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)

We discovered a series of salicylhydrazide class of compounds with remarkable anticancer activity against a panel of hormone receptor-positive and -negative cell lines. In the present study, we evaluated the in vitro activity of SC21 and SC23 against a range of human tumor cell types and the in vivo efficacy of compound SC21 in a PC3 human prostate cancer xenograft model in mice. We also determined the effects of SC21 on cell cycle regulation and apoptosis. Our in vitro results show that salicylhydrazides are highly potent compounds effective in both hormone receptor-positive and -negative cancer cells. SC21 induced apoptosis and blocked the cell cycle in G(0)/G(1) or S phase, depending on the cell lines used and irrespective of p53, p21, pRb, and p16 status. SC21 effectively reduced the tumor growth in mice without apparent toxicity. Although the mechanism of action of SC21 is not completely elucidated, the effect on cell cycle, the induction of apoptosis and the activity against a panel of tumor cell lines of different origins prompted us to carry out an in-depth preclinical evaluation of SC21.
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PMID:Discovery and preclinical evaluation of a novel class of small-molecule compounds in hormone-dependent and -independent cancer cell lines. 1602 Jun 68

Endometrial adenocarcinoma is the most common malignant neoplasm of the female genital tract and, despite its relative frequency, the molecular events that contribute to the development and progression of the lesion remain poorly understood. The normal human endometrium is characterized by hormone-dependent variations during the menstrual cycle. This tightly controlled system is disturbed in endometrial hyperplasia and carcinomas and a series of changes initiate and promote progression towards the malignant phenotype. These changes can be subdivided into discrete steps, involving activation of oncogenes, inactivation of tumour suppressor genes, deregulation of cell cycle regulators or other proteins involved in tumour invasion and progression. Immunohistochemical expression of different biomarkers such as hormone receptor status (ER, PR), proliferation associated indices (PCNA, MIB1), oncogene (c-erbB-2), tumour suppressor gene products (pRb, p53 protein), cell cycle related proteins (cyclin D1, cyclin E, p21/WAF1), anti-apoptotic protein (bcl-2), adhesion molecule (CD44s), proteolytic enzyme (cathepsin D), heat shock protein (hsp27) and metallothionein (MT) has shown the contribution of these molecules to endometrial carcinogenesis in a hormone-dependent or independent manner as an early or late event. In addition, these biomarkers seem to be correlated with tumour differentiation or myometrial invasion, and therefore could be considered as indicators of the biological behaviour of endometrial carcinoma. Furthermore, the interrelationships of these molecular markers show that these genetic dysregulations could be implicated in the control of cell proliferation and differentiation, and thereby in the multistep process of endometrial carcinogenesis.
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PMID:Immunohistochemical tumour markers in endometrial carcinoma. 1612 80

Primary chemotherapy represents an ideal model to evaluate the relationships between treatments and the prognostic and predictive parameters provided by the new technologies. First- and second-generation trials have shown that primary chemotherapy significantly improves the rate of breast conservation without increasing the risk of ipsilateral recurrence and while assuring survival rates comparable with those achieved with postoperative chemotherapy. Moreover, patients who exhibited a pathologic complete response (pCR) showed better progression-free survival and overall survival. The third-generation trials were aimed at improving the percentage of pCR, identifying and validating gene and protein biomarkers of chemotherapy sensitivity, and better defining the individual risk of relapse. Several parameters, such as index of proliferation and apoptosis, expression of proteins (eg, p53 and Bcl-2), and hormone receptor and epidermal growth factor family receptors, have been related to response to primary chemotherapy. Negative hormone receptors and greater proliferative activity seem to be the only parameters more consistently associated with greater chemotherapy sensitivity. However, the strength of this association is not sufficient to differentiate patients at different degrees of risk and does not allow for an individualized therapeutic choice. Newer technologies offer the possibility of evaluating thousands of genes and identifying clusters of gene expression associated with significantly different risks of relapse and patterns of sensitivity/resistance to specific drugs. The primary chemotherapy model is the ideal clinical setting in which to validate the relationship between tumor molecular profiling and treatment outcomes and to design tailored therapies based on observed effects on individual tumors.
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PMID:Predictive value of biologic parameters for primary chemotherapy in operable breast cancer. 1627 81

