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)

Fine-needle aspiration cytology has been already established as a reliable method for the diagnosis of breast cancer. Its application has been recently extended to immunocytochemical analysis of biological parameters. In the current study estrogen and progesterone receptors, Ki67 growth fraction, and p53 protein expression were immunocytochemically evaluated on the cellular material sampled by the same fine-needle aspirate used for the conventional cytologic diagnosis of malignancy. Fine-needle aspiration specimens from 100 patients with primary breast carcinoma were submitted to the immunocytochemical analysis. Twenty-eight percent were in premenopause; 23% had tumors with a diameter less than 2 cm, 59% from 2 to 5 cm, and 18% more than 5 cm; 60% had axillary nodal status negative, 34% positive, and 6% unknown. The concomitant immunocytochemical evaluation of all parameters was possible in 70% of the patients. A significant association was found between p53 overexpression and Ki67 values (p = 0.004), and between Ki67 values and progesterone receptor status (p = 0.003). No correlation was found between any parameter and clinical tumor size. Estrogen (p = 0.02) and progesterone (p = 0.04) receptor negativity and high Ki67 growth fraction (p = 0.005) were significantly associated with the clinical evidence of axillary node involvement. This study suggests that fine-needle aspiration cytology represents an effective practice for a simultaneous evaluation of multiple biologic indicators and could be useful as a preoperative procedure in patients who are candidates for neoadjuvant chemotherapy and/or endocrine therapy.
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PMID:Fine-needle aspiration technique for the concurrent immunocytochemical evaluation of multiple biologic parameters in primary breast carcinoma. 786 51

Cervical cancer is not considered a hormone-responsive tumor in spite of the presence of estrogen receptors (ER) and progesterone receptors (PgR) in some of them. Endocrine treatments have not achieved clinical responses, however, tamoxifen has been reported to induce PgR and to inhibit cell growth of many cervical carcinoma cell lines. In this study we investigated whether tamoxifen administration affects the histopathological characteristics of cervical cancer and the expression of ER, PgR, HER-2/neu and p53 protein. Nineteen patients with invasive cervical cancer free of previous treatments were studied. The triphenylethylene antiestrogen tamoxifen was given orally during 10 days (20 or 40 mg/day). Pre- and post-tamoxifen biopsies were evaluated using slides stained with hematoxylin and eosin and immunostained (ER, PgR, HER-2/neu, p53, PCNA, keratin, heat shock protein 27,000 daltons). Estrogen receptors were present in 37% and PgR in 16% of the biopsies from untreated patients. Only one case that was PgR-negative before tamoxifen administration showed weak PgR-positivity following antiestrogen administration. No obvious changes were observed in ER, HER-2/neu and p53 proteins. A statistically significant decrease in the number of mitotic figures was obtained in 16% (3/19) of the post-tamoxifen biopsies and two of them showed higher differentiation. The results showed that tamoxifen did not induce changes in estrogen-regulated proteins in cervical cancer. However, the data showed that certain cervical carcinomas had changes in their proliferation and differentiation levels following tamoxifen administration. These findings suggest that tamoxifen may affect some cervical cancer tissues by a hormone-independent mechanism(s).
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PMID:Effects of short-term tamoxifen administration in patients with invasive cervical carcinoma. 790 50

The selection of patients with axillary lymph node-negative breast cancer who should receive adjuvant therapy today is confused by an expanding arsenal of putative prognostic factors. The size of the primary tumor remains the dominant factor in sorting among this group of patients, with general agreement that tumors 1 cm or less should be spared adjuvant systemic therapy outside of a clinical trial. There are a few favorable histologic subgroups that may be added to this excluded group: ductal carcinoma in situ and pure tubular, papillary, and typical medullary tumors. For the larger tumor (generally > 2 cm in diameter, but always > 3 cm), there is little disagreement that adjuvant therapy is indicated. The host of additional prognostic factors are directed mainly toward the group of tumors that fall between these two categories. Nuclear grade, S-phase, and perhaps p53 mutations influence decisions for treatment by their elevation. Although the decision remains with the patient and the recommendation with the mature judgment of the clinician, the prognostic indicators available continue to multiply. That an indicator can retrospectively sort prognosis is of limited interest. It requires prospective validation in another patient population, reproducibility in other laboratories, and multivariate analysis among factors measured on the same population of patients to integrate a factor into clinical decision-making. It is only beginning to be accomplished. The next generation of factors being sought are those that predict for response or lack of response to specific therapies, rather than merely indicating natural history. Estrogen and progesterone receptors are the prototypes of this class of indicators.
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PMID:Integration of risk factors to allow patient selection for adjuvant systemic therapy in lymph node-negative breast cancer patients. 819 75

