Biomedical subjects

B L Weber

Publications and source records attributed to B L Weber.

At least 37 records · Page 2Linked to original sources

PubMed2001

Breast cancer genetics: what we know and what we need.

Breast cancer results from genetic and environmental factors leading to the accumulation of mutations in essential genes. Genetic predisposition may have a strong, almost singular effect, as with BRCA1 and BRCA2, or may represent the cumulative effects of multiple low-penetrance susceptibility alleles. Here we review high- and low-penetrance breast-cancer-susceptibility alleles and discuss ongoing efforts to identify additional susceptibility genes. Ultimately these discoveries will lead to individualized breast cancer risk assessment and a reduction in breast cancer incidence.

BRCA2 Protein↗

PubMed2001

"Other" breast cancer susceptibility genes: searching for more holy grail.

While germline mutations in BRCA1 and BRCA2 account for most, if not all families with autosomal dominant transmission of susceptibility to both breast and ovarian cancer, it has become clear that together these genes only account for a small proportion of hereditary site-specific breast cancer susceptibility. However, difficulties due to genetic heterogeneity, reduced penetrance and perhaps gene mutation frequency complicate ongoing efforts to identify additional susceptibility genes. Therefore, multiple approaches are being used to identify additional high and low penetrance genes. Families with three or more breast cancer cases are being used in traditional linkage studies, which are expected to yield only moderate or high penetrance susceptibility genes. Breast cancer case-control studies are being used to look for genetic variants or polymorphisms that confer an increased risk of breast cancer in a wide variety of cellular pathways, ranging from the detoxification of environmental carcinogens to steroid hormone metabolism, DNA damage repair and immune surveillance, an approach useful primarily to identify low penetrance susceptibililty genes. However, neither approach has yielded convincing results to date. A third approach, using BRCA1 and BRCA2 mutation carriers to identify genes that are associated with modification of breast cancer risk has met with some limited success, perhaps because effects on breast cancer risk in BRCA1 and BRCA2 mutation carriers are more readily detected in smaller studies, given the much higher number of events in these cohorts at very high risk of breast cancer. Clearly, hereditary breast cancer susceptibility is a complex phenomenon, in which multiple genes may play a role. It will be necessary to use all of these approaches, as well as more comprehensive genomic studies, to identify additional breast cancer-related genes.

BRCA2 Protein↗

PubMed2001

Recent advances in breast cancer biology.

Within the past year, the draft sequence of the human genome was completed and made available to researchers worldwide. Recent advances in technology along with the vast amount of sequence data on the human genome now provide a previously unimagined means of defining the genetic architecture of cancer cells. Implicit in this approach is the ability to describe the evolution of that architecture as normal breast cells progress toward the malignant phenotype. Ongoing experiments involving the simultaneous analysis of the entire genome in a high-throughput manner are expected to reveal those genes and regulatory mechanisms that are critical at each step of progression toward malignancy, including (1) providing a growth advantage over normal cells, (2) maintaining the malignant state, (3) modulating response to therapy, and (4) developing metastatic potential. Once these data are available, the ability to design preventive, diagnostic, prognostic, and therapeutic tools directed at those targets will be within reach.

Antineoplastic Agents↗

PubMed2000

BRCA1 physically and functionally interacts with ATF1.

BRCA1, a breast and ovarian cancer susceptibility gene, encodes a 220-kDa protein whose precise biochemical function remains unclear. BRCA1 contains an N-terminal RING finger that mediates protein-protein interaction. The C-terminal domain of BRCA1 (BRCT) can activate transcription and interacts with RNA polymerase holoenzyme. Using the yeast two-hybrid system, we identified an interaction between the BRCA1 RING finger and ATF1, a member of the cAMP response element-binding protein/activating transcription factor (CREB/ATF) family. We demonstrate that BRCA1 and ATF1 can physically associate in vitro, in yeast, and in human cells. BRCA1 stimulated transcription from a cAMP response element reporter gene in transient transfections. BRCA1 also stimulated transcription from a natural promoter, that of tumor necrosis factor-alpha, in a manner dependent on the integrity of the cAMP response element. These results implicate BRCA1 in transcriptional activation of ATF1 target genes, some of which are involved in the transcriptional response to DNA damage.

