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

The expansion of triplet repeat microsatellite sequences is the molecular correlate of anticipation in a number of rare Mendelian neurodegenerative disorders. This finding prompted us to study these sequences in primary breast cancer in which there is evidence of genetic anticipation. We used a PCR/silver stain method to determine whether triplet-repeat instability (TRI) was present in DNA from malignant breast tumors, and analyzed microsatellite instability (MSI) in triplets SCA1, SCA2, SCA3, SCA6, HD, DRPLA and X25-GAA. We studied 54 consecutive primary breast cancers previously analyzed for dinucleotide instability (DI) at 9 loci. Microsatellite instability (TRI and/or DI) was found in 28/54 (52%) cases, ranging from 0 to 56% in each patient. Dinucleotide instability occurred at > or =2 loci in 19/54 (35%) cases and TRI in 6/54 (11%). Considering single locus instability, we found DI in 26/54 (48%) tumors and TRI in 13/54 (24%). Triplets DRPLA and X25-GAA were most frequently unstable (14% of cases); SCA2 instability was not detected. Interestingly, most tumors with TRI had DI (11/13, 85%). There was a correlation between TRI and DI in the same tumor (42 vs 7% in DI+ and DI- tumors respectively, p=0.0028). Furthermore, TRI appears more frequently associated with lymph node metastases and more advanced clinical stages and more frequent in patients <50 years old, with positive steroidal hormone receptor status, positive p185 and negative p53. These findings are of interest because they demonstrate a relationship between TRI and the clinicopathological characteristics of cancer aggressiveness. Triplet repeat alterations can interfere with gene expression and proteomic functions, which suggests they can play a role in the neoplastic progression of mammary cells. Furthermore, the association of TRI and DI in the same tumor suggests that alterations in the DNA repair gene could culminate in selective phenotypes and breast cancer progression in a considerable number of patients.
 ...
PMID:Triplet repeat instability correlates with dinucleotide instability in primary breast cancer. 1714 98

A distinct morphologic and molecular phenotype has been reported for BRCA1-associated breast cancers; however, the phenotype of BRCA2-associated breast cancers is less certain. To comprehensively characterize BRCA2-associated breast cancers we performed a retrospective case control study using tumors accrued through the Breast Cancer Family Registry. We examined the tumor morphology and hormone receptor status in 157 hereditary breast cancers with germline mutations in BRCA2 and 314 control tumors negative for BRCA1 and BRCA2 mutations that were matched for age and ethnicity. Tissue microarrays were constructed from 64 BRCA2-associated and 185 control tumors. Tissue microarray sections were examined for HER2/neu protein overexpression, p53 status and the expression of basal markers, luminal markers, cyclin D1, bcl2, and MIB1 by immunohistochemistry. The majority of BRCA2-associated tumors and control tumors were invasive ductal, no special-type tumors. In contrast to control tumors, BRCA2-associated cancers were more likely to be high grade (P<0.0001) and to have pushing tumor margins (P=0.0005). Adjusting for grade, BRCA2-associated tumors were more often estrogen receptor positive (P=0.008) and exhibited a luminal phenotype (P=0.003). They were less likely than controls to express the basal cytokeratin CK5 (P=0.03) or to overexpress HER2/neu protein (P=0.06). There was no difference in p53, bcl2, MIB1, or cyclin D1 expression between BRCA2-associated and control tumors. We have demonstrated, in the largest series of BRCA2-associated breast cancers studied to date, that these tumors are predominantly high-grade invasive ductal carcinomas of no special type and they demonstrate a luminal phenotype despite their high histologic grade.
 ...
PMID:BRCA2 mutation-associated breast cancers exhibit a distinguishing phenotype based on morphology and molecular profiles from tissue microarrays. 1719 28

