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)

Antiestrogens have been the therapeutic agents of choice for breast cancer patients whose tumors express estrogen receptors, regardless of menopausal status. Unfortunately, many patients will eventually develop resistance to these drugs. Antiestrogens primarily act by preventing endogenous estrogen from activating estrogen receptors and promoting cell growth, which can ultimately lead to tumor cell death. Understanding the mechanisms by which antiestrogens cause cell death or apoptosis is critical to our efforts to develop ways to circumvent resistance. This article focuses on antiestrogen-induced apoptosis both in vitro and in vivo. We review the clinical utility of both antiestrogens and aromatase inhibitors and their apoptogenic mechanisms in cell culture models. Among the key signaling components discussed are the roles of Bcl-2 family members, several cytokines, and their receptors, p53, nuclear factor kappa B (NFkappaB), IRF-1, phosphatidylinositol 3-kinase (PI3K)/Akt, and specific caspases. Finally, we discuss the evidence supporting a role for apoptotic defects in acquired and de novo antiestrogen resistance.
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PMID:Antiestrogens, aromatase inhibitors, and apoptosis in breast cancer. 1611 69

Breast cancer is a hormone-dependent cancer, and the presence of estrogen receptor (ER) and progesterone receptor (PgR) in tumors is used clinically to predict the likelihood of response to hormonal therapies. This review describes the roles of (1) hormone related factors (ER, PgR, phosphorylated ER, ERbeta, aromatase), (2) growth related factors (HER2, Ki67, p53), (3) ER cofactors (AIB1, NcoR1), (4) estrogen dependent genes derived from gene expression profiling (HDAC6, IGFBP4/5), and (5) gene profiling using cDNA microarray. There are, however, considerable methodological difficulties in identifying useful predictive factors but on the basis of current evidence other biomarkers add little additional information. The prospective and multi-centered analyses will be warranted to develop the predictive factors for directing use of these therapies.
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PMID:[Predictive factors of hormonal therapy in breast cancer]. 1652 49

Chemoprevention has the potential to be a major component of colon, breast, prostate and lung cancer control. Epidemiological, experimental, and clinical studies provide evidence that antioxidants, anti-inflammatory agents, n-3 polyunsaturated fatty acids and several other phytochemicals possess unique modes of action against cancer growth. However, the mode of action of several of these agents at the gene transcription level is not completely understood. Completion of the human genome sequence and the advent of DNA microarrays using cDNAs enhanced the detection and identification of hundreds of differentially expressed genes in response to anticancer drugs or chemopreventive agents. In this review, we are presenting an extensive analysis of the key findings from studies using potential chemopreventive agents on global gene expression patterns, which lead to the identification of cancer drug targets. The summary of the study reports discussed in this review explains the extent of gene alterations mediated by more than 20 compounds including antioxidants, fatty acids, NSAIDs, phytochemicals, retinoids, selenium, vitamins, aromatase inhibitor, lovastatin, oltipraz, salvicine, and zinc. The findings from these studies further reveal the utility of DNA microarray in characterizing and quantifying the differentially expressed genes that are possibly reprogrammed by the above agents against colon, breast, prostate, lung, liver, pancreatic and other cancer types. Phenolic antioxidant resveratrol found in berries and grapes inhibits the formation of prostate tumors by acting on the regulatory genes such as p53 while activating a cascade of genes involved in cell cycle and apoptosis including p300, Apaf-1, cdk inhibitor p21, p57 (KIP2), p53 induced Pig 7, Pig 8, Pig 10, cyclin D, DNA fragmentation factor 45. The group of genes significantly altered by selenium includes cyclin D1, cdk5, cdk4, cdk2, cdc25A and GADD 153. Vitamine D shows impact on p21(Waf1/Cip1) p27 cyclin B and cyclin A1. Genomic expression profile with vitamin D indicated differential expression of gene targets such as c-JUN, JUNB, JUND, FREAC-1/FoxF1, ZNF-44/KOX7, plectin, filamin, and keratin-13, involved in antiproliferative, differentiation pathways. The agent UBEIL has a remarkable effect on cyclin D1. Curcumin mediated NrF2 pathway significantly altered p21(Waf1/Cip1) levels. Aromatase inhibitors affected the expression of cyclin D1. Interestingly, few dietary compounds listed in this review also have effect on APC, cdk inhibitors p21(Waf1/Cip1) and p27. Tea polyphenol EGCG has a significant effect on TGF-beta expression, while several other earlier studies have shown its effect on cell cycle regulatory proteins. This review article reveals potential chemoprevention drug targets, which are mainly centered on cell cycle regulatory pathway genes in cancer.
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PMID:Chemopreventive agents alters global gene expression pattern: predicting their mode of action and targets. 1716 75