Activating Transcription Factor 1↗

PubMed2000

Effect of radiotherapy after breast-conserving treatment in women with breast cancer and germline BRCA1/2 mutations.

PURPOSE: Recent laboratory data suggest a role for BRCA1/2 in the cellular response to DNA damage. There is a paucity of clinical data, however, examining the effect of radiotherapy (RT), which causes double-strand breaks, on breast tissue from BRCA1/2 mutation carriers. Thus the goals of this study were to compare rates of radiation-associated complications, in-breast tumor recurrence, and distant relapse in women with BRCA1/2 mutations treated with breast-conserving therapy (BCT) using RT with rates observed in sporadic disease. PATIENTS AND METHODS: Seventy-one women with a BRCA1/2 mutation and stage I or II breast cancer treated with BCT were matched 1:3 with 213 women with sporadic breast cancer. Conditional logistic regression models were used to compare matched cohorts for rates of complications and recurrence. RESULTS: Tumors from women in the genetic cohort were associated with high histologic (P =.0004) and nuclear (P =.009) grade and negative estrogen (P=.0001) and progesterone (P=.002) receptors compared with tumors from the sporadic cohort. Using Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer toxicity scoring, there were no significant differences in acute or chronic morbidity in skin, subcutaneous tissue, lung, or bone. The 5-year actuarial overall survival, relapse-free survival, and rates of tumor control in the treated breast for the patients in the genetic cohort were 86%, 78%, and 98%, respectively, compared with 91%, 80%, and 96%, respectively, for the sporadic cohort (P = not significant). CONCLUSION: There was no evidence of increased radiation sensitivity or sequelae in breast tissue heterozygous for a BRCA1/2 germline mutation compared with controls, and rates of tumor control in the breast and survival were comparable between BRCA1/2 carriers and controls at 5 years. Although additional follow-up is needed, these data may help in discussing treatment options in the management of early-stage hereditary breast cancer and should provide reassurance regarding the safety of administering RT to carriers of a germline BRCA1/2 mutation.

Adult↗

PubMed2000

Screening for genomic rearrangements in families with breast and ovarian cancer identifies BRCA1 mutations previously missed by conformation-sensitive gel electrophoresis or sequencing.

The frequency of genomic rearrangements in BRCA1 was assessed in 42 American families with breast and ovarian cancer who were seeking genetic testing and who were subsequently found to be negative for BRCA1 and BRCA2 coding-region mutations. An affected individual from each family was tested by PCR for the exon 13 duplication (Puget et al. 1999a) and by Southern blot analysis for novel genomic rearrangements. The exon 13 duplication was detected in one family, and four families had other genomic rearrangements. A total of 5 (11. 9%) of the 42 families with breast/ovarian cancer who did not have BRCA1 and BRCA2 coding-region mutations had mutations in BRCA1 that were missed by conformation-sensitive gel electrophoresis or sequencing. Four of five families with BRCA1 genomic rearrangements included at least one individual with both breast and ovarian cancer; therefore, 4 (30.8%) of 13 families with a case of multiple primary breast and ovarian cancer had a genomic rearrangement in BRCA1. Families with genomic rearrangements had prior probabilities of having a BRCA1 mutation, ranging from 33% to 97% (mean 70%) (Couch et al. 1997). In contrast, in families without rearrangements, prior probabilities of having a BRCA1 mutation ranged from 7% to 92% (mean 37%). Thus, the prior probability of detecting a BRCA1 mutation may be a useful predictor when considering the use of Southern blot analysis for families with breast/ovarian cancer who do not have detectable coding-region mutations.

BRCA2 Protein↗

PubMed2000

Genetic and hormonal risk factors in breast cancer.

Breast cancer poses a serious public health problem, and it is hoped that identification of genetic and environmental factors that contribute to the development of breast cancer will enhance prevention efforts. Two breast cancer susceptibility genes (BRCA1 and BRCA2) have been identified, and germline mutations in these genes are thought to account for between 5% and 10% of all breast cancer cases. Current findings suggest that mutations in other highly penetrant genes may play an important role in breast cancer susceptibility, and studies aimed at the isolation of these genes are under way. In addition, common variants in a number of gene classes are thought to act as low-penetrance susceptibility alleles, and efforts to identify and characterize these variants are under way. This review discusses the genetic components of susceptibility to breast cancer from the standpoint of both human genetics and rat models.

