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)

The BRCA/RAD51 complex of tumor suppressor genes plays a major role in the DNA damage response. In this explorative study, BRCA1, BRCA2, and RAD51 mRNA expression was quantified in highly defined laser microdissected tissue samples of simple adenomas, adenocarcinomas of the mammary gland, and their lymph node metastases by real-time quantitative reverse transcription polymerase chain reaction. Expression levels in the tumors were normalized to the geometric mean of 3 housekeeping genes and quantified relative to normal mammary epithelium of the same dog. In adenomas, mRNA expression was reduced for BRCA1 (6/10 dogs, 60%), BRCA2 (4/10 dogs, 40%), and RAD51 (4/10, 40%). In adenocarcinomas BRCA1 expression varied with increased expression in 3 of 10 (30%) dogs and no differences in 7 of 10 (70%) dogs when compared with normal mammary gland. BRCA2 and RAD51 were overexpressed in 5 of 10 (50%) and 6 of 10 (60%) of adenocarcinomas, respectively. An overexpression of RAD51 and BRCA2 was found in 8 of 10 (80%) and 5 of 10 (50%) of the lymph node metastases, respectively. Direct comparison of primary tumors and metastases revealed increased mRNA expression of BRCA1 (2/10 dogs, 20%), BRCA2 (2/10 dogs, 20%), and RAD51 (3/10 dogs, 30%) in lymph node metastases. Taken together, the results suggest that RAD51 is upregulated in the majority of lymph node metastases of canine mammary tumors. Further experimental studies are needed to clarify whether these changes in gene expression are a direct carcinogenetic stimulus or a protective response due to genetic instability during tumor progression.
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PMID:Increased expression of BRCA2 and RAD51 in lymph node metastases of canine mammary adenocarcinomas. 1917 91

Risk-reducing salpingo-oophorectomy (RRSO) is an effective prophylactic procedure for women with mutations in BRCA1 or BRCA2 genes, both of which confer an increased lifetime risk for ovarian, tubal, peritoneal, and breast cancer. In addition to lowering this risk, RRSO also offers the opportunity to detect occult early-stage fallopian tube or ovarian carcinoma. The differential diagnosis of occult tubal/ovarian cancer includes a spectrum of benign tubal and ovarian alterations and also occult metastatic breast cancer, although only rare cases of the latter have been reported in RRSO. Neoadjuvant breast cancer chemotherapy may contribute to diagnostic difficulty due to treatment-induced cytologic alterations. With the aim of elucidating features which may help with differential diagnosis, this study reports the incidence and pathologic features of benign ovarian alterations, benign ovarian tumors, and occult primary and metastatic malignancies in prophylactic oophorectomies from 108 women with a BRCA mutation and from 35 women with other strong risk factors for hereditary breast/ovarian carcinoma. We direct particular emphasis on morphologic features of primary ovarian lesions that may mimic occult metastatic breast cancer. We also evaluate histologic alterations due to neoadjuvant breast cancer chemotherapy in the ovary and fallopian tube of patients who received such treatment immediately preceding RRSO. Comparison is made to ovarian metastases of breast cancer in our hospital-based population of breast cancer patients, none of whom underwent RRSO. Overall, 69% of RRSO patients had a personal history of breast cancer. Neoadjuvant breast cancer chemotherapy was administered in 15%. Occult primary carcinoma occurred in 7 (6.5%) BRCA patients (5 in fallopian tube, 1 in fallopian tube and ovary, 1 in ovary). Ovarian metastasis of breast cancer occurred in 1 (1%) BRCA patient undergoing RRSO and in up to a similar proportion (0.8%) of the hospital-based population of breast cancer patients. The metastasis in the RRSO patient was clinically occult, unilateral, 0.2 cm, and demonstrated mild atypia without mitoses. Abundant foamy, vacuolated cytoplasm due to neoadjuvant chemotherapy exposure was notable. In contrast, ovarian metastases in the non-RRSO population were all clinically detected, bilateral, large, and exhibited well-developed malignant cytologic features. None of the normal cell types in the ovary or tube demonstrated any cytologic alterations in RRSO patients who received neoadjuvant chemotherapy. The main morphologic mimics of metastasis with superimposed chemotherapy-induced alterations in RRSO were stromal hyperthecosis (n=8), nodular hyperthecosis (n=2), adrenal rests (n=3), hilus cell nodules (n=43), and hilus cell hyperplasia (n=4). Occult primary ovarian carcinoma was reliably distinguished from ovarian metastases of breast cancer by WT-1+, p53+, mammaglobin-, GCDPF-immunoprofile. These results demonstrate that evaluation of RRSO specimens requires awareness of a spectrum of ovarian lesions which may mimic occult primary or metastatic carcinoma; awareness of the masquerading effects of neoadjuvant chemotherapy; and awareness of the potential morphologic differences between occult metastatic breast cancer in RRSO and non-RRSO specimens.
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PMID:Ovarian pathology in risk-reducing salpingo-oophorectomies from women with BRCA mutations, emphasizing the differential diagnosis of occult primary and metastatic carcinoma. 1944 Jan 48