Breast cancers arising in carriers of germline BRCA1 mutations frequently have a basal-like phenotype. Basal-like cancers are characterized by high histological grade, central necrotic areas, foci with metaplastic differentiation, lack of hormone receptor and HER2 (ErbB2) expression, and consistent positivity for basal markers, including CK5/6, CK14, and EGFR. We have used germline manipulation to generate a conditional mouse model of Brca1 deficiency. Transgenic expression of Cre recombinase in the mammary gland of these mice results in deletion of exons encoding the C-terminus of Brca1 and leads to tumour formation when combined with heterozygosity for a p53 mutation. Histologically, these mammary gland tumours were characterized by high histological grade, central necrotic areas, and presence of homologous metaplastic elements. These metaplastic elements consisted of neoplastic spindle cells or squamous cell differentiation in the form of keratin pearls or individual cell keratinization. Immunohistochemical analysis revealed expression of basal-like markers in all cases. The tumour phenotype generated in our mouse model was compared with published data on human basal-like breast carcinomas and also with metaplastic breast cancers with a basal-like phenotype; the comparison showed that we have generated a mouse model of basal-like breast cancer, which should prove useful in testing new and targeted treatments for this type of breast cancer.
 ...
PMID:A mouse model of basal-like breast carcinoma with metaplastic elements. 1721 42

It is not clear whether invasive breast carcinomas with medullary features (IBCMFs, atypical medullary carcinomas) constitute a specific phenotype of breast cancer that is of biologic significance. Because medullary features are common in BRCA1-associated carcinomas and these tumors frequently show a basal-like phenotype, we examined whether IBCMFs expressed basal/myoepithelial markers and had a basal-like phenotype. We studied the immunohistochemical expression of 15 markers in tissue microarrays containing samples from 35 IBCMFs and 39 grade 3 invasive ductal carcinomas (IDCG3s) of no special type. In addition, we analyzed EGFR, C-MYC, and CCNE gene amplification by fluorescence in situ hybridization, because the expression of these genes is known to be associated with the basal-like phenotype. We defined the basal-like phenotype according to the criteria of Nielsen et al as being those tumors that were ER/HER2-negative and cytokeratin (CK) 5/6- and/or epidermal growth factor receptor-positive. IBCMFs were more frequently hormone receptor- and HER2-negative, but had greater expression of proliferation markers and p53. In addition, IBCMFs more frequently expressed basal/myoepithelial markers, such as CK5/6 and P-cadherin. A basal-like phenotype was found in 62.9% of IBCMFs but in only 18.9% of IDCG3s. No differences in gene amplification were found between IBCMFs and IDCG3s, although C-MYC amplification was more common in tumors without a basal-like phenotype. The identification of IBCMF as an independent group of tumors could be of clinical significance, given the high incidence of cases with a basal-like phenotype, which is a group of tumors with different prognosis and chemotherapy response from those of IDCG3s of no special type.
 ...
PMID:Sporadic invasive breast carcinomas with medullary features display a basal-like phenotype: an immunohistochemical and gene amplification study. 1741 96

The cAMP-protein kinase A (PKA) pathway is the major signal transduction pathway involved in melanocyte-stimulating hormone receptor-mediated signaling and melanin production, whereas its role in the control of melanocyte proliferation is still controversial. In this study, we evaluated the effects of selective activation of the different PKA regulatory subunits type 1A (R1A) and type 2B (R2B) on melanocyte proliferation. Immunohistochemistry demonstrated that normal melanocytes lacked R1A protein whereas this subunit was highly expressed in all human melanomas studied (N=20) and in six human melanoma cell lines. Pharmacological activation of the R2 subunits by the cAMP analogue 8-Cl-cAMP inhibited proliferation and increased caspase-3 activity by 68.77+/-10.5 and 72+/-9% respectively, in all cell lines with the exception of the only p53-mutated one. Similar effects were obtained by activating R2 subunits with other analogues and by silencing R1A expression. The antiproliferative and proapoptotic effects of 8-Cl-cAMP were comparable to those observed with commonly used antitumoral drugs. Moreover, 8-Cl-cAMP potentiated the effects of these drugs on both cell proliferation and caspase-3 activity. In conclusion, this study first reports that human melanomas are characterized by a high R1/R2 ratio and that pharmacological and genetic manipulations able to revert this unbalanced expression cause significant antiproliferative and proapoptotic effects in melanoma cells.
 ...
PMID:High expression of PKA regulatory subunit 1A protein is related to proliferation of human melanoma cells. 1790 91

