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)

Glutathione peroxidase is a selenium-containing, antioxidant enzyme previously implicated in the risk and development of lung and breast cancer, in part the result of allelic loss at the GPx-1 locus. This study examined allelic loss at the same locus in squamous cell carcinomas of the head and neck. The frequency of a polymorphism at codon 198 resulting in either a leucine or a proline at that position was surveyed by comparing 133 DNA samples obtained from head and neck tumors and 517 samples obtained from cancer-free individuals. Tumor DNAs exhibited fewer pro/leu heterozygotes as compared to DNA obtained from the cancer-free population. Fewer GPx-1 heterozygotes were verified by determining the frequency of highly polymorphic alanine repeat sequences in the same gene. The analysis revealed an approximately 42% reduction in heterozygosity in the DNA from the tumor samples. In order to assess loss of heterozygosity (LOH) at the GPx-1 locus, DNA was genotyped from peripheral lymphocytes, tumor tissue, and microscopically normal tissues adjacent to the tumor, derived from the same patients. These studies indicated LOH at the GPx-1 locus in each of the three tumor/normal tissues sample sets examined. Furthermore, LOH in the microscopically normal tissues at the tumor margin occurred in two of the three sample sets examined. These data implicate GPx-1 in the development of squamous cell carcinoma the head and neck and suggest that allelic loss of this gene, or one tightly linked to it, is an early event in the development of this type of malignancy.
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PMID:Allelic loss at the GPx-1 locus in cancer of the head and neck. 1555 74

Human progesterone receptors (PR) are phosphorylated by cyclin-dependent protein kinase 2 (CDK2) at multiple sites, including Ser400. Herein, we have addressed the significance of phosphorylation of this residue. PR phospho-Ser400-specific antibodies revealed regulated phosphorylation of Ser400 in response to progestins and mitogens, and this correlated with increased CDK2 levels and activity. Expression of cyclin E elevated CDK2 activity and downregulated PR independently of ligand. Similarly, overexpression of activated mutant CDK2 increased PR transcriptional activity in the absence and presence of progestin. Mutation of PR Ser400 to alanine (S400A) blocked CDK2-induced PR activity in the absence, but not in the presence, of progestin. PR was unresponsive to activated CDK2 in breast cancer cells with elevated p27, and RNA interference knock-down of p27 partially restored CDK2-induced ligand-independent PR activation. Similarly, in p27(-/-) mouse embryonic fibroblasts, elevated CDK2 activity increased wild-type (wt) but not S400A PR transcriptional activity in the absence of progestin. CDK2 induced nuclear localization of unliganded wt but not S400A PR; liganded S400A PR exhibited delayed nuclear accumulation. These studies demonstrate that CDK2 regulates PR in the absence of progestins via phosphorylation of Ser400, thus revealing a novel mechanism for upregulated PR transcriptional activity in human breast cancer cells expressing altered cell cycle regulatory molecules.
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PMID:Phosphorylation of progesterone receptor serine 400 mediates ligand-independent transcriptional activity in response to activation of cyclin-dependent protein kinase 2. 1557 62

Endogenous oestrogens play a crucial role in endometrial cancer pathogenesis, with most endometrial cancer risk factors causing an increase in oestrogens. Adipose tissue, where androgens are converted to oestrogens by the enzyme aromatase, is an important source of endogenous oestrogen production in the postmenopausal woman. The peroxisome proliferator-activated receptor-gamma (PPARgamma), a key transcriptional regulator of adipogenesis, may also play a role in the regulation of aromatase expression in adipose tissue. We hypothesized that the functional PPARgamma ProAla polymorphism may alter aromatase expression, ultimately affecting endometrial cancer susceptibility. We genotyped the PPARgamma ProAla polymorphism in a study of invasive endometrial cancer cases (n = 222) and matched controls (n = 666) nested within the Nurses' Health Study Cohort. We found little or no evidence of an association between the Ala allele of the PPARgamma codon 12 polymorphism and endometrial cancer risk (adjusted odds ratio = 1.18, 95% confidence interval = 0.80-1.76). Furthermore, we found no association with the PPARgamma ProAla polymorphism and the ratio of oestrone to androstenedione or oestradiol to testosterone plasma hormone levels, measures of aromatase activity. Consistent with previous findings for breast cancer, these results suggest that the PPARgamma ProAla polymorphism does not play a major role in mediating circulating oestrogen levels or endometrial cancer susceptibility.
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PMID:No evidence of a role for PPARgamma Pro12Ala polymorphism in endometrial cancer susceptibility. 1560 64

