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)

The steroid hormones are recognized and fixed by special cytoplasmic proteins in the target tissue called receptors. Most circulating natural steroids are tied to transport proteins. Estradiol and progesterone are active as such in the receptor cells, but testosterone is transformed into dihydrotestosterone in situ under the influence of the enzyme 5 alpha reductase before combining with the receptor. Receptivity may be exacerbated or reduced. Exacerbation is particularly likely when physiological control mechanisms are deficient. Testosterone has a biological effect at the level of the Wolfian apparatus in the embryo and in the muscle and bone of the adult. The activity of perineal 5 alpha reductase implicated in these phenomena and the hepatic 5 alpha reductase activity implicated in the degradation of testosterone are found in both sexes and are under genetic influence independent of the male hormone. Problems in receptivity to the male hormone are well known to clinicians. Hirsutism, whatever its cause, is always associated with great cutaneous 5 alpha reductase activity. The use of antiandrogens derived from synthetic progestagens has transformed treatment of hirsutism. Male pseudohermaphrodism may be secondary to an insufficient testosterone production or to primary resistence to the male hormone, in which case the plasma concentration of testosterone is always greater than normal. The characteristic case is of a deficit of 5 alpha reductase and feminization of the testicle. 5 alpha reductase deficiency causes sexual ambiguity at birth. Absence of the testosterone receptor at both the perineal and public levels explains why attempts to treat these disorders with high doses of testosterone or dihydrotestosterone always fail. Problems in receptivity to the male hormone have been found to cause other pathologies, such as severe oligospermia. The quantity of estradiol and progesterone receptors varies according to the volume of circulating estradiol and of progesterone. Progesterone is a natural antiestrogen; it limits the activity of estradiol by favoring the transformation of estradiol into estrone and decreases the synthesis of estradiol receptors. The normal endometrium may become hyperplasic after menopause, the 1st stage in development of endometrial cancer. Continuous estrogen stimulation not countebalanced by progesterone permits the transformation. Study of estradiol and progesterone receptors in mammary fibroadenomas has shown that estradiol receptors increase to a maximum in the preovulatory period and diminish in the luteal phase. The increase in estradiol is followed by an increase in progesterone receptors. Since 1971 it has been apparent that breast cancer susceptible to improvement by hormonal treatment were rich in estrogen receptors.
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PMID:[Receptivity to the sex steroids, physiopathological aspects]. 1231 77

The development and the effect of immunoliposomes directed against human breast cancer cells overexpressing p185/HER2 are described. These immunoliposomes carry an antisense oligonucleotide directed toward the translational start site of dihydrofalate reductase (DHFR) RNA, which causes high cytotoxicity. To prepare the immunoliposomes, we followed two methodologies based on the high affinity between streptavidin and biotin and the use of biotinylated antibodies. In the first approach, the streptavidin molecule is covalently attached to the phospholipid DOPE, which is mixed with the cationic liposome DOTAP complexed with the antisense oligonucleotide. The second approach, which is much easier to perform, involves the binding of streptavidin to antibody and oligonucleotide, both biotinylated, and the latter complexed with DOTAP. The formation of the intermediary complexes of this immunoliposome was studied sequentially by gel electrophoresis. The uptake of the oligonucleotide carried by the immunoliposome was monitored by flow cytometry and confocal microscopy. As a model, we used SKBR3 cells that overexpress p185. The full immunoliposomes were more toxic than the antisense oligonucleotide in the absence of the antibody, thus increasing the sensitivity of the treatment.
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PMID:Development and effects of immunoliposomes carrying an antisense oligonucleotide against DHFR RNA and directed toward human breast cancer cells overexpressing HER2. 1247 81

