38 results on '"Silver DP"'
Search Results
2. Chek2 DNA damage response pathway and inherited breast cancer risk.
- Author
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Tung N and Silver DP
- Published
- 2011
3. Synthetic lethality--a new direction in cancer-drug development.
- Author
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Iglehart JD and Silver DP
- Published
- 2009
- Full Text
- View/download PDF
4. PARP Inhibitors for the Treatment of BRCA1/2-Mutated Metastatic Breast Cancer: A Systematic Review and Meta-analysis.
- Author
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Kunwor R, Silver DP, and Abu-Khalaf M
- Subjects
- Female, Humans, BRCA1 Protein genetics, Temozolomide therapeutic use, BRCA2 Protein metabolism, Breast Neoplasms drug therapy, Breast Neoplasms genetics, Poly(ADP-ribose) Polymerase Inhibitors therapeutic use
- Abstract
Background: The PARP inhibitors (PARPis) olaparib and talazoparib are currently approved for the treatment of deleterious germline BRCA1/2-mutated (gBRCA+) metastatic breast cancer (MBC). These approvals were based on improvements in progression-free survival (PFS) observed in two randomized controlled trials (RCTs). Other PARPis, such as veliparib and niraparib, have also been studied. We conducted this meta-analysis of RCTs to assess the PFS and overall survival (OS) benefits of PARPis in gBRCA + MBC., Methods: We performed a systematic search for RCTs using the Cochrane Library, PubMed, Embase, and Web of Science databases up to March 2021. Only phase II and III RCTs evaluating PFS and OS for PARPis alone or in combination with chemotherapy (CT) and comparing the findings with standard CT were included in this meta-analysis. Pooled analysis of the hazard ratio (HR) was performed with RevMan v5.4 using a random effects method., Results: Five RCTs with a total of 1563 BRCA-mutated MBC patients were included in this meta-analysis. Temozolomide was used in the treatment arm in the BROCADE trial. Since temozolomide has limited effects on breast cancer, this arm was excluded from our meta-analysis. A statistically significant increase in PFS was observed in the PARPi group compared to the standard CT group (HR, 0.64; 95% CI, 0.56-0.74; P < 0.00001). However, the differences in OS did not reach statistical significance (HR, 0.89; 95% CI, 0.77-1.02; P = 0.09). Moreover, differences were not observed in the adverse event profile between the two groups (odds ratio, 1.18; 95% CI, 0.84-1.64; P = 0.33)., Conclusion: The results of our meta-analysis confirm the previously reported PFS benefit of PARPis over standard CT. PARPis lead to superior PFS in gBRCA + MBC when used alone or in combination with standard CT. The OS benefit is similar between PARPis and standard CT. Ongoing trials are evaluating the benefits of PARPis in early stage gBRCA + BC.
- Published
- 2023
- Full Text
- View/download PDF
5. Genomic Aberrations in Circulating Tumor DNAs from Palbociclib-Treated Metastatic Breast Cancer Patients Reveal a Novel Resistance Mechanism.
- Author
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Abu-Khalaf M, Wang C, Zhang Z, Luo R, Chong W, Silver DP, Fellin F, Jaslow R, Lopez A, Cescon T, Jiang W, Myers R, Wei Q, Li B, Cristofanilli M, and Yang H
- Abstract
Previously undescribed molecular mechanisms of resistance will emerge with the increased use of cyclin-dependent kinase 4/6 inhibitors in clinical settings. To identify genomic aberrations in circulating tumor DNA associated with treatment resistance in palbociclib-treated metastatic breast cancer (MBC) patients, we collected 35 pre- and post-treatment blood samples from 16 patients with estrogen receptor-positive (ER
+ ) MBC, including 9 with inflammatory breast cancer (IBC). Circulating cell-free DNAs (cfDNAs) were isolated for sequencing using a targeted panel of 91 genes. Our data showed that FBXW7 and CDK6 were more frequently altered in IBC than in non-IBC, whereas conversely, PIK3CA was more frequently altered in non-IBC than in IBC. The cfDNA samples collected at follow-up harbored more mutations than baseline samples. By analyzing paired samples, we observed a higher percentage of patients with mutations in RB1 , CCNE1 , FBXW7 , EZH2 , and ARID1A , but a lower proportion of patients with mutated TSC2 at the post-treatment stage when they developed progression. Moreover, acquisition of CCNE1 mutations or loss of TSC2 mutations after treatment initiation conferred an unfavorable prognosis. These data provide insights into the relevance of novel genomic alterations in cfDNA to palbociclib resistance in MBC patients. Future large-scale prospective studies are warranted to confirm our findings.- Published
- 2022
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6. Duodenal and Biliary Obstruction due to Extrinsic CompressionDuodenal and Biliary Obstruction due to Extrinsic Compression by Recurrent Lobular Breast Carcinoma: A Case Report.
- Author
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Bashir Hamidu R, Asif B, Lavu H, Kowalski T, and Silver DP
- Abstract
Metastases to the gastrointestinal tract (GIT) from breast carcinoma are rare, detected in approximately <5% of all breast cancer patients. Invasive lobular carcinoma (ILC) is the most common histological type of breast cancer to metastasize to the GIT. We report a case of abdominal recurrence of ILC of the breast causing intra-abdominal contracture leading to extrinsic compression of the duodenum and periampullary biliary tree. Four years after the patient's diagnosis of a left breast pT1c, pN2, cM0 invasive lobular breast cancer, she presented with liver function tests consistent with biliary obstruction, and there was concern for a periampullary malignancy. Definitive diagnosis was achieved at laparotomy. This case demonstrates the importance of considering metastatic breast cancer as a potential cause of GI symptoms and radiological abnormalities affecting any part of the GIT of women with a previous history of lobular breast cancer. This case also highlights the effectiveness of chemotherapy in improving the survival and quality of life of these patients. Early recognition of this scenario enables prompt initiation of systemic therapy and avoids unnecessary surgical treatment. Despite the rarity, such patients will be encountered in clinical practice given the high prevalence of breast cancer. Moreover, the fact that the presenting symptoms of GI metastasis from breast cancer are usually not specific to the origin and mimic a primary intestinal disorder, health-care professionals beyond oncologists, especially gastroenterologists and primary care physicians, should be aware of this entity., Competing Interests: The authors have no conflicts of interest to declare., (Copyright © 2021 by S. Karger AG, Basel.)
- Published
- 2021
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7. Whole-exome sequencing identifies somatic mutations and intratumor heterogeneity in inflammatory breast cancer.
- Author
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Luo R, Chong W, Wei Q, Zhang Z, Wang C, Ye Z, Abu-Khalaf MM, Silver DP, Stapp RT, Jiang W, Myers RE, Li B, Cristofanilli M, and Yang H
- Abstract
Inflammatory breast cancer (IBC) is the most aggressive form of breast cancer. Although it is a rare subtype, IBC is responsible for roughly 10% of breast cancer deaths. In order to obtain a better understanding of the genomic landscape and intratumor heterogeneity (ITH) in IBC, we conducted whole-exome sequencing of 16 tissue samples (12 tumor and four normal samples) from six hormone-receptor-positive IBC patients, analyzed somatic mutations and copy number aberrations, and inferred subclonal structures to demonstrate ITH. Our results showed that KMT2C was the most frequently mutated gene (42%, 5/12 samples), followed by HECTD1, LAMA3, FLG2, UGT2B4, STK33, BRCA2, ACP4, PIK3CA, and DNAH8 (all nine genes tied at 33% frequency, 4/12 samples). Our data indicated that PTEN and FBXW7 mutations may be considered driver gene mutations for IBC. We identified various subclonal structures and different levels of ITH between IBC patients, and mutations in the genes EIF4G3, IL12RB2, and PDE4B may potentially generate ITH in IBC.