The human p53-binding protein murine double minute 2 (MDM2) is believed to function as a negative regulator of p53. The MDM2 gene was cloned and sequenced only recently and was found to be amplified in a variety of sarcomas. Although mutations in the p53 gene have been shown to occur in human breast carcinoma (HBC), no information is available on MDM2 gene expression in HBC. In this study we report for the first time that the MDM2 gene is differentially expressed in HBC. Our results demonstrate a correlation between the estrogen receptor (ER) status and the MDM2 mRNA levels. In contrast to the ER-negative cell lines, all the ER-positive cell lines were found to express higher levels of MDM2 mRNA. ER-positive ZR-75 cells express 30-fold higher levels of MDM2 mRNA than does the ER-negative cell line Hs578T. Estrogen enhanced albeit modestly the MDM2 mRNA levels in ER-positive MCF-7 cells. Estrogen enhancement of MDM2 mRNA levels was also observed in ER-negative MDA-MB-231 cells transfected with functional ERs. Our data thus suggest that estrogen may play an important role in HBC growth stimulation by modulating the expression of MDM2, which in turn may inactivate the p53 function.
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PMID:The p53-binding protein MDM2 gene is differentially expressed in human breast carcinoma. 832 31

Thirty-nine mammographically detected, (M-detected) small invasive carcinomas of the breast (< or = 5 mm) were compared with 78 consecutive clinical cancers (> or = 10 mm) for a variety of morphological and biological markers of prognostic importance. There were more tubular carcinomas in the M-detected group (12.8% v 3.8%), but this did not reach statistical significance. Incidences of other histological types were similar. The types of associated in situ component were similar in the two groups. M-detected cancers were of lower overall grade (P < .001), lower architectural and nuclear grades (P = .0164 and P < .0001 respectively), and had fewer mitotic cells (P < .0001). None showed positive lymph nodes (P < .0001). Estrogen and progesterone receptor expression was similar in both groups. M-detected cancers expressed p53 nuclear protein less frequently than clinical cancers (P = .0398), had lower levels of microvessel density (P = .0001), and were more often diploid (P = .0131). S-phase of diploid tumors in the two groups was similar, but S-phase of aneuploid tumors was lower in the M-detected group (P = .0057). Ki67 expression was lower in M-detected cancers (P < .0001). In conclusion, M-detected small breast cancers, although invasive, represent an evolutionary phase of breast cancer that generally lacks morphological and biologic markers of aggressive behavior. The presence or absence of these markers, collectively, may explain the influence of tumor size on survival in patients with breast cancer.
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PMID:Morphological and biological characteristics of mammogram-detected invasive breast cancer. 881 90

If exposure to xenoestrogens or electromagnetic fields (EMFs) such as 60 Hz contributes to the etiology of breast cancer, it is likely that they must stimulate the growth of breast cells, damage genetic material or enhance the effects of other mitogenic or mutagenic agents (co-promotion). Therefore, the ability of xenoestrogens or exposure to 60-Hz fields to stimulate the entry of growth-arrested human breast cancer cells into the cell cycle was determined using cyclin-dependent kinase 2 (Cdk2) activity, synthesis of cyclin D1 and cdc2 activity. Exposure of estrogen receptor-positive MCF-7 or T-47D cells to estrogen and xenoestrogens (DDT and Red No. 3) increased Cdk2 and cyclin B1-cdc2 activity and cyclin D1 synthesis. Exposure of breast cancer cells to 12 mG or 1 or 9 G electromagnetic fields at 60 Hz failed to stimulate Cdk2 or cyclin B1-cdc2 activity or cyclin D1 synthesis. Simultaneous co-exposure of cells to 60-Hz fields and chemical promoters did not enhance Cdk2 activation above the levels produced by the chemical promoter alone. Estrogen and xenoestrogens also stimulated binding of the estrogen receptor to the estrogen receptor element but the EMF did not. Phorbol 12-myristate 13-acetate (PMA) induced phosphorylation of p53 and pRb1O5 in MCF-7 cells, but EMF exposure had no effect. DNA-damaging chemotherapeutic agents and Red Dye No. 3 were found to increase p53 site-specific DNA binding in breast cancer cells, but EMF exposure did not. Differential display analysis failed to detect any effect of EMF exposure on gene expression in MCF-7 cells, whereas the effects of estradiol were detected. These studies suggest that estrogen and xenoestrogens stimulate growth-arrested breast cancer cells to enter the growth cycle, but EMF exposure does not. Site-specific p53-DNA binding was increased in MC F-7 cells treated with DNA-damaging agents, but not by EMF exposure. EMF exposure does not appear to act as a promoter or DNA-damaging agent for human breast cancer cells in vitro.
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PMID:Effects of 60-Hz fields, estradiol and xenoestrogens on human breast cancer cells. 892 16

