Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027627 (metastases)
 103,950 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Glycodelin (encoded by PAEP gene) is a secreted lipocalin protein mainly expressed in reproductive tissues, but also in several tumour types. In the breast, glycodelin is expressed both in normal epithelial and cancerous tissue. To investigate the association of glycodelin with clinicopathological features of breast cancer and outcome of patients we evaluated the protein expression of glycodelin in a large series of breast tumours. Immunohistochemical analysis of tissue microarrays was used to study glycodelin expression on 399 sporadic and 436 familial non-BRCA1/2 tumours with strong family history. Gene expression analysis was used to define genes co-expressed with PAEP in sporadic and familial non-BRCA1/2 breast tumours. In the sporadic series, the glycodelin expression associated with low proliferation rate (P < 0.001), with a tendency towards well-differentiated tumours (grades 1 and 2, P = 0.012) and high cyclin D1 (P = 0.034) expression. However, in familial non-BRCA1/2 cases with strong family history glycodelin expression associated with a less favourable phenotype, i.e. positive lymph node status (P = 0.003) and HER2-positive tumours (P = 0.009). Moreover, the patients with glycodelin-positive tumours had an increased risk for distant metastases (P = 0.001) and in multivariate analysis glycodelin expression was an independent predictor of metastasis (hazard ratio (HR) = 2.22, 95% confidence interval (95% CI) = 1.22-4.03, P = 0.009) in familial non-BRCA1/2 breast cancer. Gene expression analysis further revealed different gene expression profiles correlating with the PAEP expression in the sporadic and familial non-BRCA1/2 breast cancers. Our findings suggest differential progression pathways in the sporadic and familial non-BRCA1/2 breast tumours expressing glycodelin.
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PMID:Glycodelin expression associates with differential tumour phenotype and outcome in sporadic and familial non-BRCA1/2 breast cancer patients. 2067 58

Advances in the systemic treatment of early breast cancer have led to significant improvements in survival for patients with hormone receptor- and/or HER2-positive disease. In recent years, interest has focused on tumors that lack expression of the estrogen receptor, progesterone receptor and HER2, the so-called triple-negative subgroup. As a group, triple-negative cancers have a relatively aggressive clinical course, with early development of visceral metastases and a poor long-term prognosis. These tumors, however, encompass a wide range of subtypes with varying prognosis, including a number of special types with a good prognosis (e.g., adenoid cystic carcinomas and secretory carcinoma). There is considerable overlap between triple-negative and basal-like tumors; however, microarray studies have demonstrated that the overlap between basal-like and triple-negative cancers is not complete. The similarities between sporadic triple-negative cancers and tumors arising in BRCA1 mutation carriers and the fact that the majority of BRCA1 tumors display a triple-negative phenotype have led to studies demonstrating a potential loss of BRCA1 function in triple-negative cancers and offered potential therapeutic avenues for patients with these cancers. However, it should be noted that triple-negative breast cancers comprise a heterogeneous group of tumors. Understanding the molecular underpinning of distinct subgroups of these cancers is crucial for the identification of novel therapeutic targets and individualization of treatment for patients with triple-negative disease.
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PMID:Beyond triple-negative breast cancer: the need to define new subtypes. 2073 7

This Review outlines the understanding and management of triple-negative breast cancer (TNBC). TNBC shares morphological and genetic abnormalities with basal-like breast cancer (BLBC), a subgroup of breast cancer defined by gene-expression profiling. However, TNBC and BLBC tumors are heterogeneous and overlap is incomplete. Breast cancers found in BRCA1 mutation carriers are also frequently triple negative and basal like. TNBC and BLBC occur most frequently in young women, especially African Americans, and tend to exhibit aggressive, metastatic behavior. These tumors respond to conventional chemotherapy but relapse more frequently than hormone receptor-positive, luminal subtypes and have a worse prognosis. New systemic therapies are urgently needed as most patients with TNBC and/or BLBC relapse with distant metastases, and hormonal therapies and HER2-targeted agents are ineffective in this group of tumors. Poly (ADP-ribose) polymerase inhibitors, angiogenesis inhibitors, EGFR-targeted agents, and src kinase and mTOR inhibitors are among the therapeutic agents being actively investigated in clinical trials in patients with TNBC and/or BRCA1-associated tumors. Increased understanding of the genetic abnormalities involved in the pathogenesis of TNBC, BLBC and BRCA1-associated tumors is opening up new therapeutic possibilities for these hard-to-treat breast cancers.
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PMID:Triple-negative breast cancer: disease entity or title of convenience? 2087 96