The objective of this study was to evaluate the coexpression patterns of hormonal markers in breast cancer tissue and their relationship with pathologic characteristics and epidemiologic risk factors. We evaluated the expression of 17 markers by immunohistochemistry in 842 invasive breast carcinomas collected in a population-based case-control study conducted in Poland. Based on marker correlations, factor analysis identified four major coexpression patterns (factors): "nuclear receptor factor" [estrogen receptor (ER)-alpha, progesterone receptor, androgen receptor, cyclin D1, and aromatase], "estrogen metabolism/ER-beta factor" (ER-beta, peroxisome proliferator-activated receptor-gamma, steroid sulfatase, estrogen sulfonotransferase, and cytochrome P450 1B1), "HER2 factor" (human epidermal growth factor receptor 2, E-cadherin, cyclooxygenase-2, aromatase, steroid sulfatase), and "proliferation factor" (cytokeratin 5, cytokeratin 5/6, epidermal growth factor receptor, P53). Three of these factors corresponded to molecular subtypes previously defined by expression profiling; however, the estrogen metabolism/ER-beta factor seemed to be distinctive. High scores for this factor were associated with high tumor grade (P heterogeneity = 0.02), younger age at menarche (P heterogeneity = 0.04), lower current body mass index among premenopausal women (P heterogeneity = 0.01), and older age at menopause (P heterogeneity = 0.04). High scores for the proliferation factor were also associated with early menarche (P heterogeneity < 0.0001), and in contrast to the estrogen metabolism/ER-beta factor, higher current body mass index among premenopausal women (P heterogeneity = 0.03). Our analysis of hormonal pathway markers independently confirmed several previously defined molecular subtypes identified by gene expression profiling and augmented these findings by suggesting the existence of additional relationships related to ER-beta and enzymes involved in hormone metabolism.
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PMID:Hormonal markers in breast cancer: coexpression, relationship with pathologic characteristics, and risk factor associations in a population-based study. 1796 31

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.
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PMID:Overview of resistance to systemic therapy in patients with breast cancer. 1799 29

Controversies are still seen in the histological differential diagnosis of hyperplasia and well-differentiated endometrial carcinoma. Prediction of endometrial cancer in patients with hyperplasia with atypia, with the available markers has not been reliable yet. Hence these patients require more attention in the clinical management. Endometrial hyperplasia is proliferation of endometrial glands resulting in a higher gland : stroma ratio. Cytological atypia, which may progress to or co-exist with endometrial cancer and other pathological changes, result from estrogen stimulation unopposed by progesterone. Biomarkers whose expression is altered in cases of endometrial hyperplasia or cancer such as progesterone receptor, insulin-like growth factor I, retinaldehyde dehydrogenase type II, and secreted frizzled-related protein 4, seem to be promising to use as early-stage tumor markers. Mutation of PTEN is present in 83% of endometrial adenocarcinoma cases, making it the most frequent early molecular genetic alteration in type 1 endometrial tumors, which are generally associated with hyperplasia. p53 gene mutation is not found in endometrial hyperplasia, but researchers have detected this mutation in 20% of cases of endometrial carcinoma and 90% of cases of serous endometrial tumors. Cyclooxygenase-2 is important in tumorogenic transformation of hyperplasia. Expression of cyclooxygenase-2 decreases apoptosis, increases angiogenesis, and is related to invasiveness. Cyclooxygenase-2 expression increases significantly in cases of well-differentiated endometrial adenocarcinoma. Prostaglandin E2 is known to regulate aromatase gene expression and is the product of cyclooxygenase-2. The data about aromatase inhibitors are promising; in breast cancer patients, treatment with tamoxifen induces uterine abnormalities as early as 3 months after the initiation of therapy. In contrast, these abnormalities are not seen in patients who receive aromatase inhibitors and switched therapy after tamoxifen withdrawal may reverse tamoxifen-associated endometrial thickening.
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PMID:From endometrial hyperplasia to endometrial cancer: insight into the biology and possible medical preventive measures. 1828 70