Estrogen-like chemicals are unique compared to nonestrogenic xenobiotics, because in addition to their chemical properties, the estrogenic property of these compounds allows them to act like sex hormones. Whether weak or strong, the estrogenic response of a chemical, if not overcome, will add extra estrogenic burden to the system. At elevated doses, natural estrogens and environmental estrogen-like chemicals are known to produce adverse effects. The source of extra or elevated concentration of estrogen could be either endogenous or exogenous. The potential of exposure for humans and animals to environmental estrogen-like chemicals is high. Only a limited number of estrogen-like compounds, such as diethylstilbestrol (DES), bisphenol A, nonylphenol, polychlorinated biphenyls (PCBs), and dichlorodiphenyltrichloroethane (DDT), have been used to assess the biochemical and molecular changes at the cellular level. Among them, DES is the most extensively studied estrogen-like chemical, and therefore this article is focused mainly on DES-related observations. In addition to estrogenic effects, environmental estrogen-like chemicals produce multiple and multitype genetic and/or nongenetic hits. Exposure of Syrian hamsters to stilbene estrogen (DES) produces several changes in the nuclei of target organ for carcinogenesis (kidney): (1) Products of nuclear redox reactions of DES modify transcription regulating proteins and DNA; (2) transcription is inhibited; (3) tyrosine phosphorylation of nuclear proteins, including RNA polymerase II, p53, and nuclear insulin-like growth factor-1 receptor, is altered; and (4) DNA repair gene DNA polymerase beta transcripts are decreased and mutated. Exposure of Noble rats to DES also produces several changes in the mammary gland: proliferative activity is drastically altered; the cell cycle of mammary epithelial cells is perturbed; telomeric length is attenuated; etc. It appears that some other estrogenic compounds, such as bisphenol A and nonylphenol, may also follow a similar pattern of effects to DES, because we have recently shown that these compounds alter cell cycle kinetics, produce telomeric associations, and produce chromosomal aberrations. Like DES, bisphenol A after metabolic activation is capable of binding to DNA. However, it should be noted that a particular or multitype hit(s) will depend upon the nature of the environmental estrogen-like chemical. The role of individual attack leading to a particular change is not clear at this stage. Consequences of these multitypes of attack on the nuclei of cells could be (1) nuclear toxicity/cell death; (2) repair of all the hits and then acting as normal cells; or (3) sustaining most of the hits and acting as unstable cells. Proliferation of the last type of cell is expected to result in transformed cells.
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PMID:Biochemical and molecular changes at the cellular level in response to exposure to environmental estrogen-like chemicals. 901 29

Estrogen binds to two classes of proteins in the cells, the high-affinity estrogen receptor (ER) as well as a low affinity estrogen type II binding site (EBS-II). Methyl p-hydroxyphenyllactate (MeHPLA) is an endogenous ligand for EBS-II. Binding of MeHPLA to EBS-II has a growth regulatory effect in estrogen-responsive cells, and levels of MeHPLA are decreased in breast cancer due to degradation by a specific esterase. 2,6-bis((3, 4-dihydroxyphenyl)-methylene) cyclohexanone (BDHPC) is an esterase-resistant analogue of MeHPLA which binds irreversibly to EBS-II and inhibits growth of breast cancer cells. In the present study, we analyzed the mechanism of growth inhibition by BDHPC. Treatment with BDHPC resulted in accumulation of cells in G1 phase and apoptosis. The G1 accumulation was not dependent on a functional p53 gene. The G1-specific growth inhibition by BDHPC was found to act synergistically with the G2/M-specific inhibition induced by the tyrosine kinase inhibitor genistein, suggesting this drug combination could be effectively used in cancer treatment.
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PMID:2,6-Bis((3,4-dihydroxyphenyl)-methylene)cyclohexanone (BDHPC)-induced apoptosis and p53-independent growth inhibition: synergism with genistein. 934 53

