Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tamoxifen (TAM) is a triphenylethylene antiestrogen used for the treatment, and in clinical trials for the prevention, of breast cancer in women. In rats, TAM is a strong liver carcinogen which induces the formation of liver DNA adducts. The DNA of 24 hepatocarcinomas (HCCs) collected at necropsy from individual female Sprague-Dawley rats that were given 22.6 mg/kg TAM daily for 12 months was studied for the presence of mutations in exons 5-9 of the p53 gene by single-strand conformation polymorphism and DNA sequencing analysis. The sequences of introns 5-8 of the rat p53 gene were determined in order to design primers homologous to regions located in these introns. p53 mutations were found in 50% (12 of 24) of the HCCs. These mutations were all specifically clustered in two sites, codons 231 (exon 6-7) and 294 (exon 8). Nine HCCs contained a transition from adenine to guanine in the second base of codon 231 (CAC to CGC), which resulted in a histidine to arginine amino acid substitution; 4 HCCs contained a nonmiscoding transition from cytosine to thymidine in the third base of codon 294 (TGC to TGT; cysteine to cysteine). One HCC contained both mutations. The present report supports previous observations on the genotoxicity of TAM in rodents and raises concerns about its use as a chemopreventive agent against breast cancer in women.
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PMID:Frequent and specific mutations of the rat p53 gene in hepatocarcinomas induced by tamoxifen. 803 8

Tamoxifen exerts a variety of genomic effects which explains, in part, its efficacy in both hormone-responsive and independent tumours. The above quotation expresses this in a timeless and elegant way: our understanding of antiestrogen action has been narrowly fettered by the simplistic interpretation of this drug as an antihormone. The regulatory and controlling influence of Tamoxifen on numerous genes involved in apoptosis (p53, Bcl 2, c-myc, erb-B2 and others) will be discussed in this review.
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PMID:Genomic effects of tamoxifen. 904 18

The current literature on endometrial neoplasia deals with proliferative lesions such as endometrial proliferation in early pregnancy, atypical polypoid adenomyofibromata and their possible relationship to carcinoma, and histological grading of endometrial cancer with emphasis on nuclear grading and subtypes of endometrial cancer including the newly described intestinal and hepatoid types. Recent publications dealing with p53 protein, genetic studies, and nucleolar organizer regions are of interest but have provided no striking new insight into endometrial neoplasia. Angiogenesis has appeared for the first time in the literature in connection with endometrial neoplasia. Tamoxifen continues to occupy an important place in the literature, and endometrial adenosarcoma has been identified recently as one of the myriad of lesions which patients treated with tamoxifen are prone to develop.
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PMID:Endometrial pathology. 909 Apr 83

To elucidate potential mechanisms involved in the increased incidence of endometrial carcinomas in tamoxifen-treated patients, we examined the in-vitro effects of tamoxifen on endometrial cancer cells. The effects of tamoxifen, alone and in combination with oestradiol, on cell proliferation, plasminogen activator (PA) activity, glycogen synthase and phosphorylase activities, p53 protein concentration, and collagenase expression were assessed in two human adenocarcinoma cell lines. These lines were the oestrogen receptor-positive (Ishikawa) cells, representing a well-differentiated endometrial adenocarcinoma, and oestrogen receptor-negative (HEC-1A) cells, derived from a poorly differentiated endometrial adenocarcinoma. Tamoxifen or oestradiol alone and their combination significantly enhanced cellular proliferation of Ishikawa but not of HEC-1A cells. Both lines produced appreciable PA activity, most of which was of the urokinase type. Tamoxifen and oestradiol stimulated this activity in Ishikawa cells but not in HEC-1A cells. The effect of oestradiol was dose-dependent in a linear fashion, while tamoxifen produced a stimulation peaking at 10(-8) M and declining at higher concentrations. Tamoxifen in combination with oestradiol exhibited a synergistic effect on proliferation and on PA activity. The response of PA extended beyond the increase in proliferation, leading to higher specific activity of PA in the tamoxifen-treated cultures. In Ishikawa cells, oestradiol also increased glycogen synthase and glycogen phosphorylase activities, while tamoxifen markedly suppressed these enzymes. Oestradiol, tamoxifen, and their combination had no apparent effect on the expression of protein p53 in Ishikawa cells, or on gelatinase activity in either Ishikawa or HEC-1A cells. The present findings imply that tamoxifen produces oestrogen-agonistic effects on cell proliferation and PA activity, and oestrogen antagonistic effects on glycogen synthase and glycogen phosphorylase activities, but fails to regulate p53 and gelatinase expression. The tamoxifen-responsive systems were only observed in oestrogen-responsive adenocarcinoma cells. Thus, only certain potential oncogenic effects of tamoxifen can be simulated in vitro, and when present, these effects are enhanced in the presence of oestradiol.
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PMID:Tamoxifen exerts oestrogen-agonistic effects on proliferation and plasminogen activation, but not on gelatinase activity, glycogen metabolism and p53 protein expression, in cultures of oestrogen-responsive human endometrial adenocarcinoma cells. 946 46

