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PubMedDate not supplied

[Epidemiology and economics of chemotherapy combinations in the treatment of advanced breast cancer].

125 oncologists, taken at random from a French professional list, followed up a cohort of 836 patients suffering from advanced breast cancer and treated by chemotherapy. The following data were collected prospectively: socio-demographics of patients and practitioners, disease history, characteristics of one chemotherapy cycle (type, utility and cost). A total of 89 chemotherapy combinations were described during the first-line treatment, independently of doses, eight combinations representing 70 per cent of all the prescriptions. No statistically significant differences were found when comparing the utility of the most often used combinations. Chemotherapy was the main cost driver of administration, rising to 90 per cent of the total cost when using taxans, followed by CSF. The cost price of taxan administration was twice to three times that of FEC or vinorelbine associations. These differences were poorly taken into account by the French budget allocation system as based on Diagnosis Related Groups.

Antineoplastic Agents, Phytogenic↗

PubMed2002

Cancerous hyper-mutagenesis in p53 genes is possibly associated with transcriptional bypass of DNA lesions.

The database of tumor-associated p53 base substitutions includes about 5% of tumors with two or more base substitutions. These multiplet base substitutions in one tumor are evidence for hyper-mutagenesis. Our retrospective analysis of this database indicates that most multiplets arise from a single transient hyper-mutagenic event in one cell that subsequently proliferated into a clonal tumor. The hyper-mutagenesis, 1.8 x 10(-4) substitutions per base pair, is detected as multiple mutations in p53 genes of tumors. It requires one strongly tumorigenic p53 substitution, usually missense, called the driver mutation. The occurrence frequencies of ancillary base substitutions, those that hitch-hike along with the driver mutation, are independent of their amino acid coding properties. In this respect, they act like neutral mutations. In support of this neutrality, we find that the frequency distribution of hitch-hiking CpG transitions along the p53 exons, their mutational spectrum, approximates the spontaneous pre-selection mutational spectrum of most human tissues and is correlated with the mutational spectrum of p53 pseudogenes in mammalian germ cells. The driver substitutions of multiplets predominantly originate along the transcribed strand while the ancillary substitutions tend to originate along the non-transcribed strand. This data is consistent with a model of time-dependent mutagenesis in non-dividing stem cells for generating multiple strand-asymmetric p53 mutations in tumors. By transcriptional bypass of DNA lesions with concomitant misincorporation, transcriptional mutagenesis generates a transient mutant p53 mRNA. The associated mutant p53 protein could allow the host cell a growth advantage, release from G1-arrest. Then, during subsequent DNA replication and misreading of the same lesion, the damaged base along the transcribed DNA strand would serve as the origin of the p53 base substitution that drives the hyper-mutagenic event leading to tumors with multiple p53 mutations.

Animals↗

PubMed1987

Tobacco smoking, occupational exposure and bladder cancer in Argentina.

The highest rate for bladder cancer in Latin America has been reported from La Plata, Argentina. A case-control study was carried out to investigate the reasons for this high rate. A total of 117 cases, 117 hospital controls and 117 neighbourhood sex- and age-matched controls were interviewed regarding their smoking and drinking habits and occupational exposures. Cigarette smoking and coffee drinking were identified as the major risk factors, and a significant association was also found for truck and railway drivers and for oil refinery workers. The relative risks for male smokers who ever smoked cigarettes vs. non-smokers was 4.3 (95% Cl: 1.9-10.3). The risk associated with black tobacco cigarettes was 2-3 times higher than that of blond cigarettes. For male ex-smokers the risk after 5 years of no smoking is less than one third of that of current smokers. The RR for drinking coffee was 2.4 (95% Cl: 1.4-4.4) after adjusting for the effects of tobacco smoking, and the risk increased with the number of cups per day. No association was found with the use of saccharin.

Age Factors↗

PubMedDate not supplied

Acid, helicobacter and immunity: a new paradigm for oesophagogastric cancer.