Thioredoxin (Trx) expression is increased in several human primary cancers and the Trx/Trx reductase (TrxR) system therefore provides an attractive target for cancer drug development. Novel organotellurium antioxidants, especially a primitive analog of vitamin E (compound 1d) and compounds 7, 9 and 10--all carrying highly functionalized 4-(dialkylamino)phenyltelluro groups to secure high antioxidative capacity--were found to inhibit TrxR with IC50 values in the low micromolar range. Whereas antioxidant 1d also inhibited the growth of MCF-7 human breast cancer cells in culture at a similar level (IC50 = 1.8 microM), the other TrxR inhibitors were inactive in concentrations below about 10 M.
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PMID:Thioredoxin reductase and cancer cell growth inhibition by organotellurium antioxidants. 1256 2

Relatively new targets in drug design projects in cancer pharmacology include cytostatic agents, immune system modulators, and angiogenesis inhibitors. Preventive oncology applies pharmacological agents to reverse, retard, or halt progression of neoplastic cells to invasive malignancy. Prevention of cancer, however, can be accomplished through many strategies, including changes in diet and lifestyle. For example, the vast majority of lung cancers (80-90%) can be attributed to cigarette smoking and therefore, the most effective primary preventive strategy for lung cancer is to quit smoking. Chemoprevention through interruption of multistage careinogenesis include different molecular targets. Selective estrogen receptor modulators (SERMs) act as estrogen receptor (ER) agonists. Ligands for the peroxisome proliferator-activated receptor gamma (PPAR-gamma) suppress breast carcinogenesis in experimental models and induce differentiation of human liposarcoma cells. Selective PPAR modulators (SPARMs), by analogy to the SERM concept, are designed to have desired effects on specific genes relevant to carcinogenesis. Enzymatic approach in endocrine-related tumors involve inhibition of aromatase to prevent breast cancer and inhibition of 5-alpha-reductase to prevent prostate cancer. Down-regulation of inflammatory prostaglandin synthesis by inhibition of cyclooxygenase-2 (COX-2). inhibition of the inducible nitric oxide synthase (iNOS), and stimulation of phase II detoxication system, are currently examined in experimental models and clinical trials. Overall, potential targets in preventive strategies to reduce the risk of cancer involve agonists of endocrine receptors, factors down-regulating inflammation, factors inducing programmed cell death (PCD)/apoptosis, enzymatic inhibitors and gene therapy.
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PMID:Current strategies for anticancer chemoprevention and chemoprotection. 1266 76

Beta-lapachone (beta-Lap) triggers apoptosis in a number of human breast and prostate cancer cell lines through a unique apoptotic pathway that is dependent upon NQO1, a two-electron reductase. Recently, our laboratory showed that beta-lap-exposed MCF-7 cells exhibited an early increase in intracellular cytosolic Ca(2+) from endoplasmic reticulum stores, and that BAPTA-AM (an intracellular Ca(2+) chelator) blocked these early increases and partially inhibited all aspects of beta-lap-induced apoptosis. We now show that exposure of NQO1-expressing breast cancer cells to beta-lap stimulates a unique proteolytic apoptotic pathway involving mu-calpain activation. No apparent activation of m-calpain was noted. Upon activation, mu-calpain translocated to the nucleus concomitant with specific nuclear proteolytic events. Apoptotic responses in beta-lap-exposed NQO1-expressing cells were significantly delayed and survival enhanced by exogenous over-expression of calpastatin, a natural inhibitor of mu- and m-calpains. Furthermore, purified mu-calpain cleaved PARP to a unique fragment (approximately 60 kDa), not previously reported for calpains. We provide evidence that beta-lap-induced, mu-calpain-stimulated apoptosis does not involve any known apoptotic caspases; the activated fragments of caspases were not observed after beta-lap exposures, nor were there any changes in the pro-enzyme forms as measured by Western blot analyses. The ability of beta-lap to trigger an apparently novel, p53-independent, calpain-mediated apoptotic cell death further support the development of this drug for improved breast cancer therapy.
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PMID:Mu-calpain activation in beta-lapachone-mediated apoptosis. 1275 May 53