Alcohol Drinking↗

PubMed2000

An Alu-mediated 7.1 kb deletion of BRCA1 exons 8 and 9 in breast and ovarian cancer families that results in alternative splicing of exon 10.

Constitutive large deletions and duplications of BRCA1 resulting from Alu-mediated recombination account for a significant proportion of disease-causing mutations in breast and/or ovarian cancer families. Using Southern blot analysis and a protein truncation test (PTT), we have identified a 7.1 kb germline deletion in two families with breast and ovarian cancer. This deletion, which includes exons 8 and 9 and leads to a frameshift at the mRNA level, appears to result from homologous recombination between closely related Alu repeats, one in intron 7 and one in intron 9. In addition to the transcript without exons 8 and 9, analysis of RNA by protein truncation test from individuals with the deletion also identified the presence of alternative splicing of exon 10 from the mutant allele, which results in a transcript that lacks exons 8, 9, and 10. Of interest is that the two American families who carry this deletion are of northern European ancestry and share a common haplotype, suggesting that this deletion may represent a founder mutation. Genes Chromosomes Cancer 28:300-307, 2000.

Adult↗

PubMed2000

Kinetics of BRCA1 regulation in response to UVC radiation.

To investigate changes in BRCA1 following DNA damage, we exposed MCF-7 cells to increasing doses of ultraviolet C. We observed an increase in BRCA1 protein levels above 78 J/m2. This increase was observed as early as 5 min after irradiation. BRCA1 levels were then observed to decrease after 2 h, consistent with the previously published data. By pretreating with cycloheximide prior to irradiation, we observed a decrease in the protein half-life, from 3.5 h to 53 min, suggesting that a decrease in protein half-life may cause the lower levels of BRCA1 after irradiation. We also observed an increase in BRCA1 mRNA within 15 min of irradiation, followed by a decrease after 4 h. These data suggest that newly translated protein may contribute to increases in BRCA1 protein levels. The very rapid changes in BRCA1 support its role as a sensor of DNA damage, as opposed to being a repair gene.

BRCA1 Protein↗

PubMed2000

Low penetrance genes associated with increased risk for breast cancer.

Much effort in recent years has been focused on understanding the factors that contribute to breast cancer risk. Two major susceptibility alleles, BRCA1 and BRCA2, have been identified, and the prevalence and penetrance of mutations in these genes have been studied extensively. However, this work highlights the fact that only a small proportion of breast cancer is due to mutations in the genes. Evidence for additional high penetrance genes exists, but it is becoming clear that an understanding of multiple lower penetrance alleles will be necessary to fully define breast cancer risk. Work in this area has focused on the analysis of polymorphisms of potential functional significance in several classes of genes, including those involved in carcinogen metabolism, oestrogen metabolite biosynthesis, steroid hormone receptor activation and DNA damage response. These studies are reviewed and a strategy to use modification of breast cancer penetrance in families with known mutations in BRCA1 as a means of identifying additional low penetrance, or modifier, genes is discussed.

Arylamine N-Acetyltransferase↗

PubMed2000

NFBD1/KIAA0170 is a novel nuclear transcriptional transactivator with BRCT domain.

The BRCT (BRCA1 C-terminus) superfamily includes a large number of nuclear proteins closely involved in DNA repair, recombination, and cell-cycle control. The human cDNA clone NFBD1 (previously designated KIAA0170) encodes a novel protein (2089 amino acids in length; calculated molecular mass 226,440 D) with possible BRCT domains at its carboxy terminus (amino acid residues 1894-2089). This gene product has been described as one of the BRCT superfamily proteins. However, its biological significance has been unclarified. Expression of green fluorescent protein (GFP)-tagged full-length NFBD1 or a series of deletion mutants indicated that NFBD1 was localized to the nucleus in various mammalian cells, and a 197-amino acid segment near the amino terminus (amino acid residues 142-338) contained a nuclear targeting signal. In vitro DNA-binding experiments showed that the highly basic region of NFBD1 (amino acid residues 1841-1893) possessed DNA-binding activity. The region encoding amino acids 508-995 of NFBD1 fused inframe with GAL4 DNA-binding domain activated transcription in both yeast and mammalian cells, while the possible BRCT domains of NFBD1 failed to induce transcription in mammalian cells. Overexpression of antisense NFBD1 RNA in a p53-deficient human osteogenic sarcoma cell line (SAOS-2) resulted in remarkable suppression of SAOS-2 colony formation. These results suggest that NFBD1 is a nuclear transcriptional transactivator with possible BRCT domains and may contribute to cell growth control.