Epidemiological evidence has clearly shown a highly significant relationship between Helicobacter pylori infection and the development of duodenal ulcer and distal gastric adenocarcinoma. Despite H. pylori being a common aetiological factor for both disorders, the two disease phenotypes are virtually mutually exclusive. This indicates that the host response to infection has a pivotal role in determining outcome; these disease phenotypes relate to the effect of infection on gastric acid secretion, duodenal ulcer being closely related to sustained acid secretion whereas gastric cancer follows gastric atrophy and impaired gastric acid secretion. Cancer at the oesophageal junction and that associated with Barrett's oesophagus is now the most rapidly increasing tumour in the gastrointestinal tract. The challenge for the next millennium, therefore, is to try and develop methods for identifying patients at risk of developing oesophagogastric cancer. A common feature in the pathogenesis of both gastric and oesophageal adenocarcinoma is inflammation presenting clinically as gastritis and oesophagitis. The pathway from gastritis to gastric atrophy, dysplasia and carcinoma is thought to be a multi-step process, probably triggered by free radicals within the gastric epithelium and increased exposure to luminal carcinogens. However, it has been unclear as to which aspect of the host response determines whether an individual will move along the neoplasia pathway. Recent work has shown that qualitative aspects of the immune environment in the stomach may account for a substantial part of the phenotypic divergence following H. pylori infection. Interleukin-1 beta polymorphisms relate closely to the propensity for an individual to develop distal gastric cancer and maybe useful for predicting risk in family members. In Barrett's oesophagus, we have recently shown that the immune environment may also be important in determining whether an individual will develop cancer. Although we did not find that Barrett's oesophagus was a profoundly inflammatory condition (unlike esophagitis in the squamous epithelium), where there was evidence of inflammation it was qualitatively different from that of oesophagitis in that a Th-2 response with increased expression of IL-4 predominated in Barrett's, whereas a Th-1 proinflammatory response characterised oesophagitis in squamous epithelium. It seems likely that the specific immune environment within Barrett's metaplasia may be an important driver towards dysplasia and carcinoma. Thus, the immune environment in the stomach and esophagus may be critical in determining whether an individual is at risk of developing neoplastic complications of H. pylori infection and gastroesophageal reflux. Identification of the genetic factors which underpin these responses may ultimately result in development of methods to identify individuals at high risk.

Esophageal Neoplasms↗

PubMed2004

A cost-effectiveness analysis of docetaxel in the second-line treatment of non-small cell lung cancer.

BACKGROUND: Whilst lung cancer is the most common form of cancer in England and Wales (annual incidence rate of 50 per 100,000) it does not always receive the policy attention accorded to other types of cancer, such as breast and colorectal. Nevertheless, the burden of lung cancer is significant and the UK NHS Plan for cancer has set out the government's commitment to improving all cancer services. The question faced by the NHS is which interventions are most cost effective in implementing this plan. OBJECTIVE: To develop a model to assess the economics of second-line treatment of non-small cell lung cancer (NSCLC) from the perspective of the UK NHS, based on the resources and outcomes from the pivotal clinical study comparing docetaxel 75 mg/m(2) with best supportive care (BSC). METHODS: The area under the survival curve for each treatment was analysed and the difference in mean survival between the docetaxel group and the BSC group was calculated as 3.82 months. Measurable incremental costs for the docetaxel group were largely driven by drug acquisition and administration. These cost drivers, as well as toxicity treatment costs and cost offsets, were varied in the sensitivity analysis. Although the overall timeframe for the model was 2 years, discounting was not applied as the resources and benefits of docetaxel use in this setting are realised relatively immediately. RESULTS: The base case cost-effectiveness analysis (mean values) reported a cost per life-year gained of 13,863 pounds sterling for docetaxel 75 mg/m(2) (year 2000/2001 values). Sensitivity analysis showed that the number of treatment cycles per patient, which affected total treatment cost, had most influence on the cost per life-year gained in the base case scenario. Using the 95% confidence intervals around the mean number of treatment cycles, the base case cost per life-year gained varied from 10,985 pounds sterling to 16,738 pounds sterling. Using the 95% confidence intervals around the mean difference in survival, to represent best and worst case scenarios, the cost per life-year saved ranged from 10,020 pounds sterling to 32,781 pounds sterling . CONCLUSION: This model suggests, with its underlying assumptions and data, docetaxel 75 mg/m(2) in 3-weekly cycles is a cost-effective second-line treatment, from the perspective of the NHS, for pretreated NSCLC in terms of survival gains made for a reasonable increase in costs.