Tirapazamine (TPZ) is the lead member of a class of bioreductive drugs currently in phase II and III clinical trials. TPZ requires metabolic activation to give a cytotoxic free radical species, and this hypoxia-mediated process is carried out by a variety of cellular reductases, including NADPH cytochrome c (P450) reductase (P540R). Nitric-oxide synthase (NOS) is widely expressed in human tumors, and this enzyme consists of an oxidase and a reductase domain, the latter showing striking homology to P450R. Thus, in this article, we have investigated the role of one of the cytosolic isoforms of NOS [inducible NOS (NOSII)] in the bioactivation of this DNA-damaging antitumor agent. To achieve this, we have constitutively overexpressed NOSII in human breast tumor MDA231 cells by employing an optimized expression vector in which the strong human polypeptide chain elongation factor 1alpha promoter drives a bicistronic message encoding the genes for human NOSII and the puromycin-resistant gene (pac). Subcellular localization of NOSII in the stably transfected clones was determined after differential centrifugation and showed that NOSII catalytic activity was exclusively cytosolic as determined by conventional activity assay. This was confirmed by immunostaining followed by fluorescent microscopy studies. The increase in NOSII activity in a series of transfected clones was associated with an increase in TPZ metabolism and toxicity under hypoxic conditions. There was no similar increase in aerobic toxicity. These findings are of significance for two reasons. First, cellular NOSII activity, similar to that seen in human breast cancer, could contribute to TPZ toxicity; second, this will be a result of NOS-derived/cytosol-associated TPZ radicals.
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PMID:Non-nuclear localized human NOSII enhances the bioactivation and toxicity of tirapazamine (SR4233) in vitro. 1276 34

We previously reported the identification of a novel zinc-finger gene, designated ZSG, fused to Ewing sarcoma gene (EWS) by a submicroscopic paracentric inversion of 22q12 in a small round cell sarcoma presenting a translocation t(1;22)(p34;q12). We report here the molecular cloning and characterization of the breakpoint in 1p34, which encompasses the gene coding for mitochondrial Hinge protein ubiquinol-cytochrome C reductase hinge gene (UQCRH). All the three breakpoints, two on 22q12 and one in 1p34, interrupt different genes: EWS, ZSG and UQCRH. We determined the genomic structure of UQCRH, characterized its splicing variants and identified a transcribed processed pseudogene. The analysis of UQCRH expression in normal tissues and cancer cell lines revealed absent expression of UQCRH in two ovarian and one breast cancer cell lines and reduced expression in a further breast carcinoma cell line. CpG island methylation upstream exon 1 was detected in all the three cell lines with absent expression. Moreover, treatment with demethylating agent 5-azacytidine restored UQCRH expression in OAW42 ovarian cancer cells. These data provide preliminary evidence of the inactivation of UQCRH gene in cancer either by structural rearrangements or epigenetic mechanisms.
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PMID:UQCRH gene encoding mitochondrial Hinge protein is interrupted by a translocation in a soft-tissue sarcoma and epigenetically inactivated in some cancer cell lines. 1288 16

Doxorubicin is a useful antineoplastic drug with multiple mechanisms of cytotoxicity. One such mechanism involves the reductive bioactivation of the quinone ring to a semiquinone radical, which can exert direct toxic effects and/or undergo redox cycling. We hypothesized that human NADPH-cytochrome p450 reductase (CYPRED) catalyzes doxorubicin reduction and that overexpression of this enzyme sensitizes human breast cancer cell lines to the aerobic cytotoxicity of doxorubicin. cDNA-expressed human CYPRED catalyzed doxorubicin reduction, measured as the rate of doxorubicin-stimulated NADPH consumption. Using a bank of 17 human liver microsomal samples, the rate of doxorubicin reduction correlated with CYPRED catalytic activity and CYPRED protein immunoreactivity. Diphenyliodonium chloride, a mechanism-based inactivator of CYPRED, inhibited CYPRED activity and doxorubicin reduction in human liver microsomes with similar concentration dependence. Stably transfected clones of MDA231 human breast cancer cells overexpressing human CYPRED immunoreactive protein and catalytic activity showed enhanced sensitivity to the aerobic cytotoxicity of tirapazamine, a bioreductive drug known to be activated by CYPRED; however, no sensitization to the cytotoxic effects of doxorubicin was observed. Although human CYPRED is an important catalyst of doxorubicin reduction, overexpression of this enzyme does not confer enhanced sensitivity of human breast cancer cells to the aerobic cytotoxicity of doxorubicin.
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PMID:Human NADPH-cytochrome p450 reductase overexpression does not enhance the aerobic cytotoxicity of doxorubicin in human breast cancer cell lines. 1458 91