Adaptor Proteins, Signal Transducing↗

PubMed2000

Recent advances in breast cancer biology.

Approximately 1 in 10 US women will be diagnosed with breast cancer in her lifetime. With such a high incidence, breast cancer is a serious health concern for all American women. Within the past year, clues about the function of genes associated with breast cancer have been garnered, and novel genes that may contribute to breast tumorigenesis have been discovered. In addition, unique animal models and improvements in gene expression profiling technology have given researchers new tools to address previously unanswerable questions about this disease.

Animals↗

PubMed2000

Anticipated versus actual emotional reactions to disclosure of results of genetic tests for cancer susceptibility: findings from p53 and BRCA1 testing programs.

PURPOSE: We examined the ability of individuals undergoing genetic testing for cancer susceptibility in two structured research protocols to accurately anticipate emotional reactions to disclosure of their test result. We explored whether accuracy of emotional anticipation was associated with postdisclosure psychologic adjustment. METHODS: Data from 65 individuals were analyzed; 24 members of Li-Fraumeni cancer syndrome families were tested for p53 mutations (all 24 were unaffected), and 41 subjects with hereditary breast-ovarian cancer susceptibility were tested for BRCA1 mutations (34 were unaffected and seven were affected). Subjects were from families in which a germline mutation had been previously identified. At the pretest session, subjects rated the extent to which they anticipated feeling each of six emotional states (relief, happiness, sadness, guilt, anger, and worry) after disclosure that they did or did not carry the familial mutation. After receiving their test result, they rated their feelings on the same scale of emotions for the appropriate condition. Extent of accuracy and association with psychologic distress at 6 months, as assessed with standardized measures, were evaluated. RESULTS: Overall, mean levels of emotional reactions after receiving test results were not different from those anticipated before result disclosure. However, affected BRCA1 carriers experienced higher levels of anger and worry than they had anticipated. Underestimation of subsequent distress emotions related to test result was associated with a significant increase in general psychologic distress at 6 months. CONCLUSION: Unaffected individuals in cancer-predisposition testing programs are generally accurate in anticipating emotional reactions to test results. However, cancer patients may underestimate their distress after disclosure of positive results and could benefit from intervention strategies.

Adult↗

PubMed2000

Prophylactic surgery in women with a hereditary predisposition to breast and ovarian cancer.

PURPOSE: To review the published literature on the efficacy and adverse effects of prophylactic mastectomy (PM) and prophylactic oophorectomy (PO) in women with a hereditary predisposition to breast and ovarian cancer and to provide management recommendations for these women. METHODS: Using the terms "prophylactic," "preventive," "bilateral," "mastectomy," "oophorectomy," and "ovariectomy," a MEDLINE search of the English-language literature for articles related to PM and PO was performed. The bibliographies of these articles were reviewed to identify additional relevant references. RESULTS: There have been no prospective trials of PM or PO for the reduction of breast cancer or ovarian cancer incidence or mortality. Most of the available retrospective studies are composed of women who had surgery for a variety of indications and in whom genetic risk was not well characterized. However, some reports in women at increased risk of breast or ovarian cancer have shown that PM and PO can reduce cancer incidence. CONCLUSION: Interest in and use of PM and PO are high among physicians and high-risk women. PM and PO seem to be associated with considerable reduction in the risk of breast and ovarian cancer, albeit incomplete. The surgical morbidity of PM and PO is low, but the complications of premature menopause may be significant, and few studies address quality-of-life issues in women who have opted for PM and PO. Management recommendations for high-risk individuals are presented on the basis of the available evidence.

Breast Neoplasms↗

PubMed2000

Distress and psychiatric morbidity among women from high-risk breast and ovarian cancer families.