Estrogens are important for both normal cell growth and malignant proliferation in the mammary gland as well as in the endometrium. Tamoxifen is a non-steroidal anti-estrogen widely used in breast cancer treatment. In recent years reports have been made of an increased risk of endometrial carcinoma during tamoxifen treatment. We used surgically menopausal cynomolgus macaques to study proliferation and p53 expression during hormonal replacement therapy (HRT) and tamoxifen treatment. Animals were treated continuously for 35 months with either conjugated equine estrogens (CEE; n = 20); medroxyprogesterone acetate (MPA; n = 17); the combination of CEE + MPA (n = 13); or tamoxifen (n = 17) for 35 months. We found an increased expression of p53 in normal breast and endometrial tissue linked to CEE but not tamoxifen treatment. In the breast alveoli there was an association between proliferation measured by morphometry and p53 expression in all groups. However, in the endometrium CEE induced significantly more p53 positivity than tamoxifen, 9/20 vs. 3/17 in glands and 9/19 vs. 0/17 in stroma, respectively. If indeed long-term treatment with tamoxifen as in the present study could inactivate the tumor-suppressive function of p53, endometrial cells might thereby become more susceptible to genetic lesions associated with carcinogenesis.
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PMID:p53 expression in breast and endometrium during estrogen and tamoxifen treatment of surgically postmenopausal cynomolgus macaques. 1020 73

Tamoxifen, a rat liver carcinogen, can induce mutations in the lacI gene in the livers of lambda/lacI transgenic rats. However, the presence of persistent tamoxifen adducts on the liver DNA raises the possibility that some contribution to the mutagenesis from ex vivo mutations during the in vitro lacI assay cannot be ruled out. To address this issue, mutagenesis at the cII gene of the transgenic shuttle vector was determined using a selection based assay which is unaffected by the presence of tamoxifen-DNA adducts. Female lambda/lacI transgenic rats were dosed orally with tamoxifen (20 mg/kg body wt) daily for 6 weeks, causing a 3.2-fold increase in the mutant frequency (MF) in the cII gene compared with that obtained with solvent treated animals. This was similar to the MF found previously at the lacI gene and confirms that tamoxifen is mutagenic in vivo. The major class of mutation induced by tamoxifen in the cII gene was G:C-->T:A transversions as was found previously in the lacI gene. However, in the one unreplicated study of mutations in the p53 gene of liver tumours induced by tamoxifen, no G:C-->T:A transversions were found; possible differences between mutagenesis in normal and tumour tissues are explored. The major proportion of the G:C-->T:A transversions occurred at 5'-CpG-3' dinucleotide (CpG) sites in the lacI gene, but not at such sites in the cII gene. The methylation of CpG sites greatly enhances the targeting of deoxyguanosine by carcinogens, thus this finding might be explained by differences in the methylation patterns at their respective CpG sites; however, nothing is known about the methylation status of either the lacI nor the cII gene in this transgenic rat. This study raises the important issue of which target genes (mammalian or transgenic) should be used as endpoints in mammalian mutagenesis assays.
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PMID:Tamoxifen induces G:C-->T:A mutations in the cII gene in the liver of lambda/lacI transgenic rats but not at 5'-CpG-3' dinucleotide sequences as found in the lacI transgene. 1038 11

Tamoxifen (TAM) has been shown to induce apoptosis in breast cancer cells. bcl-2 family genes, which can interact with each other, have been shown to interfere with apoptosis after various stimuli. In this study, we investigated the effects of TAM on bcl-2 family gene products bcl-2, bax, and bcl-X(L) and on p53 levels in estrogen receptor-positive MCF-7 breast cancer cells. We found that TAM induced time- and concentration-dependent down-regulation of bcl-2 at both the mRNA and protein level. Down-regulation of bcl-2 correlated with TAM-induced apoptosis. In addition, estradiol treatment significantly increased bcl-2 protein expression and blocked the reduction of bcl-2 by TAM. TAM did not, however, affect bax, bcl-X(L), or p53 expression at the mRNA or protein level. Our results demonstrate that TAM can induce apoptosis in a time- and dose-dependent manner by modulating bcl-2 levels in breast cancer cells, and down-regulation of bcl-2 induced by TAM was not accompanied by alterations in p53 levels.
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PMID:Tamoxifen-induced apoptosis in breast cancer cells relates to down-regulation of bcl-2, but not bax and bcl-X(L), without alteration of p53 protein levels. 1053 67