- Published
- 2021
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8. Neuroendocrine Tumors Are Enriched in Cowden Syndrome.
- Author
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Greidinger A, Miller-Samuel S, Giri VN, Woo MS, Akumalla S, Zeigler-Johnson C, Keith SW, and Silver DP
- Abstract
Competing Interests: The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/po/author-center. Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open Payments). Veda N. GiriStock and Other Ownership Interests: Novopyxis (I)Michele Sue-Ann WooEmployment: Foundation Medicine, Daiichi Sankyo Patents, Royalties, Other Intellectual Property: Royalty distributions for licensing the TRPA1 mouse model through Harvard University and Howard Hughes Medical Institute (I) Travel, Accommodations, Expenses: Foundation Medicine, Daiichi SankyoSaranya AkumallaEmployment: Foundation MedicineDaniel P. SilverStock and Other Ownership Interests: Merrimack Honoraria: Immunomedics Consulting or Advisory Role: Immunomedics Patents, Royalties, Other Intellectual Property: Royalties from intellectual property licensed to Myriad for HRD assay Travel, Accommodations, Expenses: Immunomedics No other potential conflicts of interest were reported.
- Published
- 2020
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9. Association of Tumor-Infiltrating Lymphocytes with Homologous Recombination Deficiency and BRCA1/2 Status in Patients with Early Triple-Negative Breast Cancer: A Pooled Analysis.
- Author
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Telli ML, Chu C, Badve SS, Vinayak S, Silver DP, Isakoff SJ, Kaklamani V, Gradishar W, Stearns V, Connolly RM, Ford JM, Gruber JJ, Adams S, Garber J, Tung N, Neff C, Bernhisel R, Timms KM, and Richardson AL
- Subjects
- Adult, Aged, Clinical Trials, Phase II as Topic, Female, Follow-Up Studies, Humans, Meta-Analysis as Topic, Middle Aged, Multicenter Studies as Topic, Prognosis, Prospective Studies, Survival Rate, Triple Negative Breast Neoplasms genetics, Triple Negative Breast Neoplasms immunology, Triple Negative Breast Neoplasms surgery, Young Adult, BRCA1 Protein genetics, BRCA2 Protein genetics, Biomarkers, Tumor genetics, Homologous Recombination, Lymphocytes, Tumor-Infiltrating immunology, Mutation, Triple Negative Breast Neoplasms pathology
- Abstract
Purpose: Patients with triple-negative breast cancer (TNBC) with homologous recombination deficient tumors achieve significantly higher pathologic complete response (pCR) rates when treated with neoadjuvant platinum-based therapy. Tumor-infiltrating lymphocytes (TIL) are prognostic and predictive of chemotherapy benefit in early stage TNBC. The relationship between TILs, BRCA1/2 mutation status, and homologous recombination deficiency (HRD) status in TNBC remains unclear., Experimental Design: We performed a pooled analysis of five phase II studies that included patients with TNBC treated with neoadjuvant platinum-based chemotherapy to evaluate the association of TILs with HRD status (Myriad Genetics) and tumor BRCA1/2 mutation status. Furthermore, the relationship between pathologic response assessed using the residual cancer burden (RCB) index and HRD status with adjustment for TILs was evaluated., Results: Among 161 patients, stromal TIL (sTIL) density was not significantly associated with HRD status ( P = 0.107) or tumor BRCA1/2 mutation status ( P = 0.391). In multivariate analyses, sTIL density [OR, 1.23; 95% confidence interval (CI), 0.94-1.61; P = 0.139] was not associated with pCR, but was associated with RCB 0/I status (OR 1.62; 95% CI, 1.20-2.28; P = 0.001). HRD was significantly associated with both pCR (OR 12.09; 95% CI, 4.11-44.29; P = 7.82 × 10
-7 ) and RCB 0/I (OR 10.22; 95% CI, 4.11-28.75; P = 1.09 × 10-7 ) in these models., Conclusions: In patients with TNBC treated with neoadjuvant platinum-based therapy, TIL density was not significantly associated with either tumor BRCA1/2 mutation status or HRD status. In this pooled analysis, HRD and sTIL density were independently associated with treatment response, with HRD status being the strongest predictor., (©2019 American Association for Cancer Research.)- Published
- 2020
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10. Prognostic value of HER2 status on circulating tumor cells in advanced-stage breast cancer patients with HER2-negative tumors.
- Author
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Wang C, Mu Z, Ye Z, Zhang Z, Abu-Khalaf MM, Silver DP, Palazzo JP, Jagannathan G, Fellin FM, Bhattacharya S, Jaslow RJ, Tsangaris TN, Berger A, Neupane M, Cescon TP, Lopez A, Yao K, Chong W, Lu B, Myers RE, Hou L, Wei Q, Li B, Cristofanilli M, and Yang H
- Subjects
- Breast Neoplasms blood, Breast Neoplasms genetics, Breast Neoplasms metabolism, Female, Humans, Middle Aged, Neoplasm Staging, Neoplastic Cells, Circulating metabolism, Receptor, ErbB-2 genetics, Survival Rate, Biomarkers, Tumor blood, Breast Neoplasms pathology, Neoplastic Cells, Circulating pathology, Receptor, ErbB-2 metabolism
- Abstract
Purpose: Discordance between HER2 expression in tumor tissue (tHER2) and HER2 status on circulating tumor cells (cHER2) has been reported. It remains largely underexplored whether patients with tHER2
- /cHER2+ can benefit from anti-HER2 targeted therapies., Methods: cHER2 status was determined in 105 advanced-stage patients with tHER2- breast tumors. Association between cHER2 status and progression-free survival (PFS) was analyzed by univariate and multivariate Cox models and survival differences were compared by Kaplan-Meier method., Results: Compared to the patients with low-risk cHER2 (cHER2+ < 2), those with high-risk cHER2 (cHER2+ ≥ 2) had shorter survival time and an increased risk for disease progression (hazard ratio [HR] 2.16, 95% confidence interval [CI] 1.20-3.88, P = 0.010). Among the patients with high-risk cHER2, those who received anti-HER2 targeted therapies had improved PFS compared with those who did not (HR 0.30, 95% CI 0.10-0.92, P = 0.035). In comparison, anti-HER2 targeted therapy did not affect PFS among those with low-risk cHER2 (HR 0.70, 95% CI 0.36-1.38, P = 0.306). Similar results were obtained after adjusting covariates. A longitudinal analysis of 67 patients with cHER2 detected during follow-ups found that those whose cHER2 status changed from high-risk at baseline to low-risk at first follow-up exhibited a significantly improved survival compared to those whose cHER2 remained high-risk (median PFS: 11.7 weeks vs. 2.0 weeks, log-rank P = 0.001)., Conclusion: In advanced-stage breast cancer patients with tHER2- tumors, cHER2 status has the potential to guide the use of anti-HER2 targeted therapy in patients with high-risk cHER2.- Published
- 2020
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11. Association of clinical outcomes in metastatic breast cancer patients with circulating tumour cell and circulating cell-free DNA.