Life diversity can now be clearly explored with the next-generation DNA sequencing technology, allowing the discovery of genetic variants among individuals, patients and tumors. However, beyond causal mutations catalog completion, systems medicine is essential to link genotype to phenotypic cancer diversity towards personalized medicine. Despite advances with traditional single genes molecular research, including rare mutations in BRCA1/2 and CDH1 for primary prevention and trastuzumab for treating HER2-overexpressing breast and gastric tumors, overall, treatment failure and death rates are still alarmingly high. Revolution in sequencing reveals that, now both a huge number and widespread variability of driver mutations, including single-nucleotide polymorphisms, genomic rearrangements and copy-number changes involved in breast cancer development. All these genetic alterations result in a heterogeneous deregulation of signaling pathways, including EGFR, HER2, VEGF, Wnt/Notch, TGF and others.Cancer initiation, progression and metastases are driven by complex molecular networks rather than linear genotype-phenotype relationship. Therefore, clinical expectations by traditional molecular research strategies targeting single genes and single signaling pathways are likely minimal. This review discusses the necessity of molecular networks modeling to understand complex gene-gene, protein-protein and gene-environment interactions. Moreover, the potential of systems clinico-biological approaches to predict intracellular signaling pathways components networks and cancer heterogeneous cells within an individual tumor is described. A flowchart specific for three steps in cancer evolution separately tumorigenesis, early-stage and advanced-stage breast cancer is presented. Using reverse engineering starting with the integration of available established clinical, environmental, treatment and oncological outcomes (survival and death) data and then the still incomplete but progressively accumulating genotypic data into computational networks modeling may lead to bionetworks-based discovery of robust biomarkers and highly effective cancer drugs targets.
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PMID:Trastuzumab and beyond: sequencing cancer genomes and predicting molecular networks. 2097 37

Metastasis and drug resistance are the major causes of mortality in patients with pancreatic cancer. Once developed, the progression of pancreatic cancer metastasis is virtually unstoppable with current therapies. Here, we report the remarkable clinical outcome of a patient with advanced, gemcitabine-resistant, pancreatic cancer who was later treated with DNA damaging agents, on the basis of the observation of significant activity of this class of drugs against a personalized xenograft generated from the patient's surgically resected tumor. Mitomycin C treatment, selected on the basis of its robust preclinical activity in a personalized xenograft generated from the patient's tumor, resulted in long-lasting (36+ months) tumor response. Global genomic sequencing revealed biallelic inactivation of the gene encoding PalB2 protein in this patient's cancer; the mutation is predicted to disrupt BRCA1 and BRCA2 interactions critical to DNA double-strand break repair. This work suggests that inactivation of the PALB2 gene is a determinant of response to DNA damage in pancreatic cancer and a new target for personalizing cancer treatment. Integrating personalized xenografts with unbiased exomic sequencing led to customized therapy, tailored to the genetic environment of the patient's tumor, and identification of a new biomarker of drug response in a lethal cancer.
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PMID:Personalizing cancer treatment in the age of global genomic analyses: PALB2 gene mutations and the response to DNA damaging agents in pancreatic cancer. 2113 51

Mutations in the BRCA1 tumor suppressor predispose to the development of breast and ovarian cancers. Noticeably, the majority of BRCA1-associated breast cancers are triple-negative (ER-, PR- and HER2-) and display a basal-like phenotype, which are features relatively uncommon among sporadic breast cancers. It is well documented that BRCA1 is involved in a number of cellular functions converging to the maintenance of genomic stability. However, the control over DNA integrity does not seem to account for the peculiar phenotype of BRCA1-associated tumors since mutations in other genes involved in such a function, namely BRCA2, associate to a broader spectrum of breast carcinoma subtypes. Indeed, an increasing body of evidence indicates that BRCA1 is implicated also in the regulation of transcription by impinging upon general components of the transcriptional machinery. Thus, elucidating the complex biochemical network regulated by BRCA1 may allow a better understanding also of the biology of sporadic triple-negative/basal-like tumors and lay down the basis for novel preventive measures and more effective therapeutic strategies. This review summarizes recent findings on the role of BRCA1 in the regulation of transcription and how this might set the ground for the development of cancers with triple-negative/basal-like features.
Cancer Metastasis Rev 2012 Jun
PMID:BRACking news on triple-negative/basal-like breast cancers: how BRCA1 deficiency may result in the development of a selective tumor subtype. 2210 51