Both the functional loss of p53 and the overexpression of aromatase are important for the progression of breast cancer in postmenopausal women. Here, we found that aromatase expression was up-regulated in primary cultures of mammary epithelial cells (p53(Delta)(5,6) MEC) isolated from mice with a defect in exons 5 and 6 of the p53 gene. Aromatase basal activity and expression levels were significantly increased in p53(Delta)(5,6) MEC when compared with wild-type MEC. Reporter gene activity in p53(Delta)(5,6) MEC transfected with the aromatase promoter or the cAMP-responsive element (CRE) minimal promoter was higher than wild-type MEC. p53 inactivation increased both Ser133-phosphorylated CRE-binding protein (CREB) and the nuclear accumulation of CREB. Inhibition of extracellular signal-regulated kinase (ERK) or Src tyrosine kinase blocked aromatase gene transactivation and CREB activation in the p53(Delta)(5,6) MEC. These results support the hypothesis that a genetic defect in the function of p53 enhances the expression of aromatase via ERK or Src activation in MEC, which suggests that aromatase expression is closely related to the p53 status in MEC.
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PMID:Enhanced expression of aromatase in p53-inactivated mammary epithelial cells. 1831 Feb 82

Extensive research within the last decade has revealed that most chronic illnesses such as cancer, cardiovascular and pulmonary diseases, neurological diseases, diabetes, and autoimmune diseases exhibit dysregulation of multiple cell signaling pathways that have been linked to inflammation. Thus mono-targeted therapies developed for the last two decades for these diseases have proven to be unsafe, ineffective and expensive. Although fruits and vegetables are regarded to have therapeutic potential against chronic illnesses, neither their active component nor the mechanism of action is well understood. Resveratrol (trans-3, 5, 4'-trihydroxystilbene), a component of grapes, berries, peanuts and other traditional medicines, is one such polyphenol that has been shown to mediate its effects through modulation of many different pathways. This stilbene has been shown to bind to numerous cell-signaling molecules such as multi drug resistance protein, topoisomerase II, aromatase, DNA polymerase, estrogen receptors, tubulin and F1-ATPase. Resveratrol has also been shown to activate various transcription factor (e.g; NFkappaB, STAT3, HIF-1alpha, beta-catenin and PPAR-gamma), suppress the expression of antiapoptotic gene products (e.g; Bcl-2, Bcl-X(L), XIAP and survivin), inhibit protein kinases (e.g; src, PI3K, JNK, and AKT), induce antioxidant enzymes (e,g; catalase, superoxide dismutase and hemoxygenase-1), suppress the expression of inflammatory biomarkers (e.g., TNF, COX-2, iNOS, and CRP), inhibit the expression of angiogenic and metastatic gene products (e.g., MMPs, VEGF, cathepsin D, and ICAM-1), and modulate cell cycle regulatory genes (e.g., p53, Rb, PTEN, cyclins and CDKs). Numerous animal studies have demonstrated that this polyphenol holds promise against numerous age-associated diseases including cancer, diabetes, Alzheimer, cardiovascular and pulmonary diseases. In view of these studies, resveratrol's prospects for use in the clinics are rapidly accelerating. Efforts are also underway to improve its activity in vivo through structural modification and reformulation. Our review describes various targets of resveratrol and their therapeutic potential.
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PMID:Resveratrol: a multitargeted agent for age-associated chronic diseases. 1841 53

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.
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PMID:Recent advances and current controversies in the management of DCIS of the breast. 1849 Jan 11

Endocrine therapy is often given together with postoperative radiotherapy in patients with breast cancer and positive hormone-receptor status. However, few experimental or clinical studies address the combined effects of hormone and radiation therapy. Preclinical models have shown changes in tumour cell kinetics with the addition of tamoxifen, and some show reduced tumour cell death with concurrent anti-oestrogen treatment and radiotherapy. Although data from in-vitro studies support the notion of antagonistic effects of concurrent tamoxifen and radiotherapy on tumour cells, in-vivo research suggests a synergistic effect that could be attributable to micro-environmental changes in tumour responsiveness to ionising radiation and hormone therapy. Retrospective studies suggest that in practical application, concurrent administration of tamoxifen with radiotherapy does not compromise local control but might increase toxicity. Preliminary results from simultaneous treatment with aromatase inhibitors and radiation indicate that this combination of endocrine and radiation therapy could enhance cytotoxicity and improve tumour response. Further studies are needed to clarify the physiological mechanisms activated by oestrogens, which will allow a more thorough understanding of the complex interactions between 17beta-oestradiol and P53/P21(WAF1/CIP1)/Rb pathways and of the interaction between endocrine therapy and radiotherapy.
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PMID:Concurrent hormone and radiation therapy in patients with breast cancer: what is the rationale? 1941 Jan 92


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