Antineoplastic Agents, Phytogenic↗

PubMed1994

Occupational risk factors for renal-cell carcinoma in Denmark.

OBJECTIVES: Risk factors for renal-cell carcinoma, the most frequent type of kidney cancer, remains enigmatic. Time trends in incidence and changes in the regional distribution of this cancer are suggestive of environmental risk factors. This study reports on occupational risk factors for renal-cell carcinoma in Denmark. METHODS: In a population-based study, 365 persons with histologically verified renal-cell carcinoma and 396 referents were interviewed. Information was collected on occupation, education, and occupational exposure to a number of suspected substances, including hydrocarbons, asbestos, and radiation. RESULTS: Risk of renal-cell carcinoma was found to be associated with employment as a truck driver, exposure to gasoline, other hydrocarbons, and insecticides and herbicides. The risk of renal-cell carcinoma was higher in the lower socioeconomic strata for both the men and the women. Nonsignificantly elevated risks were observed for employment in oil refineries, gasoline stations, and the iron and steel industry. No association was found for exposure to radiation or for employment in industries such as leather manufacturing and health care, which have previously been linked to an increased risk of renal-cell carcinoma. CONCLUSIONS: The risk of renal-cell carcinoma is increased in lower socioeconomic strata, and previously identified or suspected risk factors do not explain the excess in risk. This study adds additional support to the hypothesis of a link between renal-cell carcinoma and hydrocarbons and also demonstrates the need for further studies on occupational risk factors for renal-cell carcinoma.

Adult↗

PubMed2026

Anaplastic lymphoma kinase immunohistochemical positivity in high-grade pulmonary neuroendocrine carcinoma: an actionable signal or merely a shadow?

AIMS: Anaplastic lymphoma kinase (ALK) rearrangements are actionable drivers in non-small cell lung carcinoma (NSCLC), but the biological significance of ALK-immunohistochemistry (IHC) positivity in high-grade pulmonary neuroendocrine carcinoma (NEC) remains unclear. This study evaluated the diagnostic and therapeutic implications of discordant ALK IHC and genomic findings and the role of multimodal molecular testing in resolving them. METHODS: We retrospectively analysed eight South Asian patients (Indian and Nepali) with de novo high-grade pulmonary NEC and diffuse ALK immunoreactivity treated at a tertiary cancer centre in India. Comprehensive molecular profiling using DNA- and RNA-based next-generation sequencing (NGS) and ALK fluorescence in situ hybridisation (where tissue was adequate) was performed. Clinical outcomes and responses to ALK-targeted tyrosine kinase inhibitors (TKIs) were assessed. RESULTS: ALK IHC positivity was observed in 8 of 100 selectively tested cases among 319 high-grade pulmonary NECs diagnosed between 2019 and 2025. The cohort included seven SCLCs (one combined adenocarcinoma-SCLC) and one large-cell neuroendocrine carcinoma (LCNEC). Median age was 51 years; 75% were female and 87.5% never-smokers. Among five comprehensively profiled cases, true ALK rearrangements were confirmed in two (one LCNEC and one SCLC), both detectable only by RNA sequencing. Durable benefit from ALK-TKI therapy was seen only in the molecularly confirmed LCNEC case (>16 months), whereas ALK IHC-positive but NGS-negative cases progressed rapidly. CONCLUSIONS: True ALK rearrangements in high-grade pulmonary NEC are rare but highly actionable. ALK IHC alone is an unreliable predictor of therapeutic benefit. RNA-based sequencing is essential for fusion detection. Comprehensive molecular confirmation, with RNA sequencing as the preferred modality, should precede any initiation of ALK-targeted therapy in high-grade pulmonary NEC.

IMMUNOHISTOCHEMISTRY↗

PubMed2006

Estimating costs of care for patients with newly diagnosed metastatic colorectal cancer.