- Author
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Ye Z, Wang C, Wan S, Mu Z, Zhang Z, Abu-Khalaf MM, Fellin FM, Silver DP, Neupane M, Jaslow RJ, Bhattacharya S, Tsangaris TN, Chervoneva I, Berger A, Austin L, Palazzo JP, Myers RE, Pancholy N, Toorkey D, Yao K, Krall M, Li X, Chen X, Fu X, Xing J, Hou L, Wei Q, Li B, Cristofanilli M, and Yang H
- Subjects
- Adult, Aged, Breast Neoplasms blood, Breast Neoplasms mortality, Cell Count, Circulating Tumor DNA blood, Disease Progression, Female, Humans, Liquid Biopsy, Middle Aged, Neoplasm Metastasis, Predictive Value of Tests, Progression-Free Survival, Real-Time Polymerase Chain Reaction, Risk Assessment, Risk Factors, Time Factors, Breast Neoplasms genetics, Breast Neoplasms pathology, Circulating Tumor DNA genetics, Neoplastic Cells, Circulating pathology
- Abstract
Background: Both circulating tumour cell (CTC) and total circulating cell-free DNA (ccfDNA) predict cancer patient prognosis. However, no study has explored the prognostic value of the combined use of CTC and ccfDNA. We aimed to investigate individual and joint effects of CTC and ccfDNA on clinical outcomes of metastatic breast cancer (MBC) patients., Methods: We collected 227 blood samples from 117 MBC patients. CTCs were enumerated using the CellSearch System. ccfDNAs were quantified by quantitative real-time polymerase chain reaction and Qubit fluorometer. The individual and joint effects of CTC and ccfDNA levels on patient progression-free survival (PFS) and overall survival (OS) were analysed using Cox proportional hazards models., Results: Compared to patients with <5 CTCs, patients with ≥5 CTCs had a 2.58-fold increased risk of progression and 3.63-fold increased risk of death. High level of ccfDNA was associated with a 2.05-fold increased risk of progression and 3.56-fold increased risk of death. These associations remained significant after adjusting for other important clinical covariates and CTC/ccfDNA levels. CTC and ccfDNA levels had a joint effect on patient outcomes. Compared to patients with low levels of both CTC and ccfDNA, those with high levels of both markers exhibited a >17-fold increased death risk (P < 0.001). Moreover, longitudinal analysis of 132 samples from 22 patients suggested that the inconsistency between CTC level and outcome in some patients could possibly be explained by ccfDNA level., Conclusions: CTC and total ccfDNA levels were individually and jointly associated with PFS and OS in MBC patients., (Copyright © 2018 Elsevier Ltd. All rights reserved.)
- Published
- 2019
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12. Overexpression of BLM promotes DNA damage and increased sensitivity to platinum salts in triple-negative breast and serous ovarian cancers.
- Author
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Birkbak NJ, Li Y, Pathania S, Greene-Colozzi A, Dreze M, Bowman-Colin C, Sztupinszki Z, Krzystanek M, Diossy M, Tung N, Ryan PD, Garber JE, Silver DP, Iglehart JD, Wang ZC, Szuts D, Szallasi Z, and Richardson AL
- Subjects
- Female, Humans, Ovarian Neoplasms genetics, Ovarian Neoplasms pathology, Triple Negative Breast Neoplasms drug therapy, Triple Negative Breast Neoplasms genetics, Triple Negative Breast Neoplasms pathology, Antineoplastic Agents therapeutic use, DNA Damage, Ovarian Neoplasms metabolism, Platinum Compounds therapeutic use, RecQ Helicases physiology, Triple Negative Breast Neoplasms metabolism
- Abstract
Background: Platinum-based therapy is an effective treatment for a subset of triple-negative breast cancer and ovarian cancer patients. In order to increase response rate and decrease unnecessary use, robust biomarkers that predict response to therapy are needed., Patients and Methods: We performed an integrated genomic approach combining differential analysis of gene expression and DNA copy number in sensitive compared with resistant triple-negative breast cancers in two independent neoadjuvant cisplatin-treated cohorts. Functional relevance of significant hits was investigated in vitro by overexpression, knockdown and targeted inhibitor treatment., Results: We identified two genes, the Bloom helicase (BLM) and Fanconi anemia complementation group I (FANCI), that have both increased DNA copy number and gene expression in the platinum-sensitive cases. Increased level of expression of these two genes was also associated with platinum but not with taxane response in ovarian cancer. As a functional validation, we found that overexpression of BLM promotes DNA damage and induces sensitivity to cisplatin but has no effect on paclitaxel sensitivity., Conclusions: A biomarker based on the expression levels of the BLM and FANCI genes is a potential predictor of platinum sensitivity in triple-negative breast cancer and ovarian cancer.
- Published
- 2018
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13. Zoledronic acid alters hematopoiesis and generates breast tumor-suppressive bone marrow cells.
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Ubellacker JM, Haider MT, DeCristo MJ, Allocca G, Brown NJ, Silver DP, Holen I, and McAllister SS
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- Animals, Bone Marrow diagnostic imaging, Bone Marrow metabolism, Bone Marrow pathology, Bone and Bones diagnostic imaging, Bone and Bones metabolism, Bone and Bones pathology, Breast Neoplasms drug therapy, Breast Neoplasms pathology, Cell Line, Tumor, Colony-Forming Units Assay, Disease Models, Animal, Extracellular Matrix, Female, Hematopoietic Stem Cells drug effects, Hematopoietic Stem Cells metabolism, Humans, Leukocyte Count, Mice, Neovascularization, Pathologic drug therapy, Neovascularization, Pathologic metabolism, Osteoblasts drug effects, Osteoblasts metabolism, Osteoclasts drug effects, Osteoclasts metabolism, X-Ray Microtomography, Zoledronic Acid, Bone Density Conservation Agents pharmacology, Bone Marrow Cells drug effects, Bone Marrow Cells metabolism, Breast Neoplasms blood, Breast Neoplasms metabolism, Diphosphonates pharmacology, Hematopoiesis drug effects, Imidazoles pharmacology
- Abstract
Background: The bone-targeting agent zoledronic acid (ZOL) increases breast cancer survival in subsets of patients, but the underlying reasons for this protective effect are unknown. ZOL modulates the activity of osteoclasts and osteoblasts, which form hematopoietic stem cell niches, and therefore may affect hematopoietic cells that play a role in breast cancer progression., Method: Immunocompetent and immunocompromised strains of mice commonly used for breast cancer research were injected with a single, clinically relevant dose of ZOL (100 μg/kg) or vehicle control. The effects of ZOL on the bone marrow microenvironment (bone volume, bone cell number/activity, extracellular matrix composition) were established at various time points following treatment, using micro-computed tomography (μCT) analysis, histomorphometry, ELISA and immunofluorescence. The effects on peripheral blood and bone marrow hematopoietic progenitor populations were assessed using a HEMAVET® hematology analyzer and multicolor flow cytometry, respectively. Tumor support function of bone marrow cells was determined using an in vivo functional assay developed in our laboratory., Results: Using multiple mouse strains, we observed transient changes in numbers of hematopoietic stem cells, myeloid-biased progenitor cells, and lymphoid-biased cells concurrent with changes to hematopoietic stem cell niches following ZOL administration. Importantly, bone marrow cells from mice treated with a single, clinically relevant dose of ZOL inhibited breast tumor outgrowth in vivo. The ZOL-induced tumor suppressive function of the bone marrow persisted beyond the time point at which numbers of hematopoietic progenitor cells had returned to baseline., Conclusions: These findings provide novel evidence that alterations to the bone marrow play a role in the anti-tumor activity of ZOL and suggest possibilities for capitalizing on the beneficial effects of ZOL in reducing breast cancer development and progression.