Studies of the mechanism of actions of estrogen, antiestrogen and physical factors may provide clues to an understanding of breast cancer growth and/or regression regulation and thus identify novel targets for therapeutic intervention. Defective control of apoptosis appears to play a central role in the pathogenesis of neoplasia. Conversely, cancer therapy and ionizing radiation can induce cancer cell death by apoptosis and/or necrosis. bcl-2 gene and p-53 gene products have been both linked to programmed cell death pathways. We have analyzed the effect of estradiol, tamoxifen and UV exposure on the induction of apoptosis, expression of p53 and bcl-2 gene products as well as the proliferative activity (expressed as [3H]thymidine incorporation and PCNA and MPM2 antigens involvement) in MCF7. It has been found that estradiol increases the speed of cell cycle in MCF7 and acts as antiapoptotic factor. Tamoxifen has multiple influence on the rate of growth of cancer cells: depends on estrogen receptor (ER), conducts reduction of proliferation rate; depends on ER and other mechanisms conducts to suppressions of Bcl-2 protein expression and induction of cell death through apoptotic pathway. Estradiol prevents the apoptotic influence of tamoxifen probably by enhancement of Bcl-2 protein expression and does not prevent the inhibition of proliferation rate. The irradiation with UV induces apoptosis by over-expression of p53 and down-regulation of bcl-2 gene.
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PMID:Influence of estrogen, antiestrogen and UV-light on the balance between proliferation and apoptosis in MCF-7 breast adenocarcinoma cells culture. 1087 Jun 82

Tamoxifen is one of the most effective treatments for breast cancer. Standard practice is to select patients who are likely to respond to this therapy through the evaluation of estrogen receptor (ER) and progesterone receptor (PR) in the primary tumor tissue. Over the past 25 yr that physicians have been using ER determination to guide tamoxifen use, numerous studies have demonstrated that this molecular marker is useful in predicting benefit from tamoxifen. ER has been analyzed for many years using ligand-binding assays. However, current practice involves the use of immunohistochemical-based assays to detect ERalpha Immunohistochemistry (IHC) has several advantages. For example, IHC evaluates tumor cell heterogeneity, can be used to study small samples, is less expensive, and allows direct correlation with multiple histopathological tumor features and other molecular markers. PR, an estrogen-responsive protein, can also be useful in predicting response to tamoxifen in specific clinical situations. In recent years, several other markers of tamoxifen response have been examined, including: pS2 (another estrogen-regulated protein), heat-shock proteins 27 and 70, bcl-2 protein, c-erbB-2 (HER-2/neu) oncoprotein, and mutated p53 tumor suppressor protein. In this article, we present an analysis of the data on these new molecular markers. Overall, from numerous studies, the data indicate that in addition to ERalpha bcl-2 is a potential candidate to help further improve our ability to predict response to tamoxifen. ER and bcl-2 are the most useful molecular markers to better identify breast cancer patients who will respond to tamoxifen and who will have prolonged survival.
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PMID:Molecular markers for predicting response to tamoxifen in breast cancer patients. 1105 Oct 41

Despite the widespread clinical use of tamoxifen as a breast cancer prevention agent, the molecular mechanism of tamoxifen chemoprevention is poorly understood. Abnormal expression of p53 is felt to be an early event in mammary carcinogenesis. We developed an in vitro model of early breast cancer prevention to investigate how tamoxifen and 4-hydroxytamoxifen may act in normal human mammary epithelial cells (HMECs) that have acutely lost p53 function. p53 function was suppressed by retrovirally mediated expression of the human papillomavirus type 16 E6 protein. Tamoxifen, but not 4-hydroxytamoxifen, rapidly induced apoptosis in p53(-) HMEC-E6 cells as evidenced by characteristic morphologic changes, annexin V binding, and DNA fragmentation. We observed that a decrease in mitochondrial membrane potential, mitochondrial condensation, and caspase activation preceded the morphologic appearance of apoptosis in tamoxifen-treated early passage p53(-) HMEC-E6 cells. p53(-) HMEC-E6 cells rapidly developed resistance to tamoxifen-mediated apoptosis within 10 passages in vitro. Resistance to tamoxifen in late passage p53(-) HMEC-E6 cells correlated with an increase in mitochondrial mass and a lack of mitochondrial depolarization and caspase activation following tamoxifen treatment. We hypothesize that an early event in the induction of apoptosis by tamoxifen involves mitochondrial depolarization and caspase activation, and this may be important for effective chemoprevention.
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PMID:Tamoxifen but not 4-hydroxytamoxifen initiates apoptosis in p53(-) normal human mammary epithelial cells by inducing mitochondrial depolarization. 1109 56


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