Although protein phosphatase magnesium-dependent 1 delta (PPM1D) was initially characterized as a p53-regulated phosphatase responsible for inactivation of p38 MAPK and consequent inactivation of p53, its overexpression and amplification in human breast cancers led us to assess its role in steroid hormone action. We found that PPM1D stimulated the activity of several nuclear receptors including the progesterone receptor (PR) and estrogen receptor. Although p38 MAPK inhibited PR activity, PPM1D stimulation of PR activity was greater than that achieved by a chemical inhibitor of p38 MAPK, SB202190. This suggests an additional novel function for PPM1D. Consistent with this, the transcriptional activity of endogenous PR in MCF-7 breast cancer cells was preferentially inhibited by small interfering RNA for PPM1D; SB202190 failed to reverse the inhibition. Although PPM1D phosphatase activity was required for stimulation of transcriptional activity, the activity of a PR phosphorylation site null mutant was enhanced by PPM1D, indicating that PR is not the direct target. Additional studies revealed that PPM1D enhanced the intrinsic activity of p160 coactivators such as steroid receptor coactivator-1 and promoted the interaction between PR and steroid receptor coactivator-1 in a mammalian two-hybrid assay. Neither activity was induced by SB202190. Although PPM1D stimulated PR activity in part through inhibition of p38 MAPK, its primary action is novel and independent of p38 MAPK. Thus, we speculate that PPM1D promotes breast tumor growth both by inhibiting p53 activity and by enhancing steroid hormone receptor action.
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PMID:Dual roles for the phosphatase PPM1D in regulating progesterone receptor function. 1635 95

p63, a p53 homologue, is a myoepithelial cell marker in the normal mammary gland but p63-positive neoplastic cells may be found in up to 11% of invasive breast carcinomas. This study aims to verify the relationship between p63 expression and several clinicopathological features and tumor markers of clinical significance in breast pathology including key regulators of the cell cycle, oncogenes, apoptosis-related proteins, metalloproteinases and their inhibitors. Immunohistochemistry with 27 primary antibodies was performed in 100 formalin-fixed paraffin-embedded samples of invasive ductal carcinomas. p63-positive cells were found in 16% of carcinomas. p63-positive carcinomas were poorly differentiated, hormone receptor-negative neoplasms with a high proliferation rate. p63 also correlated with advanced pathological stage, tumor size, and the expression of human telomerase reverse transcriptase (hTERT), tissue inhibitor of matrix metalloproteinase 1 (TIMP1) and vascular endothelial growth factor (VEGF). The expression of TIMP1 suggests that the anti-proteolytic stimuli may be preponderant in p63-positive carcinomas. hTERT activity is associated with nodal metastases and cellular proliferation. VEGF regulates angiogenesis, which is also a fundamental event in the process of tumor growth and metastatic dissemination. Thus, the differential regulation of hTERT and VEGF in p63-positive breast carcinomas may contribute to the clinically more aggressive behavior of these neoplasms.
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PMID:The differential regulation of human telomerase reverse transcriptase and vascular endothelial growth factor may contribute to the clinically more aggressive behavior of p63-positive breast carcinomas. 1639 4

Biological changes in breast cancers during tumor progression can affect therapeutic parameters, such as hormone receptors. We studied a series of primary tumors and the matching recurrent lesions to analyze the frequency of this phenomenon and the impact on disease-free interval. The expression of ER, PgR, c-erbB2, CD44v6, and p53 in the primary and the locoregional tumor was analyzed in 70 patients with recurrent breast cancer. Antigen expression correlated well between the primary and the matching recurrent tumor for all antigens under study. However, hormone receptor expression was lost in more than 50% of the cases, without significant impact on the disease-free survival interval. The disease-free interval was significantly longer for PgR-positive primary tumors, but did not depend on the ER status. The expression or changes of c-erbB2, CD44v6, and p53 were not related to the recurrence-free time intervals. Therefore, for treatment, it seems important to consider a possible loss of hormone receptors during tumor progression.
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PMID:Comparison of immunohistological parameters in primary breast cancers and corresponding locoregional recurrences. 1645 45