Naturally occurring isoforms of the decapeptide gonadotropin-releasing hormone (GnRH) share residues 1-4 and 9-10. lGnRH-III, the third isoform isolated in the sea lamprey has no endocrine effect in mammals but shows a direct antiproliferative effect on human breast, prostate and endometrial cancer cell lines. To investigate these features, residues 5-8 of lGnRH-III were systematically replaced with Ala. The ability of the synthetic analogs to interact with receptors on MDA-MB 231 human breast cancer cells and their effect on the growth of the same cell line were investigated. [Ala6]lGnRH-III and [Ala7]lGnRH-III have neither receptor binding nor antiproliferative activity. Replacement of His5 with Ala resulted in an analog that binds to the receptor but does not have antiproliferative activity. The results are in agreement with previous reports that modifications of Lys at position 8 are well tolerated.
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PMID:Importance of the central region of lamprey gonadotropin-releasing hormone III in the inhibition of breast cancer cell growth. 1565 48

Cytochrome P450 1B1 (CYP1B1) and catechol-O-methyltransferase (COMT) are important estrogen-metabolizing enzymes and, thus, genetic polymorphisms of these enzymes may affect breast cancer risk. A population-based case-control study was conducted to assess the association of breast cancer risk with CYP1B1 and COMT polymorphisms. A meta-analysis was done to summarize the findings from this and previous studies. Included in this study were 1,135 incident breast cancer cases diagnosed from August 1996 through March 1998 among female residents of Shanghai and 1,235 randomly selected, age frequency-matched controls from the same general population. The common alleles of the CYP1B1 gene were Arg (79.97%) in codon 48, Ala (80.53%) in codon 119, and Leu (86.57%) in codon 432. The Val allele accounted for 72.46% of the total alleles identified in codon 108/158 of the COMT gene. No overall associations of breast cancer risk were found with any of the single nucleotide polymorphisms described above. This finding was supported by a meta-analysis of all previous published studies. No gene-gene interactions were observed between CYP1B1 and COMT genotypes. The associations of breast cancer risk with factors related to endogenous estrogen exposure, such as years of menstruation and body mass index, were not significantly modified by the CYP1B1 and COMT genotypes. We observed, however, that women who carried one copy of the variant allele in CYP1B1 codons 48 or 119 were less likely to have estrogen receptor-positive breast cancer than those who carried two copies of the corresponding wild-type alleles. The results from this study were consistent with those from most previous studies, indicating no major associations of breast cancer risk with CYP1B1 and COMT polymorphisms.
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PMID:Cytochrome P450 1B1 and catechol-O-methyltransferase genetic polymorphisms and breast cancer risk in Chinese women: results from the shanghai breast cancer study and a meta-analysis. 1573 54

It has been established that protein kinase Czeta (PKCzeta) participates in diverse signaling pathways and cellular functions in a wide variety of cells, exhibiting properties relevant to cellular survival and proliferation. Currently, however, the regulation mechanism of PKCzeta remains elusive. Here, for the first time, we determine that phospholipase D2 (PLD2) enhances PKCzeta activity through direct interaction in a lipase activity-independent manner. This interaction of the PLD2-Phox homology (PX) domain with the PKCzeta-kinase domain also induces the activation loop phosphorylation of PKCzeta and downstream signal stimulation, as measured by p70 S6 kinase phosphorylation. Furthermore, only the PLD2-PX domain directly stimulates PKCzeta activity in vitro, and it is necessary for the formation of the ternary complex with phosphoinositide-dependent kinase 1 and PKCzeta. The mutant that substitutes the triple lysine residues (Lys101, Lys102, and Lys103) within the PLD2-PX domain with alanine abolishes interaction with the PKCzeta-kinase domain and activation of PKCzeta. Moreover, breast cancer cell viability is significantly affected by PLD2 silencing. Taken together, these results suggest that the PLD2-mediated PKCzeta activation is induced by its PX domain performing both direct activation of PKCzeta and assistance of activation loop phosphorylation. Furthermore, we find it is an important factor in the survival of breast cancer cells.
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PMID:Novel functions of the phospholipase D2-Phox homology domain in protein kinase Czeta activation. 1579 5