- Published
- 2017
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14. Homologous Recombination Deficiency (HRD) Score Predicts Response to Platinum-Containing Neoadjuvant Chemotherapy in Patients with Triple-Negative Breast Cancer.
- Author
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Telli ML, Timms KM, Reid J, Hennessy B, Mills GB, Jensen KC, Szallasi Z, Barry WT, Winer EP, Tung NM, Isakoff SJ, Ryan PD, Greene-Colozzi A, Gutin A, Sangale Z, Iliev D, Neff C, Abkevich V, Jones JT, Lanchbury JS, Hartman AR, Garber JE, Ford JM, Silver DP, and Richardson AL
- Subjects
- Antineoplastic Combined Chemotherapy Protocols adverse effects, Biomarkers, Tumor, Female, Genes, BRCA1, Genes, BRCA2, Humans, Mutation, Neoplasm Staging, Odds Ratio, Platinum administration & dosage, Prognosis, Treatment Outcome, Triple Negative Breast Neoplasms mortality, Triple Negative Breast Neoplasms pathology, Allelic Imbalance, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Homologous Recombination, Loss of Heterozygosity, Telomere, Triple Negative Breast Neoplasms drug therapy, Triple Negative Breast Neoplasms genetics
- Abstract
Purpose: BRCA1/2-mutated and some sporadic triple-negative breast cancers (TNBC) have DNA repair defects and are sensitive to DNA-damaging therapeutics. Recently, three independent DNA-based measures of genomic instability were developed on the basis of loss of heterozygosity (LOH), telomeric allelic imbalance (TAI), and large-scale state transitions (LST)., Experimental Design: We assessed a combined homologous recombination deficiency (HRD) score, an unweighted sum of LOH, TAI, and LST scores, in three neoadjuvant TNBC trials of platinum-containing therapy. We then tested the association of HR deficiency, defined as HRD score ≥42 or BRCA1/2 mutation, with response to platinum-based therapy., Results: In a trial of neoadjuvant platinum, gemcitabine, and iniparib, HR deficiency predicted residual cancer burden score of 0 or I (RCB 0/I) and pathologic complete response (pCR; OR = 4.96, P = 0.0036; OR = 6.52, P = 0.0058). HR deficiency remained a significant predictor of RCB 0/I when adjusted for clinical variables (OR = 5.86, P = 0.012). In two other trials of neoadjuvant cisplatin therapy, HR deficiency predicted RCB 0/I and pCR (OR = 10.18, P = 0.0011; OR = 17.00, P = 0.0066). In a multivariable model of RCB 0/I, HR deficiency retained significance when clinical variables were included (OR = 12.08, P = 0.0017). When restricted to BRCA1/2 nonmutated tumors, response was higher in patients with high HRD scores: RCB 0/I P = 0.062, pCR P = 0.063 in the neoadjuvant platinum, gemcitabine, and iniparib trial; RCB 0/I P = 0.0039, pCR P = 0.018 in the neoadjuvant cisplatin trials., Conclusions: HR deficiency identifies TNBC tumors, including BRCA1/2 nonmutated tumors more likely to respond to platinum-containing therapy. Clin Cancer Res; 22(15); 3764-73. ©2016 AACR., (©2016 American Association for Cancer Research.)
- Published
- 2016
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15. MECP2 Is a Frequently Amplified Oncogene with a Novel Epigenetic Mechanism That Mimics the Role of Activated RAS in Malignancy.
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Neupane M, Clark AP, Landini S, Birkbak NJ, Eklund AC, Lim E, Culhane AC, Barry WT, Schumacher SE, Beroukhim R, Szallasi Z, Vidal M, Hill DE, and Silver DP
- Subjects
- 5-Methylcytosine analogs & derivatives, Alternative Splicing, Animals, Cell Line, Tumor, Cytosine metabolism, Epigenesis, Genetic, Humans, Methyl-CpG-Binding Protein 2 metabolism, Mice, Neoplasm Transplantation, Protein Isoforms metabolism, Signal Transduction, Cytosine analogs & derivatives, Gene Amplification, Methyl-CpG-Binding Protein 2 genetics, Neoplasms genetics, ras Proteins genetics
- Abstract
Unlabelled: An unbiased genome-scale screen for unmutated genes that drive cancer growth when overexpressed identified methyl cytosine-guanine dinucleotide (CpG) binding protein 2 (MECP2) as a novel oncogene. MECP2 resides in a region of the X-chromosome that is significantly amplified across 18% of cancers, and many cancer cell lines have amplified, overexpressed MECP2 and are dependent on MECP2 expression for growth. MECP2 copy-number gain and RAS family member alterations are mutually exclusive in several cancer types. The MECP2 splicing isoforms activate the major growth factor pathways targeted by activated RAS, the MAPK and PI3K pathways. MECP2 rescued the growth of a KRAS(G12C)-addicted cell line after KRAS downregulation, and activated KRAS rescues the growth of an MECP2-addicted cell line after MECP2 downregulation. MECP2 binding to the epigenetic modification 5-hydroxymethylcytosine is required for efficient transformation. These observations suggest that MECP2 is a commonly amplified oncogene with an unusual epigenetic mode of action., Significance: MECP2 is a commonly amplified oncogene in human malignancies with a unique epigenetic mechanism of action. Cancer Discov; 6(1); 45-58. ©2015 AACR.This article is highlighted in the In This Issue feature, p. 1., (©2015 American Association for Cancer Research.)
- Published
- 2016
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16. Pan-cancer analysis of genomic scar signatures associated with homologous recombination deficiency suggests novel indications for existing cancer drugs.
- Author
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Marquard AM, Eklund AC, Joshi T, Krzystanek M, Favero F, Wang ZC, Richardson AL, Silver DP, Szallasi Z, and Birkbak NJ
- Abstract
Background: Ovarian and triple-negative breast cancers with BRCA1 or BRCA2 loss are highly sensitive to treatment with PARP inhibitors and platinum-based cytotoxic agents and show an accumulation of genomic scars in the form of gross DNA copy number aberrations. Cancers without BRCA1 or BRCA2 loss but with accumulation of similar genomic scars also show increased sensitivity to platinum-based chemotherapy. Therefore, reliable biomarkers to identify DNA repair-deficient cancers prior to treatment may be useful for directing patients to platinum chemotherapy and possibly PARP inhibitors. Recently, three SNP array-based signatures of chromosomal instability were published that each quantitate a distinct type of genomic scar considered likely to be caused by improper DNA repair. They measure telomeric allelic imbalance (named NtAI), large scale transition (named LST), and loss of heterozygosity (named HRD-LOH), and it is suggested that these signatures may act as biomarkers for the state of DNA repair deficiency in a given cancer., Results: We explored the pan-cancer distribution of scores of the three signatures utilizing a panel of 5371 tumors representing 15 cancer types from The Cancer Genome Atlas, and found a good correlation between scores of the three signatures (Spearman's ρ 0.73-0.87). In addition we found that cancer types ordinarily receiving platinum as standard of care have higher median scores of all three signatures. Interestingly, we also found that smaller subpopulations of high-scoring tumors exist in most cancer types, including those for which platinum chemotherapy is not standard therapy., Conclusions: Within several cancer types that are not ordinarily treated with platinum chemotherapy, we identified tumors with high levels of the three genomic biomarkers. These tumors represent identifiable subtypes of patients which may be strong candidates for clinical trials with PARP inhibitors or platinum-based chemotherapeutic regimens.