To investigate the clinical value of somatic TP53 mutations in breast cancer, we assembled clinical and molecular data on 1,794 women with primary breast cancer with long-term follow-up and whose tumor has been screened for mutation in exons 5 to 8 of TP53 by gene sequencing. TP53 mutations were more frequent in tumors of ductal and medullar types, aggressive phenotype (high grade, large size, node positive cases, and low hormone receptor content) and in women <60 years old. TP53 mutations within exons 5 to 8 conferred an elevated risk of breast cancer-specific death of 2.27 (relative risk >10 years; P < 0.0001) compared with patients with no such mutation. The prognostic value of TP53 mutation was independent of tumor size, node status, and hormone receptor content, confirming and reconciling previous findings in smaller series. Moreover, an interaction between TP53 mutation and progesterone receptor (PR) status was revealed, TP53 mutation combined with the absence of progesterone receptor being associated with the worst prognosis. Whereas previous studies have emphasized the fact that missense mutations in the DNA-binding motifs have a worse prognosis than missense mutations outside these motifs, we show that non-missense mutations have prognostic value similar to missense mutations in DNA-binding motifs. Nonetheless, specific missense mutants (codon 179 and R248W) seem to be associated with an even worse prognosis. These results, obtained on the largest series analyzed thus far, show that TP53 mutations identified by gene sequencing have an independent prognostic value in breast cancer and could have potential uses in clinical practice.
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PMID:The clinical value of somatic TP53 gene mutations in 1,794 patients with breast cancer. 1648 69

As a clinical entity, breast cancer appears to be a series of subforms, each with a relatively specific molecular phenotype. Among the characteristics that differentiate these subforms are sex hormone receptor expression, HER2 expression, p53 mutation, high-grade histopathology, and particular gene expression array patterns. Sporadic basal-like breast cancer is one such form. It is a relatively common, high-grade, hormone receptor and HER2-expression-negative, p53 mutation-bearing tumor and is particularly lethal. Although wild type for BRCA1, it is a sporadic phenocopy of most cases of BRCA1(/) breast cancer. Not only do the cells of the two tumors resemble one another with respect to the above-noted characteristics, they also share a defect in the maintenance of an intact, inactive X chromosome (Xi). Other high-grade and most low-grade tumors are rarely defective at Xi. This evidence suggests that an Xi defect contributes to the evolution of both sporadic and BRCA1(/) basal-like breast tumors.
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PMID:Abnormalities of the inactive X chromosome are a common feature of BRCA1 mutant and sporadic basal-like breast cancer. 1686 42

Women of African descent have a lower incidence of breast cancer than their white counterparts; however, the overall age-adjusted breast cancer mortality rates are higher. They also present at a younger age, and have more advanced disease that exhibits poor prognostic features including significantly larger tumors of higher grade, higher rates of estrogen receptor and progesterone receptor negativity and a higher rate of p53 mutations and HRAS1 proto-oncogene expression, all of which confer a poor prognosis. While there are many possible contributory factors to the discrepancies in outcome in women of African descent, there is no satisfactory explanation as to why women of African origin tend to present at a younger age with hormone receptor-negative tumors and more adverse prognostic features.
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PMID:A review of the ethnic differences in breast cancer. 1698 51

The anti-apoptotic molecule, Bcl-2, is well known to play an important role in the chemoresistance of breast cancer. We have previously demonstrated that phosphorylation of Fas-associated death domain-containing protein (FADD) at 194 serine through c-jun NH2-terminal kinase (JNK) activation sensitizes breast cancer cells to chemotherapy through accelerating cell cycle arrest at G2/M, and that Bcl-2 phosphorylation downstream of JNK/FADD plays an important role in cell growth suppression by paclitaxel. In this study, the clinicopathological association of phosphorylated Bcl-2 (P-Bcl-2) with estrogen, progesterone, c-erbB-2 receptors, p53 expressions and phosphorylated FADD/JNK (P-FADD/JNK) was analyzed immunohistochemically using 107 human breast cancer specimens. Expression of P-Bcl-2 was found to significantly correlate with lymphatic invasion, lymph node metastasis, but not histological differentiation, tumor grade or vascular and fatty invasion. The positivity of P-Bcl-2 was also significantly correlated to that of P-FADD/JNK. Thus, P-Bcl-2 as well as the P-FADD/JNK parameter might be useful markers for cancer progression, independent of the hormone receptor status, in human breast cancers.
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PMID:Bcl-2 phosphorylation has pathological significance in human breast cancer. 1711 50


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