BACKGROUND: This study examines the resource use patterns and costs of care for patients with incident metastatic colorectal cancer (mCRC) based on analyses of retrospective claims data from selected health plans in the United States. PATIENTS AND METHODS: A case-control analysis was performed using claims from years 1998-2004. Incident mCRC cases were identified based on evidence of a colorectal cancer diagnosis and a metastatic disease diagnosis. Incident mCRC cases could have no other evidence of cancer in the 1-year period before the date of their first mCRC diagnosis. Cases were matched to non-mCRC controls based on age, sex, geographic region, and duration of plan enrollment. Costs were evaluated by phase of disease: diagnosis, treatment, or death phases. Ordinary least squares regressions were performed to evaluate impact of covariates in each phase. RESULTS: Total costs in the follow-up period averaged $97,031 more for mCRC cases than for controls. The main cost drivers for mCRC were hospitalizations ($37,369) and specialist visits ($34,582), which included chemotherapy administration. Approximately 40% of the 672 patients with mCRC who qualified for the phase analysis were identified with a fatal event during follow-up. Monthly costs were similar in the diagnostic phase ($12,205) and death phase ($12,328), but were significantly lower in the treatment phase ($4722). Both mean/median monthly costs increased over time during the study period, regardless of disease phase. CONCLUSION: The economic burden of mCRC is substantial for patients with commercial health plans in the United States, and costs of care have increased substantially in recent years.

Case-Control Studies↗

PubMed2001

Cloning of deleted sequences (CODE): A genomic subtraction method for enriching and cloning deleted sequences.

The deletion of specific genomic sequences is believed to influence the pathogenesis of certain diseases such as cancer. Identification of these sequences could provide novel therapeutic avenues for the treatment of disease. Here, we describe a simple and robust method called cloning of deleted sequences (CODE), which allows the selective cloning of deleted sequences from complex human genomes. Briefly, genomic DNA from two sources (human normal and tumor samples) was digested with restriction enzymes (e.g., BamHI, BglII, and BclI), then ligated to special linkers, and amplified by PCR. Tester (normal) DNA was amplified using a biotinylated primer and dNTPs. Driver (tumor) DNA was amplified using a non-biotinylated primer, but with dUTP instead of d7TP After denaturation and hybridization, all the driver DNA was destroyed with uracil-DNA glycosylase (UDG), and all imperfect hybrids were digested with mung bean nuclease. Sequences deleted from the driver DNA but present in the tester DNA were purified with streptavidin magnetic beads, and the cycle was repeated three more times. This procedure resulted in the rapid isolation and efficient cloning of genomic sequences homozygously deleted from the driver DNA sample, but present in the tester DNA fraction.

Base Sequence↗

PubMed2002

Farm exposures, parental occupation, and risk of Ewing's sarcoma in Australia: a national case-control study.

OBJECTIVE: It has been suggested that parental occupation, particularly farming, increased the risk of Ewing's sarcoma in the offspring. In a national case-control study we examined the relationship between farm and other parental occupational exposures and the risk of cancer in the offspring. METHODS: Cases were 106 persons with confirmed Ewing's sarcoma or peripheral primitive neuroectodermal tumor. Population-based controls (344) were selected randomly via telephone. Information was collected by interview (84% face-to-face). RESULTS: We found an excess of case mothers who worked on farms at conception and/or pregnancy (odds ratio (OR)=2.3. 95% confidence interval (CI) 0.5-12.0) and a slightly smaller excess of farming fathers, more case mothers usually worked as laborers, machine operators, or drivers (OR = 1.8, 95% CI 0.9-3.9). Risk doubled for those whose mothers handled pesticides and insecticides, or fathers who handled solvents and glues, and oils and greases. Further, more cases lived on farms (OR= 1.6, 95% CI 0.9-2.8). In the 0-20 years group, the risk doubled for those who ever lived on a farm (OR = 2.0, 95% CI 1.0-3.9), and more than tripled for those with farming fathers at conception and/or pregnancy (OR = 3.5, 95% CI 1.0-1 1.9). CONCLUSIONS: Our data support the general hypothesis of an association of Ewing's sarcoma family of tumors with farming, particularly at younger ages. who represent the bulk of cases, and are more likely to share etiologic factors.

Adult↗

PubMedDate not supplied

Chronic lymphocytic leukemia: economic burden and quality of life: literature review.