- Published
- 2015
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17. BRCA1 pathway function in basal-like breast cancer cells.
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Hill SJ, Clark AP, Silver DP, and Livingston DM
- Subjects
- BRCA1 Protein genetics, Breast Neoplasms, Cell Line, Tumor, DNA Breaks, Double-Stranded, DNA Replication, Female, Humans, Inhibitory Concentration 50, Methyl Methanesulfonate pharmacology, Mutagens pharmacology, Neoplasms, Basal Cell, Recombinational DNA Repair, BRCA1 Protein metabolism
- Abstract
Sporadic basal-like cancers (BLCs) are a common subtype of breast cancer that share multiple biological properties with BRCA1-mutated breast tumors. Despite being BRCA1(+/+), sporadic BLCs are widely viewed as phenocopies of BRCA1-mutated breast cancers, because they are hypothesized to manifest a BRCA1 functional defect or breakdown of a pathway(s) in which BRCA1 plays a major role. The role of BRCA1 in the repair of double-strand DNA breaks by homologous recombination (HR) is its best understood function and the function most often implicated in BRCA1 breast cancer suppression. Therefore, it is suspected that sporadic BLCs exhibit a defect in HR. To test this hypothesis, multiple DNA damage repair assays focused on several types of repair were performed on a group of cell lines classified as sporadic BLCs and on controls. The sporadic BLC cell lines failed to exhibit an overt HR defect. Rather, they exhibited defects in the repair of stalled replication forks, another BRCA1 function. These results provide insight into why clinical trials of poly(ADP-ribose) polymerase (PARP) inhibitors, which require an HR defect for efficacy, have been unsuccessful in sporadic BLCs, unlike cisplatin, which elicits DNA damage that requires stalled fork repair and has shown efficacy in sporadic BLCs., (Copyright © 2014, American Society for Microbiology. All Rights Reserved.)
- Published
- 2014
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18. Mechanisms of BRCA1 tumor suppression.
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Silver DP and Livingston DM
- Subjects
- Animals, BRCA1 Protein chemistry, Breast Neoplasms metabolism, Female, Humans, Mutation, Ovarian Neoplasms metabolism, BRCA1 Protein genetics, BRCA1 Protein metabolism, Breast Neoplasms genetics, Genes, BRCA1, Ovarian Neoplasms genetics
- Abstract
Unlabelled: The p220 BRCA1 tumor suppressor protein has been implicated in multiple biochemical and biologic functions since its molecular cloning 18 years ago. Here, we discuss those functions most relevant for its tumor-suppressing activities with an emphasis on new findings. In particular, this review focuses on what is known of the activities of those BRCA1-binding partners that have tumor suppressor functions, on the reversion of mutant BRCA1 alleles concomitant with therapy resistance, on insights gained from studies of BRCA1 structure-function relationships, recent findings from animal models, and the potential role of BRCA1 in some nonhereditary tumors. From this information, a more detailed and refined picture of BRCA1 tumor suppression is beginning to emerge. Although key mysteries remain--such as why BRCA1 tumor suppression is focused on carcinomas of the breast and ovary--the pace of discovery is increasing., Significance: BRCA1 functions as a clinically important classical tumor suppressor in hereditary breast and ovarian cancer; here, we review progress in understanding how BRCA1 operates to suppress tumor formation.
- Published
- 2012
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19. Telomeric allelic imbalance indicates defective DNA repair and sensitivity to DNA-damaging agents.
- Author
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Birkbak NJ, Wang ZC, Kim JY, Eklund AC, Li Q, Tian R, Bowman-Colin C, Li Y, Greene-Colozzi A, Iglehart JD, Tung N, Ryan PD, Garber JE, Silver DP, Szallasi Z, and Richardson AL
- Subjects
- Antineoplastic Agents, Cell Line, Tumor, Chromosome Aberrations, Cisplatin pharmacology, Drug Resistance, Neoplasm genetics, Female, Genes, BRCA1, Humans, Models, Biological, Mutation, Ovarian Neoplasms genetics, RNA, Messenger genetics, Allelic Imbalance, DNA Damage drug effects, DNA Repair drug effects, Telomere genetics
- Abstract
Unlabelled: DNA repair competency is one determinant of sensitivity to certain chemotherapy drugs, such as cisplatin. Cancer cells with intact DNA repair can avoid the accumulation of genome damage during growth and also can repair platinum-induced DNA damage. We sought genomic signatures indicative of defective DNA repair in cell lines and tumors and correlated these signatures to platinum sensitivity. The number of subchromosomal regions with allelic imbalance extending to the telomere (N(tAI)) predicted cisplatin sensitivity in vitro and pathologic response to preoperative cisplatin treatment in patients with triple-negative breast cancer (TNBC). In serous ovarian cancer treated with platinum-based chemotherapy, higher levels of N(tAI) forecast a better initial response. We found an inverse relationship between BRCA1 expression and N(tAI) in sporadic TNBC and serous ovarian cancers without BRCA1 or BRCA2 mutation. Thus, accumulation of telomeric allelic imbalance is a marker of platinum sensitivity and suggests impaired DNA repair., Significance: Mutations in BRCA genes cause defects in DNA repair that predict sensitivity to DNA damaging agents, including platinum; however, some patients without BRCA mutations also benefit from these agents. NtAI, a genomic measure of unfaithfully repaired DNA, may identify cancer patients likely to benefit from treatments targeting defective DNA repair.
- Published
- 2012
- Full Text
- View/download PDF
20. Poly(ADP-Ribose) polymerase inhibition: "targeted" therapy for triple-negative breast cancer.
- Author
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Anders CK, Winer EP, Ford JM, Dent R, Silver DP, Sledge GW, and Carey LA
- Subjects
- Disease Progression, Female, Humans, Antineoplastic Agents pharmacology, Antineoplastic Agents therapeutic use, Breast Neoplasms drug therapy, Breast Neoplasms enzymology, Enzyme Inhibitors pharmacology, Enzyme Inhibitors therapeutic use, Poly(ADP-ribose) Polymerase Inhibitors
- Abstract
In contrast to endocrine-sensitive and human epidermal growth factor receptor 2 (HER2)-positive breast cancer, novel agents capable of treating advanced triple-negative breast cancer (TNBC) are lacking. Poly(ADP-ribose) polymerase (PARP) inhibitors are emerging as one of the most promising "targeted" therapeutics to treat TNBC, with the intended "target" being DNA repair. PARPs are a family of enzymes involved in multiple cellular processes, including DNA repair. TNBC shares multiple clinico-pathologic features with BRCA-mutated breast cancers, which harbor dysfunctional DNA repair mechanisms. Investigators hypothesized that PARP inhibition, in conjunction with the loss of DNA repair via BRCA-dependent mechanisms, would result in synthetic lethality and augmented cell death. This hypothesis has borne out in both preclinical models and in clinical trials testing PARP inhibitors in both BRCA-deficient and triple-negative breast cancer. The focus of this review includes an overview of the preclinical rationale for evaluating PARP inhibitors in TNBC, the presumed mechanism of action of this novel therapeutic class, promising results from several influential clinical trials of PARP inhibition in advanced breast cancer (both TNBC and BRCA deficient), proposed mechanisms of acquired resistance to PARP inhibitors, and, finally, concludes with current challenges and future directions for the development of PARP inhibitors in the treatment of breast cancer., (©2010 AACR.)