Mutations in the breast cancer susceptibility gene 1 (BRCA1) account for a substantial percentage of familial breast and ovarian cancers. Although BRCA1 is thought to function within the nucleus, it has also been located in the cytoplasm. In addition, BRCA1 accumulates in the nucleus of cells treated with leptomycin B, an inhibitor of chromosome region maintenance 1-mediated nuclear export, indicative of its active nuclear export via this pathway. The nuclear export signal in BRCA1 has been described as consisting of amino acid residues 81-99. However, a number of other tumor suppressors have multiple nuclear export sequences, and we sought to determine whether BRCA1 did also. Here, we report that BRCA1 contains a second nuclear export sequence that comprises amino acid residues 22-30. By use of the human immunodeficiency virus-1 Rev complementation assay, this sequence was shown to confer export capability to an export-defective Rev fusion protein. The level of export activity was comparable with that of residues 81-99 comprising the previously reported nuclear export sequence in BRCA1. Mutation of leucine 28 to an alanine reduced nuclear export by approximately 75%. In MCF-7 cells stably transfected with a BRCA1 cDNA containing mutations in this novel sequence or the previously reported export sequence, BRCA1 accumulated in the nucleus. These data imply that BRCA1 contains at least two leucine-dependent nuclear export sequences.
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PMID:An amino-terminal motif functions as a second nuclear export sequence in BRCA1. 1581 49

The process of epithelial-mesenchymal transition plays a pivotal role in the conversion of early stage tumors into invasive malignancies, and has been shown to be regulated by the zinc finger phosphoprotein, Snail; however, no upstream signaling kinases have been shown to modulate Snail functions. Since the invasiveness of breast cancer cells is also influenced by p21-activated kinase 1 (Pak1) signaling, we investigated Pak1's potential mechanistic role in the regulation of Snail functions. We found for the first time that Pak1 promotes transcription repression activity of Snail from E-cadherin, occludin, and aromatase promoters. Pak1 regulates the repressor activity of Snail by phosphorylating on Ser(246). Pak1 phosphorylation of Snail supports Snail's accumulation in the nucleus as well as its repressor functions. A Ser(246)Ala substitution in Snail or Pak1 knockdown by short interference RNA blocked Pak1-mediated Snail phosphorylation, leading to increased cytoplasmic accumulation of Snail and attenuation of Snail repressor activity in breast cancer cells. The regulation of phosphorylation and function of Snail by Pak1 represents a novel mechanism by which a signaling kinase might contribute to the process of epithelial-mesenchymal transition.
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PMID:Pak1 phosphorylation of snail, a master regulator of epithelial-to-mesenchyme transition, modulates snail's subcellular localization and functions. 1583 48

The estrogen receptor alpha (ERalpha) exists as a functional receptor at the plasma membrane. The structural requirements for localization and function are not well understood. Several laboratories have recently elucidated certain requirements. We recently found the translocation of ERalpha to the membrane in the absence of estrogen is dependent on caveolin-1 and serine 522 of the ERalpha protein. Mutation of serine 522 to alanine results in a 62% decrease in membrane localization and association with caveolin-1. Similarly, deletion of the caveolin-1 scaffolding domain (amino acids 60-100) largely prevents the localization of ERalpha at the plasma membrane. In the presence of estradiol (E2), ERalpha, Src-homology and collagen homology (Shc), and insulin-like growth factor receptor-1 proteins associate with and increase the localization of ERalpha at the membrane. Membrane-localized ERalpha functions as an atypical G-protein coupled receptor. There is no good evidence that ERalpha spans the membrane or contains an extracellular domain. E2/ERalpha activates different G-proteins in cell context-related fashion. These G-proteins lead to the activation of Src through PLC, PKC, IP3 and calcium influx. In breast cancer, Src activates matrix metalloproteinase-2 and -9, which cleaves heparin binding epidermal growth factor, and thus activates EGFR. This leads to downstream signaling through ERK and PI3 kinase, imparting cell growth and survival.
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PMID:Requirements for estrogen receptor alpha membrane localization and function. 1586 18

Oxidative stress has been related to aging. Recent evidences suggest that a genetic dimorphism that encodes for either alanine or valine in superoxide dismutase (SOD2) is involved with oxidative stress. However, the current literature is still controversial, and the potential role of the Ala16Val polymorphism in human aging needs to be established. Here we investigated the role of the SOD2 polymorphism in: a) age-related mortality, b) morbidity (breast and prostate cancer), c) immunological markers, and d) DNA damage in peripheral blood cells. We did not find an association between SOD2 polymorphisms and mortality. However, the AA genotype was associated with increased risk for prostate and breast cancer, immunosenescence profile, as well as DNA damage. These data suggest that SOD2 presents characteristics that support the free radical theory of aging.
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PMID:Is the Val16Ala manganese superoxide dismutase polymorphism associated with the aging process? 1593 80


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