Beta-lapachone (beta-lap) affects a number of enzymes in vitro, including type I topoisomerase (Topo I); however, its exact intracellular target(s) and mechanism of cell killing remain unknown. We compared the cytotoxic responses of MCF-7:WS8 (MCF-7) human breast cancer cells after 4-h pulses of beta-lap or camptothecin (CPT), a known Topo I poison. A direct correlation between loss of survival and apoptosis was seen after beta-lap treatment (LD50 = 2.5 microM). A concentration-dependent, transient sub-2 N preapoptotic cell population was observed at 4-8 h. Estrogen deprivation-induced synchronization and bromodeoxyuridine-labeling studies revealed an apoptotic exit point near the G1-S border. Apoptosis activated by beta-lap was closely correlated with cleavage of lamin B but not with increases in p53/p21 or decreases in bcl-2. Loss of hyperphosphorylated forms of the retinoblastoma protein was observed within 5 h, but cyclins A, B1, and E levels were unaltered for up to 72 h after 5 microM beta-lap. Topo I and Topo IIalpha levels decreased at > 24 h. Logarithmic-phase MCF-7 cells were not affected by < or = 1 microM beta-lap. In contrast, dramatic and irreversible G2-M arrest with no apoptosis was observed in MCF-7 cells treated with 1 microM CPT, monitored for 6-10 days posttreatment. MCF-7 cells treated with supralethal doses of CPT (5 microM) resulted in only approximately 20% apoptosis. No correlation between apoptosis and loss of survival was observed. MCF-7 cells exposed to > 5 microM CPT arrested at key cell cycle checkpoints (i.e., G1, S, and G2-M), with little or no movement for 6 days. Ten-fold increases in p53/p21 and 2-5-fold decreases in bcl-2, Topo I, Topo IIalpha, and cyclins A and B1, with no change in cyclin E, were observed. Temporal decreases in bcl-2 and cleavage of lamin B corresponded to the minimal apoptotic response observed. Beta-lap activated apoptosis without inducing p53/p21 or cell cycle arrest responses and killed MCF-7 cells solely by apoptosis. In contrast, concentration-dependent increases in nuclear p53/p21 and various cell cycle checkpoint arrests were seen in MCF-7 cells after CPT. Despite dramatic p53/p21 protein induction responses, CPT-treated MCF-7 cells showed low levels of apoptosis, possibly due to protective cell cycle checkpoints or the lack of specific CPT-activated apoptotic pathways in MCF-7 cells.
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PMID:Induction of apoptosis in MCF-7:WS8 breast cancer cells by beta-lapachone. 958 28

Twenty-seven plurihormonal and 21 growth hormone- prolactin- (GH- PRL-) mixed cell adenomas obtained from patients with acromegaly undergoing transnasal-transsphenoidal surgery were investigated immunohistochemically for expression of Epidermal Growth Factor (EGF), Transforming Growth Factor alpha (TGF alpha), Insulin-like Growth Factor-1 (IGF-1), Estrogen Receptor-Related Protein (ERRP), Multidrug Resistance Marker (MDRM), Protein Kinase C (PKC), Gs alpha,. Cathepsin D and p53. Five plurihormonal adenomas grew invasively. The panel of markers used in this study represents a selection of functional and proliferative markers thought to be associated with the function and development of pituitary adenomas. Our results imply that the growth factors (EGF, TGF alpha, IGF-1), the cell signalling protein Gs alpha and the MDRM are expressed by both types of pituitary adenomas in a similar pattern. Non-invasive GH-PRL-mixed cell adenomas showed an increased expression of IGF-1, TGF alpha and MDRM compared to non-invasive plurihormonal adenomas. No factor was found which would reliably distinguish between invasive and non-invasive adenomas. We failed to confirm the findings of others that p53 and cathepsin D might be indicators of tumor aggressiveness. A participation of ERRP and PKC in the development of bi- and plurihormonal adenomas with acromegaly appears unlikely, as the immunostains were all negative.
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PMID:Markers of function and proliferation in non-invasive and invasive bi- and plurihormonal adenomas of patients with acromegaly: an immunohistochemical study. 1050 79


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