The purpose of this review was answer 2 main questions: what is the impact of chronic lymphocytic leukemia (CLL) on the patient's quality of life and how great is the economic burden of this disease on the health care payers and providers. Patients with CLL typically do not receive any treatment soon after the initial diagnosis. Although there is no known cure for CLL yet, when treated, the patients receive aggressive and expensive therapies (eg, chemotherapy or bone marrow transplantation). A rigorous and systematic literature review was performed of English-language articles published in 1990-2002. It was supplemented with additional articles published before 1990 for completeness and additional references to fill the gaps identified in the published medical literature. The literature on the quality of life (QOL) of CLL patients is very limited. We identified only 8 articles, and none of them analyzed the QOL in untreated CLL patients. Because CLL is a disease affecting adults, especially the elderly, all 8 studies measured the QOL in the adult population. QOL difficulties include fear of death and disability, problems gaining employment or health insurance, and fatigue. No specific leukemia or CLL instruments but general QOL instruments (eg, I-HRQL) were identified and some cancer-specific ones (eg, EORTC QLQ-C30, FACT-G, FACT Anemia, FACT-Fatigue). Interestingly, a FACT-Bone Marrow Transplant instrument exists, although we found no study on CLL that used it. Even the literature on the economic burden of CLL is very limited. We identified 13 studies on the cost of CLL: Most of them were cost-identification or cost-comparison studies, and 5 dealt with the cost-effectiveness of medical interventions to treat CLL. Cost drivers identified for CLL were the chemotherapy costs, intravenous immunoglobulin costs, transplantation costs, and costs associated with the differential staining cytotoxicity assay. We identified very few articles on the QOL of CLL patients and therefore cannot draw strong conclusions about the key QOL predictors. Nevertheless, patients with anemia were found to have a better QOL if they had higher hemoglobin counts and good response to erythropoietin treatment. The articles published seem to demonstrate that the older the age of the patient was, the poorer the QOL. The main cost drivers identified for CLL were related to the treatment chosen (eg, chemotherapy, bone marrow transplantation). There are hints that higher costs often result from the delivery of non-optimal therapy that leads to adverse events, infections, and drug resistance. In summary, the impact of this disease on the health care budget of the different health care providers and payers as well as on the patient's QOL is substantially unknown, calling for appropriate economic and QOL studies.

Adult↗

PubMed2003

[Identification of multidrug resistance related genes in leukemia by suppression subtractive hybridization].

OBJECTIVE: To clone and screen genes related to multidrug resistance (MDR) in leukemia. METHODS: Suppression subtractive hybridization (SSH) was performed to profile differentially expressed genes between a MDR leukemia cell line (K562/DOX, as tester) and its parent cell line (K562, as driver). Reverse Northern dot blot was carried out to further screen the subtracted cDNA library. The overexpressed cDNA fragments in K562/DOX cells were sequenced and compared with known genes in Genbank. RT-PCR and Northern blot were employed to confirm the differential expression of some identified genes. RESULTS: Eleven genes were identified being overexpressed in K562/DOX, including S3 ribosomal protein (S3rp) gene, NADH dehydrogenase subunit 2 (ND2) gene and My023 gene, which have not been reported to be related to MDR in cancer. CONCLUSION: Several genes, which might be involved in MDR were identified, indicating novel mechanisms of MDR in leukemia.

Blotting, Northern↗

PubMed2026

Investigation of Fatty Acid Metabolism-Associated Molecular CPOX and the Underlying Mechanism in Follicular Lymphoma.