Women with high androgen levels appear to be at increased risk for breast cancer. The 5-alpha-reductase type 2 enzyme (SRD5A2) is an important mediator of local androgen actions. The SRD5A2 gene contains a polymorphism leading to a valine to leucine change in codon 89 (V89L). The Leu allele has been associated with lower SRD5A2 activity and might be protective for breast cancer. At the same time, among breast cancer patients, the Leu allele has been associated with lower prostate-specific antigen expression, indicating poor prognosis. Within a cohort of breast cancer screening participants in the Netherlands (DOM-cohort) we examined whether the V89L polymorphism is associated with the risk and prognosis of breast cancer. We studied 295 postmenopausal breast cancer cases and a randomly selected reference group from the baseline cohort (n = 382). The genotype distribution in the reference group was: VV 52%; VL 40%; and LL 8%. Compared with women with the VV genotype, adjusted breast cancer rate ratios for women with VL and LL genotypes were 1.5 (95% confidence interval = 1.0-2.2) and 1.1 (95% confidence interval = 0.5-2.1), respectively. Compared with breast cancer patients with VV or VL genotypes, those with the LL genotype showed larger tumors (proportion with size > 2 cm is 26 versus 55%, respectively; P = 0.07), a higher frequency of positive lymph nodes (28 versus 55%, respectively; P = 0.09), and a higher tumor-node-metastasis stage (proportion with stage III/IV: 6 versus 25%, respectively; P = 0.04). The LL genotype is also associated with shorter survival than the VV and VL genotypes (P = 0.10). In conclusion, our findings do not provide evidence for an important role of the V89L polymorphism in the etiology of breast cancer. However, in breast cancer patients, the LL genotype may be associated with unfavorable prognosis.
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PMID:The V89L polymorphism in the 5-alpha-reductase type 2 gene and risk of breast cancer. 1465 80

Competitive inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase are commonly used in the clinic to treat hypercholesterolemia and have been reported to exert antitumor effects. Cerivastatin is a novel, synthetic and the most pharmacologically potent inhibitor of HMG-CoA reductase. We decided to examine the cytostatic/cytotoxic activity of cerivastatin against human breast cancer cell lines and to test whether the effects of cerivastatin could be potentiated by doxorubicin and cisplatin. Cytostatic/cytotoxic effects of cerivastatin used alone or in the combination with chemotherapeutics were measured with MTT assay. The cell cycle distribution and apoptosis induction were evaluated with flow cytometer. The expression of p21 and p27 cyclin-dependent kinase inhibitors was measured with Western blotting. Isobologram analysis was performed to study the drug interactions. We observed that cerivastatin exerts cytostatic/cytotoxic effects against four human tumor cell lines (T-47D, T4-2, MDA-MB-231, MCF-7). We also demonstrated that cerivastatin exerts growth inhibitory effect through induction of p21 cyclin-dependent kinase inhibitor and inhibition of cell cycle progression. In the two tumor cell lines studied, one sensitive (MDA-MB-231) and one moderately resistant (T4-2) to the cytostatic/cytotoxic effects of cerivastatin we examined the effects of combined treatment with cerivastatin and either doxorubicin or cisplatin. Cerivastatin potentiated cytostatic/cytotoxic effects of cisplatin against T4-2 cells and those of doxorubicin against both cell lines. In T4-2 cells the interaction between doxorubicin and cerivastatin and between cisplatin and cerivastatin was found to be synergistic. Altogether, these studies indicate that cerivastatin is another HMG-CoA reductase inhibitor with potent antitumor effects.
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PMID:Cerivastatin demonstrates enhanced antitumor activity against human breast cancer cell lines when used in combination with doxorubicin or cisplatin. 1506 36


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