SUMMARY: Triple-negative breast cancer (TNBC) is characterized by the lack of estrogen and progesterone receptors and the lack of HER2 expression or amplification. Much interest has recently been focused on these triple-negative (TN) subtypes because they may be aggressive and are more likely to recur and metastasize than other subtypes of breast cancer. TNBC accounts for approximately 10-24% of all breast cancer cases, and typically it occurs in younger patients and in patients with BRCA1 mutation. There is a substantial heterogeneity of TNBCs both at the morphological and the molecular level, but there are also common features, such as low tumor grade and accelerated tumor proliferation. Morphologically, TNBC may present as invasive ductal, metaplastic, medullary, apocrine, or other types. Molecularly, they are most frequently associated with a basal phenotype, but there is a distinct subgroup of cancers that are not of basal type and belong to the claudin-low or molecular-apocrine type. The basal phenotype is frequently associated with the loss of BRCA1.
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PMID:Triple-Negative Breast Cancer: Clinical and Histological Correlations. 2213 25

The co-existence of breast and ovarian cancers in the same individual should raise suspicion of a hereditary process. Patients with either BRCA1 or BRCA2 germ-line mutations have an average risk of 39% and 11% respectively of developing ovarian cancer by the age of 70; they have a risk of 35-85% of developing breast cancer in their lifetime. We report here unusual pathologic features in a BRCA2 germ-line mutation carrier recently diagnosed with synchronous breast and ovarian cancers, and summarize the findings in six other women who were diagnosed with ovarian cancer either simultaneously with the diagnosis of breast cancer or at varying times after the diagnosis. While in most instances this may be a coincidental occurrence in highly susceptible individuals, the patient we highlight raises the provocative hypothesis that at times breast cancer metastasizes to the ovaries of mutation carriers and stimulates the development of an ovarian cancer as well as other cancers. In addition, these ovarian cancers may have different mechanisms of metastases predisposing them to travel to unusual sites.
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PMID:Co-existence of breast and ovarian cancers in BRCA germ-line mutation carriers. 2227 85

Drug resistance is one of the most pressing problems in treating cancer patients today. Local and regional disease can usually be adequately treated, but patients eventually die from distant metastases that have become resistant to all available chemotherapy. Although work on cultured tumor cell lines has yielded a lot of information on potential drug resistance mechanisms, it has proven difficult to translate these results to clinical drug resistance in patients. The controversy regarding the contribution of ABC transporters to drug resistance in patients is one example. The study of genetically engineered mouse models (GEMMs), which closely resemble cancer in human patients, can help to bridge this gap. In models for BRCA1- or BRCA2-associated breast cancer, we observed a substantial synergy between the defect in homology-directed DNA repair and sensitivity to DNA-targeting drugs. Nevertheless, tumors are not easily eradicated and eventually drug resistance develops. In this review we will discuss the use of the new generation mouse models to address major clinical problems, such as mechanisms of drug resistance, predicting chemotherapy response or characterizing the nature of residual tumor cells that escape eradication. Moreover, we will address the contribution of ABC transporters to drug resistance in our model.
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PMID:Drug resistance in the mouse cancer clinic. 2233 19

The majority of human high-grade serous epithelial ovarian cancer (SEOC) is characterized by frequent mutations in p53 and alterations in the RB and FOXM1 pathways. A subset of human SEOC harbors a combination of germline and somatic mutations as well as epigenetic dysfunction for BRCA1/2. Using Cre-conditional alleles and intrabursal induction by Cre-expressing adenovirus in genetically engineered mice, we analyzed the roles of pathway perturbations in epithelial ovarian cancer initiation and progression. Inactivation of RB-mediated tumor suppression induced surface epithelial proliferation with progression to stage I carcinoma. Additional biallelic inactivation and/or missense p53 mutation in the presence or absence of Brca1/2 caused progression to stage IV disease. As in human SEOC, mice developed peritoneal carcinomatosis, ascites, and distant metastases. Unbiased gene expression and metabolomic profiling confirmed that Rb, p53, and Brca1/2-triple mutant tumors aligned with human SEOC, and not with other intraperitoneal cancers. Together, our findings provide a novel resource for evaluating disease etiology and biomarkers, therapeutic evaluation, and improved imaging strategies in epithelial ovarian cancer.
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PMID:Perturbation of Rb, p53, and Brca1 or Brca2 cooperate in inducing metastatic serous epithelial ovarian cancer. 2261 26


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