Dysregulated lipid metabolism is a key driver of follicular lymphoma (FL). This study aimed to explore the lipid metabolism-related genes (LMRGs) and clarify the underlying roles and mechanisms in FL. Bioinformatics methods, including differential analysis, WGCNA, machine learning, and Mendelian randomization, were utilized to select the LMRGs in FL. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were conducted to investigate the function of the key LMRG. Receiver operator characteristic (ROC) was used to evaluate the diagnostic value of the key gene CPOX. A pan-cancer analysis investigated CPOX's expression level and immune correlations. In vitro experiments using FL cell lines (WSU-FSCCL, DOHH2) validated CPOX expression, and CPOX knockdown in DOHH2 cells was used to assess its impact on viability, migration, invasion, and fatty acid metabolism. CPOX was confirmed to be a risk factor, significantly overexpressed in FL, and exhibited effective diagnostic ability in FL (AUC = 0.731). Functional analysis linked CPOX to mitochondrial function, oxidative phosphorylation, and heme metabolic process. Pan-cancer indicated the dysregulated CPOX across multiple cancers and closely correlation with immune characteristics. Experimentally, CPOX was higher in the more invasive DOHH2 cells; and CPOX knockdown suppressed FL progression and reduced lipid droplet formation, triglyceride, total cholesterol, and free fatty acid levels. In conclusion, this study fills the gap in understanding the significance of lipid metabolism-related molecules in FL, and innovatively proposes that CPOX is a risk factor for FL. Knockdown of CPOX inhibits the FL progression, which is regulated by fatty acid metabolism.

Lymphoma, Follicular↗

PubMed2026

A bivalent molecular glue linking lysine acetyltransferases to oncogene-induced cell death.

Developing cancer therapies that induce specific death of malignant cells is critical for preventing relapse. Highly effective strategies, such as immunotherapy, exemplify this principle. Here, we provide the mechanistic basis for a small-molecule approach that leverages chemically induced proximity (CIP) to kill diffuse large B cell lymphoma, the most common non-Hodgkin lymphoma. We developed lysine acetyltransferase (KAT)-based TCIPs (transcriptional/epigenetic chemical inducers of proximity), or KAT-TCIPs, which redirect p300/CREB-binding protein (CBP) to activate cell-death networks repressed by the oncogenic driver BCL6. Our lead KAT-TCIP reprograms the epigenome to initiate apoptosis. The crystal structure of the chemically induced p300-BCL6 complex reveals how chance protein-protein interactions may be exploited to confer the potency and selectivity of KAT-TCIPs. Thus, oncogenic drivers can be co-opted to activate robust cell death. Consistent with their gain-of-function mechanism, TCIPs recruiting different transcriptional activators-p300, BRD4, or CDK9-produce distinct genomic responses, suggesting specialized therapeutic uses.

Humans↗

PubMed2026

High-fat diet-responsive DNM1 promotes hepatocellular carcinoma progression and predicts poor prognosis in viral-associated patients.

Hepatocellular carcinoma (HCC) arises from diverse etiologies, among which metabolic dysfunction-associated liver disease and chronic viral hepatitis are the two major drivers worldwide. However, the molecular mechanisms linking metabolic stress to HCC progression remain incompletely understood. Dynamin-1 (DNM1), primarily known for its role in vesicular trafficking, has emerged as a potential oncogene, yet its prognostic and functional significance in HCC remains largely unexplored. Here, we investigated the role of DNM1 in high-fat diet (HFD)-associated hepatocarcinogenesis. Transcriptomic profiling was conducted to identify differentially expressed genes between normal and high-fat diet murine models, with human orthologs mapped. Clinical relevance was validated using The Cancer Genome Atlas (TCGA-LIHC) dataset. Survival analysis, GSEA (Gene Set Enrichment Analysis), and subgroup stratifications based on viral hepatitis status were performed. In vitro, loss-of-function assays (shRNA knockdown) were executed in HepG2 and SK-Hep1 cell lines to assess cell viability and migration. DNM1 was significantly upregulated in high-fat diet models. In the TCGA-LIHC cohort, high DNM1 expression was an independent risk factor for poor overall survival (HR=1.44, P=0.039) and correlated with advanced tumor stages (Stage III+IV, P=0.010). In vitro knockdown of DNM1 profoundly impaired cell proliferation and migration in HCC cell lines. Strikingly, DNM1 expression was further elevated in patients with concurrent viral hepatitis (P=0.009). GSEA revealed that high DNM1 expression was positively associated with viral infection pathways and negatively correlated with critical immune responses, including interferon-alpha/gamma responses and host immune cytolysis. Survival analysis stratified by four subgroups demonstrated that patients with both viral infection and high DNM1 expression exhibited the worst prognosis (Overall Log-rank P < 0.001). Our findings identify DNM1 as a high-fat diet-responsive regulator that links metabolic stress to hepatocellular carcinoma progression. Elevated DNM1 expression promotes malignant phenotypes in HCC and identifies a subgroup of viral-associated patients with particularly poor prognosis, highlighting DNM1 as a potential prognostic biomarker and therapeutic target.