Breast cancer is the most common cancer and the second leading cause of cancer death in American women. It was the second most common cancer in the world in 2002, with more than 1 million new cases. Despite advances in early detection and the understanding of the molecular bases of breast cancer biology, about 30% of patients with early-stage breast cancer have recurrent disease. To offer more effective and less toxic treatment, selecting therapies requires considering the patient and the clinical and molecular characteristics of the tumor. Systemic treatment of breast cancer includes cytotoxic, hormonal, and immunotherapeutic agents. These medications are used in the adjuvant, neoadjuvant, and metastatic settings. In general, systemic agents are active at the beginning of therapy in 90% of primary breast cancers and 50% of metastases. However, after a variable period of time, progression occurs. At that point, resistance to therapy is not only common but expected. Herein we review general mechanisms of drug resistance, including multidrug resistance by P-glycoprotein and the multidrug resistance protein family in association with specific agents and their metabolism, emergence of refractory tumors associated with multiple resistance mechanisms, and resistance factors unique to host-tumor-drug interactions. Important anticancer agents specific to breast cancer are described. Breast cancer is the most common type of cancer and the second leading cause of cancer death in American women. In 2002, 209,995 new cases of breast cancer were registered, and 42,913 patients died of it. In 5 years, the annual prevalence of breast cancer will reach 968,731 cases in the United States. World wide, the problem is just as significant, as breast cancer is the most frequent cancer after nonmelanoma skin cancer, with more than 1 million new cases in 2002 and an expected annual prevalence of more than 4.4 million in 5 years. Breast cancer treatment currently requires the joint efforts of a multidisciplinary team. The alternatives for treatment are constantly expanding. With the use of new effective chemotherapy, hormone therapy, and biological agents and with information regarding more effective ways to integrate systemic therapy, surgery, and radiation therapy, elaborating an appropriate treatment plan is becoming more complex. Developing such a plan should be based on knowledge of the benefits and potential acute and late toxic effects of each of the therapy regimens. Despite advances in early detection and understanding of the molecular bases of breast cancer biology, approximately 30% of all patients with early-stage breast cancer have recurrent disease, which is metastatic in most cases. The rates of local and systemic recurrence vary within different series, but in general, distant recurrences are dominant, strengthening the hypothesis that breast cancer is a systemic disease from presentation. On the other hand, local recurrence may signal a posterior systemic relapse in a considerable number of patients within 2 to 5 years after completion of treatment. To offer better treatment with increased efficacy and low toxicity, selecting therapies based on the patient and the clinical and molecular characteristics of the tumor is necessary. Consideration of these factors should be incorporated in clinical practice after appropriate validation studies are performed to avoid confounding results, making them true prognostic and predictive factors. A prognostic factor is a measurable clinical or biological characteristic associated with a disease-free or overall survival period in the absence of adjuvant therapy, whereas a predictive factor is any measurable characteristic associated with a response or lack of a response to a specific treatment. The main prognostic factors associated with breast cancer are the number of lymph nodes involved, tumor size, histological grade, and hormone receptor status, the first two of which are the basis for the AJCC staging system. The sixth edition of the American Joint Committee on Cancer staging system allows better prediction of prognosis by stage. However, after determining the stage, histological grade, and hormone receptor status, the tumor can behave in an unexpected manner, and the prognosis can vary. Other prognostic and predictive factors have been studied in an effort to explain this phenomenon, some of which are more relevant than others: HER-2/neu gene amplification and protein expression, expression of other members of the epithelial growth factor receptor family, S phase fraction, DNA ploidy, p53 gene