- Published
- 2010
- Full Text
- View/download PDF
21. Efficacy of neoadjuvant Cisplatin in triple-negative breast cancer.
- Author
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Silver DP, Richardson AL, Eklund AC, Wang ZC, Szallasi Z, Li Q, Juul N, Leong CO, Calogrias D, Buraimoh A, Fatima A, Gelman RS, Ryan PD, Tung NM, De Nicolo A, Ganesan S, Miron A, Colin C, Sgroi DC, Ellisen LW, Winer EP, and Garber JE
- Subjects
- Adult, Aged, Breast Neoplasms chemistry, Breast Neoplasms genetics, Cisplatin adverse effects, DNA Methylation, DNA-Binding Proteins analysis, Female, Genes, BRCA1, Genes, p53, Humans, Middle Aged, Mutation, Neoadjuvant Therapy, Nuclear Proteins analysis, Oligonucleotide Array Sequence Analysis, Promoter Regions, Genetic, Tumor Protein p73, Tumor Suppressor Proteins analysis, Antineoplastic Agents therapeutic use, Breast Neoplasms drug therapy, Cisplatin therapeutic use, Receptor, ErbB-2 analysis, Receptors, Estrogen analysis, Receptors, Progesterone analysis
- Abstract
PURPOSE Cisplatin is a chemotherapeutic agent not used routinely for breast cancer treatment. As a DNA cross-linking agent, cisplatin may be effective treatment for hereditary BRCA1-mutated breast cancers. Because sporadic triple-negative breast cancer (TNBC) and BRCA1-associated breast cancer share features suggesting common pathogenesis, we conducted a neoadjuvant trial of cisplatin in TNBC and explored specific biomarkers to identify predictors of response. PATIENTS AND METHODS Twenty-eight women with stage II or III breast cancers lacking estrogen and progesterone receptors and HER2/Neu (TNBC) were enrolled and treated with four cycles of cisplatin at 75 mg/m(2) every 21 days. After definitive surgery, patients received standard adjuvant chemotherapy and radiation therapy per their treating physicians. Clinical and pathologic treatment response were assessed, and pretreatment tumor samples were evaluated for selected biomarkers. Results Six (22%) of 28 patients achieved pathologic complete responses, including both patients with BRCA1 germline mutations;18 (64%) patients had a clinical complete or partial response. Fourteen (50%) patients showed good pathologic responses (Miller-Payne score of 3, 4, or 5), 10 had minor responses (Miller-Payne score of 1 or 2), and four (14%) progressed. All TNBCs clustered with reference basal-like tumors by hierarchical clustering. Factors associated with good cisplatin response include young age (P = .001), low BRCA1 mRNA expression (P = .03), BRCA1 promoter methylation (P = .04), p53 nonsense or frameshift mutations (P = .01), and a gene expression signature of E2F3 activation (P = .03). CONCLUSION Single-agent cisplatin induced response in a subset of patients with TNBC. Decreased BRCA1 expression may identify subsets of TNBCs that are cisplatin sensitive. Other biomarkers show promise in predicting cisplatin response.
- Published
- 2010
- Full Text
- View/download PDF
22. Prevalence and predictors of loss of wild type BRCA1 in estrogen receptor positive and negative BRCA1-associated breast cancers.
- Author
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Tung N, Miron A, Schnitt SJ, Gautam S, Fetten K, Kaplan J, Yassin Y, Buraimoh A, Kim JY, Szász AM, Tian R, Wang ZC, Collins LC, Brock J, Krag K, Legare RD, Sgroi D, Ryan PD, Silver DP, Garber JE, and Richardson AL
- Subjects
- Age Factors, Biomarkers, Tumor, Breast Neoplasms pathology, DNA Methylation, ErbB Receptors analysis, Female, Humans, Keratins analysis, Microarray Analysis, Mutation, Polymerase Chain Reaction, Receptors, Estrogen analysis, Tumor Suppressor Protein p53 analysis, Breast Neoplasms diagnosis, Breast Neoplasms genetics, Genes, BRCA1, Receptors, Estrogen genetics
- Abstract
Introduction: The majority of breast cancers that occur in BRCA1 mutation carriers (BRCA1 carriers) are estrogen receptor-negative (ER-). Therefore, it has been suggested that ER negativity is intrinsic to BRCA1 cancers and reflects the cell of origin of these tumors. However, approximately 20% of breast cancers that develop in BRCA1 carriers are ER-positive (ER+); these cancers are more likely to develop as BRCA1 carriers age, suggesting that they may be incidental and unrelated to BRCA1 deficiency. The purpose of this study was to compare the prevalence of loss of heterozygosity due to loss of wild type (wt) BRCA1 in ER+ and ER- breast cancers that have occurred in BRCA1 carriers and to determine whether age at diagnosis or any pathologic features or biomarkers predict for loss of wt BRCA1 in these breast cancers., Methods: Relative amounts of mutated and wt BRCA1 DNA were measured by quantitative polymerase chain reaction performed on laser capture microdissected cancer cells from 42 ER+ and 35 ER- invasive breast cancers that developed in BRCA1 carriers. BRCA1 gene methylation was determined on all cancers in which sufficient DNA was available. Immunostains for cytokeratins (CK) 5/6, 14, 8 and 18, epidermal growth factor receptor and p53 were performed on paraffin sections from tissue microarrays containing these cancers., Results: Loss of wt BRCA1 was equally frequent in ER+ and ER- BRCA1-associated cancers (81.0% vs 88.6%, respectively; P = 0.53). One of nine cancers tested that retained wt BRCA1 demonstrated BRCA1 gene methylation. Age at diagnosis was not significantly different between first invasive ER+ BRCA1 breast cancers with and without loss of wt BRCA1 (mean age 45.2 years vs 50.1 years, respectively; P = 0.51). ER+ BRCA1 cancers that retained wt BRCA1 were significantly more likely than those that lost wt BRCA1 to have a low mitotic rate (odds ratio (OR), 5.16; 95% CI, 1.91 to ∞). BRCA1 cancers with loss of wt BRCA1 were more likely to express basal cytokeratins CK 5/6 or 14 (OR 4.7; 95% CI, 1.85 to ∞)., Conclusions: We found no difference in the prevalence of loss of wt BRCA1 between ER+ and ER- invasive BRCA1-associated breast cancers. Our findings suggest that many of the newer therapies for BRCA1 breast cancers designed to exploit the BRCA1 deficiency in these cancers may also be effective in ER+ cancers that develop in this population.