This study assessed psychological distress and psychiatric disorder in high-risk women enrolled in a hereditary breast and ovarian cancer registry, and it evaluated the concordance between self-report data and interview-based psychiatric diagnosis. A sample of 464 women completed the Hopkins Symptom Checklist-25 and were interviewed using modules of the Structured Clinical Interview for DSM-IV. Level of psychological distress and the prevalence of psychiatric disorder were low and in the range that would be expected for a sample of community-residing women. Screening proved inefficient: Less than 10% of distressed women met criteria for a clinical disorder. High-risk women seeking genetic testing in research settings may not require extensive psychological screening and diagnostic assessment. Caution is expressed about possible self-selection biases in women enrolled in hereditary cancer registries.

Adult↗

PubMed2000

BRCA1 and BRCA2 mutations in breast cancer families with multiple primary cancers.

Ninety-eight women ascertained from high-risk breast/ovarian cancer clinics with breast cancer reporting at least one other primary cancer in themselves or in a relative with breast cancer were compared with 99 women with breast cancer who reported a family history of breast cancer only. All DNA was screened for coding region mutations in BRCA1 and BRCA2 using heteroduplex analysis, followed by direct sequencing. Our data indicate that 42.9% of families reporting breast and any second nonbreast type of primary cancer in the same individual had a BRCA1 or BRCA2 mutation, as compared with the 12.1% of families reporting breast cancer only (P < 0.001). Among the 66 women reporting breast cancer and a nonovarian second primary cancer, 15 (22.7%) had mutations in BRCA1 or BRCA2 (P = 0.04). Among the 32 families where ovarian cancer was the second primary cancer, 27 (84.4%) had a mutation in BRCA1 or BRCA2 (P < 0.001). BRCA1 and BRCA2 mutations were twice as common in the presence of a reported second nonovarian cancer. These data suggest that the presence of multiple primary cancer of any kind may predict for an increased likelihood of finding a BRCA1 or BRCA2 mutation and supports previous studies suggesting that BRCA1 and BRCA2 mutations may be associated with an increased susceptibility to cancers other than breast and ovarian cancer.

BRCA2 Protein↗

PubMed1999

The Brn-3b POU family transcription factor represses expression of the BRCA-1 anti-oncogene in breast cancer cells.

The BRCA-1 tumour supressor gene was identified on the basis of mutations which occur in familial breast cancer indicating that its inactivation can cause this disease. Although BRCA-1 does not appear to be mutated in sporadic breast cancer, its expression has been shown to be reduced in tumour material from such cases. We show here that mammary tumours which have reduced levels of BRCA-1 expression show enhanced expression of the Brn-3b POU family transcription factor at both the mRNA and protein levels. This elevated expression of Brn-3b is not found in normal mammary cells, benign tumours or in malignant tumour samples which do not exhibit reduced levels of BRCA-1. In contrast, no correlation was noted between BRCA-1 and expression of the related factor Brn-3a. Moreover, Brn-3b but not Brn-3a can strongly repress the BRCA-1 promoter approximately 20-fold in mammary tumour cells. To our knowledge, this is the first report of a transcription factor which regulates BRCA-1 expression. Thus, Brn-3b may play an important role in regulating expression of BRCA-1 in mammary tumours with enhanced expression of Brn-3b resulting in reduced BRCA-1 expression and thereby being potentially important in tumour development.

Base Sequence↗

PubMed1999

BRCA1 signals ARF-dependent stabilization and coactivation of p53.

The hereditary breast and ovarian tumor suppressor BRCA1 can activate p53-dependent gene expression. We show here that BRCA1 increases p53 protein levels through a post-transcriptional mechanism. BRCA1-stabilized p53 has increased sequence-specific DNA-binding and transcriptional activity. BRCA1 does not stabilize p53 in p14ARF-deficient cells. A deletion mutant of BRCA1 which inhibits p53-dependent transcription confers resistance to topoisomerase II-targeted chemotherapy. Our results suggest that BRCA1 may trigger the p53 pathway through two potentially separate mechanisms: accumulation of p53 through a direct or indirect induction of p14ARF as well as direct transcriptional coactivation of p53. BRCA1 may also enhance chemosensitivity and repair of DNA damage through binding to and coactivation of p53.

ADP-Ribosylation Factors↗