mutations, cyclin E, p27 dysregulation, the presence of tumor cells in the circulation or bone marrow, and perineural and lymphovascular space invasion. Systemic treatment of breast cancer includes the use of cytotoxic, hormonal, and immunotherapeutic agents. All of these agents are used in the adjuvant, neoadjuvant, and metastatic setting. Adjuvant systemic therapy is used in patients after they undergo primary surgical resection of their breast tumor and axillary nodes and who have a significant risk of systemic recurrence. Multiple studies have demonstrated that adjuvant therapy for early-stage breast cancer produces a 23% or greater improvement in disease-free survival and a 15% or greater increase in overall survival rates. Recommendations for the use of adjuvant therapy are based on the individual patient's risk and the balance between absolute benefit and toxicity. Anthracycline-based regimens are preferred, and the addition of taxanes increases the survival rate in patients with lymph node-positive disease. Adjuvant hormone therapy accounts for almost two thirds of the benefit of adjuvant therapy overall in patients with hormone-receptor-positive breast cancer. Tamoxifen is considered the standard of care in premenopausal patients. In comparison, the aromatase inhibitor anastrozole has been proven to be superior to tamoxifen in postmenopausal patients with early-stage breast cancer. The adjuvant use of monoclonal antibodies and targeted therapies other than hormone therapy is being studied. Interestingly, some patients have an early recurrence even though they have a tumor with good prognostic features and at a favorable stage. These recurrences have been explained by the existence of certain cellular characteristics at the molecular level that make the tumor cells resistant to therapy. Selection of resistant cell clones of micrometastatic disease has also been proposed as an explanation for these events. Neoadjuvant systemic therapy, which is the standard of care for patients with locally advanced and inflammatory breast cancer, is becoming more popular. It reduces the tumor volume, thus increasing the possibility of breast conservation, and at the same time allows identification of in vivo tumor sensitivity to different agents. The pathological response to neoadj uvant systemic therapy in the breast and lymph nodes correlates with patient survival. Use of this treatment modality produces survival rates identical to those obtained with the standard adjuvant approach. The rates of pathological complete response (pCR) to neoadjuvant systemic therapy vary according to the regimen used, ranging from 6% to 15% with anthracycline-based regimens to almost 30% with the addition of a noncross-resistant agent such as a taxane. In one study, the addition of neoadjuvant trastuzumab in patients with HER-2-positive breast tumors increased the pCR rate to 65%. Primary hormone therapy has also been used in the neoadjuvant systemic setting. Although the pCR rates with this therapy are low, it significantly increases breast conservation. Currently, neoadjuvant systemic therapy is an important tool in not only assessing tumor response to an agent but also studying the mechanisms of action of the agent and its effects at the cellular level. However, no tumor response is observed in some cases despite the use of appropriate therapy. The tumor continues growing during treatment in such cases, a phenomenon called primary resistance to therapy. The use of palliative systemic therapy for metastatic breast cancer is challenging. Five percent of newly diagnosed cases of breast cancer are metastatic, and 30% of treated patients have a systemic recurrence. Once metastatic disease develops, the possibility of a cure is very limited or practically nonexistent. In this heterogeneous group of patients, the 5-year survival rate is 20%, and the median survival duration varies from 12 to 24 months. In this setting, breast cancer has multiple clinical presentations, and the therapy for it should be chosen according to the patient's tumor characteristics, previous treatment, and performance status with the goal of improving survival without compromising quality of life. Treatment resistance is most commonly seen in such patients. They initially may have a response to different agents, but the responses are not sustained, and, in general, the rates of response to subsequent agents are lower. Table 1 summarizes metastatic breast cancer response rates to single-agent systemic therapy.
 ...
PMID:Overview of resistance to systemic therapy in patients with breast cancer. 1799 29