Male breast cancer accounts for around 1% of all breast cancer cases, but the incidence has increased over the past 25 years. The rarity of this entity precludes prospective randomized clinical trials. Although breast carcinoma in both genders share certain characteristics, notable differences have emerged. Familial cases usually have BRCA2 rather than BRCA1 mutations. Klinefelter syndrome is the strongest risk factor for developing male breast carcinoma. Men tend to be diagnosed at an older age than women. Presentation is usually a painless lump, but is often late, with more than 40% of individuals having stage III or IV disease. When survival is adjusted for age at diagnosis and stage of disease, outcomes for male and female patients with breast cancer is similar. Surgery is usually mastectomy with axillary clearance or sentinel node biopsy. Because 90% of tumors are hormonal receptor positive, tamoxifen is standard adjuvant therapy. Indications for radiotherapy and chemotherapy are similar to female breast cancer. For metastatic disease, hormonal therapy is the main treatment, but chemotherapy can also provide palliation.
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PMID:Male breast cancer. 2019 84

In the past few years, ovarian cancer research has focused increasingly on disease prevention; but an increasing number of women refer to gynecology and clinical genetics clinics with a family history of ovarian cancer and inherited familial mutations. The interest on the issue has increased also due to the identification of BReast CAncer1 (BRCA1) and BRCA2 genes mutations. The importance of recognizing the characteristics of hereditary ovarian cancer (HOC) and manage women at risk appropriately will provide more accurate care of the high-risk population. Women at risk can be identified by pedigree analysis and may receive counseling from interdisciplinary cancer genetics clinics, while those at high risk need to receive genetic testing. Risk calculation programs define risks and assist in decision-making in clinical options and genetic testing; they provide information on the risks of the disease, mutation status, and the use of genetic testing in the management of high-risk families. Furthermore, while a large number of surrogate preliminary markers have been identified, there are still limited studies on ovarian cancer genomics. Different options for risk management of HOC are available: surveillance, chemoprevention and prophylactic surgery. Surveillance in HOC high-risk patients is still not accurate. Chemoprevention is currently a controversial topic, because a number of major issues still need to be addressed in developing and testing agents for ovarian cancer chemoprevention. Prophylactic surgery has been shown to effectively decrease cancer risk, and it has the possibility to substantially reduce ovarian cancer mortality.
Cancer Metastasis Rev 2010 Jun
PMID:Hereditary ovarian cancers: from BRCA mutations to clinical management. A modern appraisal. 2040 70

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

Routinely used prognostic factors fail to predict clinical outcome in a significant proportion of breast cancer patients, implying that they can not detect some important biological characteristics. Chromosomal changes have been described in breast carcinomas for many years but their significance is not clear. We compared chromosomal changes with clinico-pathological characteristics and clinical outcome in 203 breast cancer patients with a follow-up of 9-18 years. Combining data from classical cytogenetics and flow cytometry revealed chromosomal abnormalities in 142 cases (70%). Of these, 51 (35.9%) contained two or more cytogenetically abnormal clones. Polyclonality was significantly associated with poor breast-cancer-specific survival (P = 0.03) within 5 years, independent of tumor size, lymph node metastases, and hormone receptors. Specific changes were similar to those previously described, but a new finding was a significant association between del 3p12p21 and poor survival. Polyclonality was significantly associated with TP53-mutations but not with a germline BRCA2 mutation. Less than one third of the polyclonal samples were identified by flow cytometry alone. Cytogenetic changes were detected in 17 out of 114 samples from non-tumorous tissue (15%), two of them identical with a clone in the corresponding tumor. Several samples contained clearly unrelated clones within the tumor and outside, implying either multifocal origin or early divergence. In conclusion, the common deletion on Chromosome 3p12p21 was associated with poor clinical outcome. Chromosomal polyclonality is common in breast carcinomas and predicts poor survival. Polyclonality was poorly detected by one-sample flow cytometry. Multiple sampling might improve the detection rate.
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PMID:Cytogenetic polyclonality of breast carcinomas: association with clinico-pathological characteristics and outcome. 2191 Jan 59

Breast cancer is the most common malignancy in females. Common sites of metastases include the liver, lung, bone, and brain, while metastases to the extrahepatic digestive system are very rare. This report presents a patient diagnosed with breast carcinoma metastasis in the terminal ileum. The patient underwent breast-conserving surgery on both breasts because of breast cancer at the age of 46 years. Both breast cancers were consistent with stage I invasive ductal carcinomas. Colonoscopy during an investigation for hematochezia revealed a 2-cm ulceration in the terminal ileum 22 months later, and microscopic examination of a biopsy specimen of the ulceration revealed a poorly differentiated mass that was strongly suggestive of metastatic adenocarcinoma with endolymphatic tumor emboli. She underwent hand-assisted laparoscopic ileocecectomy because of ileal metastasis. She had a family history of breast cancer (sister) and colon cancer (brother). She exhibited HER2/neu discordance and carried the BRCA2 gene mutation. Surgeons should remain aware that breast cancer can metastasize to the gastrointestinal tract.
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PMID:Ileal metastasis of breast cancer in a patient with a BRCA2 gene mutation: report of a case. 2196 3

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

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


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