- Published
- 2010
- Full Text
- View/download PDF
23. Complex landscapes of somatic rearrangement in human breast cancer genomes.
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Stephens PJ, McBride DJ, Lin ML, Varela I, Pleasance ED, Simpson JT, Stebbings LA, Leroy C, Edkins S, Mudie LJ, Greenman CD, Jia M, Latimer C, Teague JW, Lau KW, Burton J, Quail MA, Swerdlow H, Churcher C, Natrajan R, Sieuwerts AM, Martens JW, Silver DP, Langerød A, Russnes HE, Foekens JA, Reis-Filho JS, van 't Veer L, Richardson AL, Børresen-Dale AL, Campbell PJ, Futreal PA, and Stratton MR
- Subjects
- Cell Line, Tumor, Cells, Cultured, DNA Breaks, Female, Genomic Library, Humans, Sequence Analysis, DNA, Breast Neoplasms genetics, Chromosome Aberrations, Gene Rearrangement genetics, Genome, Human genetics
- Abstract
Multiple somatic rearrangements are often found in cancer genomes; however, the underlying processes of rearrangement and their contribution to cancer development are poorly characterized. Here we use a paired-end sequencing strategy to identify somatic rearrangements in breast cancer genomes. There are more rearrangements in some breast cancers than previously appreciated. Rearrangements are more frequent over gene footprints and most are intrachromosomal. Multiple rearrangement architectures are present, but tandem duplications are particularly common in some cancers, perhaps reflecting a specific defect in DNA maintenance. Short overlapping sequences at most rearrangement junctions indicate that these have been mediated by non-homologous end-joining DNA repair, although varying sequence patterns indicate that multiple processes of this type are operative. Several expressed in-frame fusion genes were identified but none was recurrent. The study provides a new perspective on cancer genomes, highlighting the diversity of somatic rearrangements and their potential contribution to cancer development.
- Published
- 2009
- Full Text
- View/download PDF
24. Estrogen receptor-negative breast cancer: new insights into subclassification and targeting.
- Author
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Zhao JJ and Silver DP
- Subjects
- Breast Neoplasms enzymology, Breast Neoplasms genetics, Drug Delivery Systems, Female, Gene Expression Profiling, Humans, Neoplasms, Hormone-Dependent, Phosphotransferases metabolism, Signal Transduction, Breast Neoplasms classification, Breast Neoplasms metabolism, Receptors, Estrogen metabolism
- Abstract
Classification schemes for disease states can help identify distinctions with useful implications for therapy and prognosis. Speers and colleagues provide a new subclassification scheme for estrogen receptor-negative breast cancer based upon kinome-wide gene expression profiling with interesting findings that are potentially relevant for both treatment and clinical outcome.
- Published
- 2009
- Full Text
- View/download PDF
25. Cyclin A is redundant in fibroblasts but essential in hematopoietic and embryonic stem cells.
- Author
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Kalaszczynska I, Geng Y, Iino T, Mizuno S, Choi Y, Kondratiuk I, Silver DP, Wolgemuth DJ, Akashi K, and Sicinski P
- Subjects
- Animals, Cyclin A genetics, Cyclin E genetics, Cyclin E metabolism, Mice, Mice, Knockout, Cyclin A metabolism, Embryo, Mammalian cytology, Embryonic Stem Cells metabolism, Fibroblasts metabolism, Hematopoietic Stem Cells metabolism
- Abstract
Cyclins are regulatory subunits of cyclin-dependent kinases. Cyclin A, the first cyclin ever cloned, is thought to be an essential component of the cell-cycle engine. Mammalian cells encode two A-type cyclins, testis-specific cyclin A1 and ubiquitously expressed cyclin A2. Here, we tested the requirement for cyclin A function using conditional knockout mice lacking both A-type cyclins. We found that acute ablation of cyclin A in fibroblasts did not affect cell proliferation, but led to prolonged expression of another cyclin, cyclin E, across the cell cycle. However, combined ablation of all A- and E-type cyclins extinguished cell division. In contrast, cyclin A function was essential for cell-cycle progression of hematopoietic and embryonic stem cells. Expression of cyclin A is particularly high in these compartments, which might render stem cells dependent on cyclin A, whereas in fibroblasts cyclins A and E play redundant roles in cell proliferation.
- Published
- 2009
- Full Text
- View/download PDF
26. Cancer: crossing over to drug resistance.
- Author
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Livingston DM and Silver DP
- Subjects
- BRCA2 Protein deficiency, BRCA2 Protein genetics, Breast Neoplasms drug therapy, DNA Breaks, Drug Resistance, Neoplasm drug effects, Female, Humans, Ovarian Neoplasms drug therapy, Poly(ADP-ribose) Polymerase Inhibitors, Antineoplastic Agents pharmacology, Breast Neoplasms genetics, Drug Resistance, Neoplasm genetics, Genes, BRCA2, Mutation genetics, Ovarian Neoplasms genetics, Recombination, Genetic genetics
- Published
- 2008
- Full Text
- View/download PDF
27. Further evidence for BRCA1 communication with the inactive X chromosome.
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Silver DP, Dimitrov SD, Feunteun J, Gelman R, Drapkin R, Lu SD, Shestakova E, Velmurugan S, Denunzio N, Dragomir S, Mar J, Liu X, Rottenberg S, Jonkers J, Ganesan S, and Livingston DM
- Subjects
- Animals, BRCA1 Protein genetics, Cell Line, Tumor, Embryo, Mammalian cytology, Female, Fibroblasts, Genes, BRCA1, Genes, BRCA2, Mammary Neoplasms, Experimental genetics, Mammary Neoplasms, Experimental metabolism, Mice, Mutation, RNA Interference, RNA, Long Noncoding, BRCA1 Protein metabolism, RNA, Untranslated metabolism, X Chromosome metabolism, X Chromosome Inactivation
- Abstract
BRCA1, a breast and ovarian cancer-suppressor gene, exerts tumor-suppressing functions that appear to be associated, at least in part, with its DNA repair, checkpoint, and mitotic regulatory activities. Earlier work from our laboratory also suggested an ability of BRCA1 to communicate with the inactive X chromosome (Xi) in female somatic cells (Ganesan et al., 2002). Xiao et al. (2007) (this issue of Cell) have challenged this conclusion. Here we discuss recently published data from our laboratory and others and present new results that, together, provide further support for a role of BRCA1 in the regulation of XIST concentration on Xi in somatic cells.
- Published
- 2007
- Full Text
- View/download PDF
28. Endogenous oncogenic K-ras(G12D) stimulates proliferation and widespread neoplastic and developmental defects.
- Author
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Tuveson DA, Shaw AT, Willis NA, Silver DP, Jackson EL, Chang S, Mercer KL, Grochow R, Hock H, Crowley D, Hingorani SR, Zaks T, King C, Jacobetz MA, Wang L, Bronson RT, Orkin SH, DePinho RA, and Jacks T
- Subjects
- Animals, Cell Cycle, Cell Division, Cellular Senescence, Congenital Abnormalities pathology, Crosses, Genetic, Cyclin-Dependent Kinase Inhibitor p16, Embryo, Mammalian cytology, Female, Fibroblasts metabolism, Integrases metabolism, Male, Mice, Mice, Inbred C57BL, Mice, Transgenic, Mutation, Neoplasms pathology, Stem Cells pathology, Tumor Suppressor Protein p14ARF genetics, Tumor Suppressor Protein p14ARF metabolism, Tumor Suppressor Protein p53 genetics, Tumor Suppressor Protein p53 metabolism, Viral Proteins metabolism, Cell Transformation, Neoplastic, Congenital Abnormalities genetics, Fibroblasts pathology, Gene Expression Regulation, Developmental physiology, Genes, ras physiology, Neoplasms genetics
- Abstract
Activating mutations in the ras oncogene are not considered sufficient to induce abnormal cellular proliferation in the absence of cooperating oncogenes. We demonstrate that the conditional expression of an endogenous K-ras(G12D) allele in murine embryonic fibroblasts causes enhanced proliferation and partial transformation in the absence of further genetic abnormalities. Interestingly, K-ras(G12D)-expressing fibroblasts demonstrate attenuation and altered regulation of canonical Ras effector signaling pathways. Widespread expression of endogenous K-ras(G12D) is not tolerated during embryonic development, and directed expression in the lung and GI tract induces preneoplastic epithelial hyperplasias. Our results suggest that endogenous oncogenic ras is sufficient to initiate transformation by stimulating proliferation, while further genetic lesions may be necessary for progression to frank malignancy.
