genomic signature is acquired, has significant potential as a chemopreventive agent, protecting the normal cell from becoming malignant. This is a novel concept which challenges the current knowledge that a chemopreventive agent needs to be given for a long period of time to suppress a metabolic pathway or abrogate the function of an organ.
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PMID:Breast differentiation and its implication in cancer prevention. 1570 89


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