Mitochondria are power organelles generating biochemical energy, ATP, in the cell. Mitochondria play a variety of roles, including integrating extracellular signals and executing critical intracellular events, such as neuronal cell survival and death. Increasing evidence suggests that a cross-talk mechanism between mitochondria and the nucleus is closely related to neuronal function and activity. Nuclear receptors (estrogen receptors, thyroid (T3) hormone receptor, peroxisome proliferators-activated receptor gamma2) and transcription factors (cAMP response binding protein, p53) have been found to target mitochondria and exert prosurvival and prodeath pathways. In this context, the regulation of mitochondrial function via the translocation of nuclear receptors and transcription factors may underlie some of the mechanisms involved in neuronal survival and death. Understanding the function of nuclear receptors and transcription factors in the mitochondria may provide important pharmacological utility in the treatment of neurodegenerative conditions. Thus, the modulation of signaling pathways via mitochondria-targeting nuclear receptors and transcription factors is rapidly emerging as a novel therapeutic target.
 ...
PMID:Mitochondrial nuclear receptors and transcription factors: who's minding the cell? 1804 Oct 90

Previous studies have shown conflicting results on prognostic significance of basal-like breast tumors, but hormone receptor is a confusing factor in most of the prognostic evaluations. We aimed to characterize the prognostic features of basal-like tumors without the influence of hormone receptor status in a series of hormone receptor-negative breast tumors. Using tissue microarray and immunohistochemistry methods, according to the expression of HER2 and basal markers (CK5/6, CK14, EGFR), we categorized 713 consecutive hormone receptor-negative invasive breast cancers into 3 subtypes: HER2 (HER2+), basal-like (HER2-, any basal marker+), and null (HER2-, all basal markers-). The HER2 phenotype was subdivided into pure-HER2 (HER2+, all basal markers-) and basal-HER2 (HER2+, any basal marker+) subgroups. Expression of p53, p63, vimentin, and BRCA1 was assessed immunochemically. Basal-like tumors showed significantly higher grade, more frequent recurrence, and higher expression of vimentin and p63 than HER2 and null phenotypes. Basal-HER2 phenotype had significantly younger mean age and expressed a higher level of p53 and vimentin like basal-like and/or HER2 phenotypes. However, unlike all the other hormone receptor-negative phenotypes, they highly expressed BRCA1. No significant difference was found in 5-year survival among basal-like and the other hormone receptor-negative phenotypes, except for basal-HER2, which showed poorer 5-year overall survival than basal-like tumors. In conclusion, although basal-like breast tumors have distinct clinicopathologic and immunohistochemical features, they have similar 5-year survival compared with the other hormone receptor-negative tumors including HER2 and null phenotypes. However, there exists a small group of hormone receptor-negative tumors expressing HER2 and basal markers simultaneously. This small group of tumors showed significantly poorer 5-year overall survival than basal-like breast tumors and might require different treatment strategy.
 ...
PMID:Basal-HER2 phenotype shows poorer survival than basal-like phenotype in hormone receptor-negative invasive breast cancers. 1804 47

The aim of this paper is to determine similarities and differences between tumor cell subclones in cases of ductal invasive breast carcinoma, and which occupy primary tumor and local axillary lymph metastases. The tumor growth fraction evaluated by Ki-67 was analyzed along with the expression level of estrogen and progesterone receptors, protein p53, proto-oncogene protein bcl-2 and cathepsin D in 60 patients. Metastatic lymph node in axilla has a higher growth fraction of the tumor cells than the primary tumor (p = 0.045), as well as the higher level of bcl-2 overexpression (p = 0.014). No statistically significant difference was found in the presence of immunohistochemically identified estrogen receptors (p = 0.161) and progesterone receptors (p = 0.081) between the primary tumor and the metastatic lymph node in axilla. Likewise, no difference was found between the immunohistochemical evaluation of p53 (p = 0.356) and cathepsin D activity (p = 0.928). A higher growth fraction of the tumor cells and the higher level of bcl-2 overexpression in metastatic tumor cells indicate the more aggressive cell subclones. This study does not support the routine testing of both primary tumor and locoregional metastasis to evaluate the breast cancer hormone receptor status.
 ...
PMID:Tumor growth fraction, expression of estrogen and progesterone receptors, p53, bcl-2 and cathepsin D activity in primary ductal invasive breast carcinoma and their axillary lymph node metastases. 1821 56

Ductal carcinoma in situ (DCIS) is commonly diagnosed today, mainly due to widespread use of screening mammography. Despite a better understanding of its biological behavior, many issues regarding its optimal management remain controversial. The biological behavior of DCIS has been associated with distinct molecular and histological features (such as expression of COX2, Ki67, c-erbB2, p53 mutation, presence or absence of comedonecrosis, nuclear grade, hormone receptor status, etc.). Recent advances in the diagnosis of DCIS include using magnetic resonance imaging, and the use of stereotactic-guided directional vacuum-assisted biopsy (DVAB). Ductoscopy and ductal lavage have a limited role in the management of DCIS. Surgical treatment of DCIS includes simple local excision to various forms of wider excision (segmental resection or quadrantectomy), or even mastectomy (either simple or skin-sparing). Radiotherapy following breast-conserving surgery significantly reduces local recurrence rates. Axillary lymph node dissection is not required for the management of DCIS; however, during the last decade, sentinel lymph node biopsy is increasingly used to exclude the presence of axillary metastases (when invasive disease is present within the DCIS). This approach has many advantages (including the avoidance of a second surgery if invasive disease is diagnosed within the DCIS) and should be considered when there is an increased probability for the presence of invasive breast cancer within the DCIS. The role of other minimally invasive methods (such as the "therapeutic" application of the DVAB technique, radiofrequency ablation, laser therapy, cryotherapy and brachytherapy) in the management of small DCIS remains unproven. Tamoxifen should be considered in the management of selected patients with DCIS, such as patients with hormone receptor positive DCIS, young patients, and patients without risk factors for potential side effects. Additionally, and controversial, there is evidence that aromatase inhibitors may be better than tamoxifen in the management of DCIS.
 ...
PMID:Recent advances and current controversies in the management of DCIS of the breast. 1849 Jan 11


<< Previous 1 2 3 4 5 6 7 8 9 10