Hepatocellular carcinoma (HCC)↗

PubMed2005

Cell-nonautonomous induction of ovarian and uterine serous cystadenomas in mice lacking a functional Brca1 in ovarian granulosa cells.

Women with germline mutations in BRCA1 have a 40% risk of developing ovarian cancer by age 70 and are also predisposed to cancers of the fallopian tubes. Given that ovulatory activity is a strong risk factor for sporadic ovarian cancer, we hypothesized that reduced BRCA1 expression might predispose to gynecological cancers indirectly, by influencing ovarian granulosa cells. These cells secrete sex steroids that control the ovulatory cycle and influence the growth of ovarian epithelial tumors. Granulosa cells also secrete mullerian inhibiting substance (MIS), a hormone that inhibits both the formation of female reproductive organs in male embryos and the proliferation of ovarian epithelial tumor cells. We tested this hypothesis by using the Cre-lox system to inactivate the Brca1 gene in mouse ovarian granulosa cells. A truncated form of the Fsh receptor promoter served as the Cre driver. Here, we show that indeed, inactivation of the Brca1 gene in granulosa cells led to the development of cystic tumors in the ovaries and uterine horns. These tumors carried normal Brca1 alleles, supporting the view that Brca1 may influence tumor development indirectly, possibly through an effector secreted by granulosa cells.

Animals↗

PubMed2004

Candidate tumor-suppressor genes on chromosome arm 8p in early-onset and high-grade breast cancers.

Loss of genetic material from chromosome arm 8p occurs commonly in breast carcinomas, suggesting that this region is the site of one or more tumor-suppressor genes (TSGs). Comparative genomic hybridization analysis showed that 8p loss is more common in breast cancers from pre-menopausal compared with post-menopausal patients, as well as in high-grade breast cancers, regardless of the menopausal status. Subsequent high-resolution gene expression profiling of genes mapped to chromosome arm 8p, on an extended cohort of clinical tumor samples, indicated a similar dichotomy of breast cancer clinicopathologic types. Some of these genes showed differential downregulation in early-onset and later-onset, high-grade cancers compared with lower-grade, later-onset cancers. Three such genes were analysed further by in situ technologies, performed on tissue microarrays representing breast tumor and normal tissue samples. PCM1, which encodes a centrosomal protein, and DUSP4/MKP-2, which encodes a MAP kinase phosphatase, both showed frequent gene and protein loss in carcinomas. In contrast, there was an excess of cases showing loss of expression in the absence of reduced gene copy number of SFRP1, which encodes a dominant-negative receptor for Wnt-family ligands. These candidate TSGs may constitute some of the molecular drivers of chromosome arm 8p loss in breast carcinogenesis.

Breast Neoplasms↗

PubMed2001

Cell cycle arrest mediated by a pyridopyrimidine is not abrogated by over-expression of Bcl-2 and cyclin D1.

Inhibition of cyclin dependent kinases (Cdks) is of pivotal importance in tumor cell biology as these kinases are the drivers of cell proliferation. This inhibition can be achieved either by naturally occurring biological proteins or by small molecule compounds. They cause cell cycle arrest and/or apoptosis depending upon the specificity and efficacy of the inhibitor in question. We have reported earlier that specific pyridopyrimidines (novel Cdk inhibitors) cause cell cycle arrest in mink lung epithelial cells and the arrest is abrogated by over-expression of Cdk4. In contrast, we show here that one of these inhibitors effectively maintains cell cycle arrest in a leukemic or a breast cancer cell line even after the respective cells over-express an oncogene, either Bcl-2 or cyclin D1. However, in the leukemic cells, Bcl-2 over-expression suppresses apoptosis induced by the pyridopyrimidine. Thus, novel Cdk inhibitors can prove to be useful chemical genetics tools for understanding the underlying mechanisms of growth arrest and/or apoptosis in normal versus tumor cells. This could also lead to the development of improved inhibitors of cell proliferation.

Apoptosis↗