- Published
- 2004
- Full Text
- View/download PDF
29. Association of BRCA1 with the inactive X chromosome and XIST RNA.
- Author
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Ganesan S, Silver DP, Drapkin R, Greenberg R, Feunteun J, and Livingston DM
- Subjects
- Chromatin genetics, Female, Genes, Reporter, Green Fluorescent Proteins, Humans, Luminescent Proteins metabolism, Models, Genetic, Precipitin Tests, RNA, Long Noncoding, RNA, Untranslated genetics, Chromosomes, Human, X genetics, Dosage Compensation, Genetic, Genes, BRCA1 physiology, RNA, Untranslated metabolism
- Abstract
Breast cancer, early onset 1 (BRCA1) encodes a nuclear protein that participates in breast and ovarian cancer suppression. The molecular basis for the gender and tissue specificity of the BRCA1 cancer syndrome is unknown. Recently, we observed that a fraction of BRCA1 in female cells is localized on the inactive X chromosome (Xi). Chromatin immunoprecipitation (ChIP) experiments have demonstrated that BRCA1 physically associates with Xi-specific transcript (XIST) RNA, a non-coding RNA known to coat Xi and to participate in the initiation of its inactivation during early embryogenesis. Cells lacking wild-type BRCA1 show abnormalities in Xi, including lack of proper XIST RNA localization. Reintroduction of wild-type, but not mutant, BRCA1 can correct this defect in XIST localization in these cells. Depletion of BRCA1 in female diploid cells led to a defect in proper XIST localization on Xi and in the development of normal Xi heterchromatic superstructure. Moreover, depletion of BRCA1 led to an increased likelihood of re-expression of a green fluorescent protein (GFP) reporter gene embedded on Xi. Taken together, these findings are consistent with a model in which BRCA1 function contributes to the maintenance of proper Xi heterochromatin superstructure. Although the data imply a novel gender-specific consequence of BRCA1 loss, the relevance of the BRCA1/Xi function to the tumour suppressor activity of BRCA1 remains unclear and needs to be tested.
- Published
- 2004
- Full Text
- View/download PDF
30. HIN-1 and the nosology of breast cancer.
- Author
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Silver DP
- Subjects
- Breast Neoplasms pathology, Carcinoma, Ductal pathology, Carcinoma, Medullary pathology, Female, Genes, p53 physiology, Genetic Predisposition to Disease, Humans, Mutation genetics, Breast Neoplasms genetics, Carcinoma, Ductal genetics, Carcinoma, Medullary genetics, Cytokines genetics, DNA Methylation, Genes, BRCA1 physiology, Tumor Suppressor Proteins genetics
- Published
- 2003
- Full Text
- View/download PDF
31. BRCA1 supports XIST RNA concentration on the inactive X chromosome.
- Author
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Ganesan S, Silver DP, Greenberg RA, Avni D, Drapkin R, Miron A, Mok SC, Randrianarison V, Brodie S, Salstrom J, Rasmussen TP, Klimke A, Marrese C, Marahrens Y, Deng CX, Feunteun J, and Livingston DM
- Subjects
- Animals, BRCA1 Protein genetics, Carrier Proteins metabolism, DNA Methylation, Female, Gene Expression, Histones metabolism, Humans, Lysine metabolism, Male, Mice, RNA, Long Noncoding, RNA-Binding Proteins genetics, Spermatocytes metabolism, Staining and Labeling methods, Tumor Cells, Cultured, BRCA1 Protein metabolism, Dosage Compensation, Genetic, RNA metabolism, RNA, Untranslated genetics, RNA-Binding Proteins metabolism, Transcription Factors genetics, Tumor Suppressor Proteins, Ubiquitin-Protein Ligases, X Chromosome metabolism
- Abstract
BRCA1, a breast and ovarian tumor suppressor, colocalizes with markers of the inactive X chromosome (Xi) on Xi in female somatic cells and associates with XIST RNA, as detected by chromatin immunoprecipitation. Breast and ovarian carcinoma cells lacking BRCA1 show evidence of defects in Xi chromatin structure. Reconstitution of BRCA1-deficient cells with wt BRCA1 led to the appearance of focal XIST RNA staining without altering XIST abundance. Inhibiting BRCA1 synthesis in a suitable reporter line led to increased expression of an otherwise silenced Xi-located GFP transgene. These observations suggest that loss of BRCA1 in female cells may lead to Xi perturbation and destabilization of its silenced state.
- Published
- 2002
- Full Text
- View/download PDF
32. p16(INK4a) and p53 deficiency cooperate in tumorigenesis.
- Author
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Sharpless NE, Alson S, Chan S, Silver DP, Castrillon DH, and DePinho RA
- Subjects
- Animals, Cell Division genetics, Cell Division physiology, Cells, Cultured, Cyclin-Dependent Kinase Inhibitor p16 genetics, DNA Methylation, Female, Fibroblasts cytology, Humans, Male, Mice, Mutation, Neoplasms, Experimental genetics, Neoplasms, Experimental pathology, Promoter Regions, Genetic, Tumor Suppressor Protein p53 genetics, Cell Transformation, Neoplastic genetics, Cyclin-Dependent Kinase Inhibitor p16 deficiency, Tumor Suppressor Protein p53 deficiency
- Abstract
The combined impact of mutations in p16(INK4a) and p53 was examined in cellular growth,transformation, and tumor formation. In cultured cells, p16(INK4a) loss enhanced growth at high density and conferred susceptibility to oncogene-induced transformation. In vivo, mice doubly deficient for p16(INK4a) and p53 showed an increased rate of tumor formation with particular susceptibility to aggressive angiosarcomas. Furthermore, p16(INK4a) silencing by promoter methylation was detected in tumors derived from p16(INK4a+/-) and (+/+) mice, independent of p53 status. These data suggest at least one general feature of malignancy, resistance to density-mediated growth arrest depends on p16(INK4a) rather than p53. This cooperation between p16(INK4a) and p53 loss in tumorigenesis is consistent with the view that these genes function in distinct anticancer pathways.
- Published
- 2002
33. Self-excising retroviral vectors encoding the Cre recombinase overcome Cre-mediated cellular toxicity.
- Author
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Silver DP and Livingston DM
- Subjects
- 3T3 Cells, Animals, Cell Division, Cell Line, Chromosome Aberrations, Genes, Reporter, Humans, Integrases genetics, Integrases toxicity, Mice, Mutation, Recombinant Fusion Proteins metabolism, Retroviridae metabolism, Viral Proteins genetics, Viral Proteins toxicity, DNA metabolism, Genetic Vectors, Integrases metabolism, Retroviridae genetics, Transfection methods, Viral Proteins metabolism
- Abstract
The Cre-lox system is often used to manipulate sequences in mammalian genomes. We have observed that continuous expression of the Cre recombinase in cultured cells lacking exogenous lox sites caused decreased growth, cytopathic effects, and chromosomal aberrations. Cre mutants defective in DNA cleavage were not geno- or cytotoxic. A self-excising retroviral vector that incorporates a negative feedback loop to limit the duration and intensity of Cre expression avoided measurable toxicity, retained the ability to excise a target sequence flanked by lox sites, and may provide the basis of a less toxic strategy for the use of Cre or similar recombinases.
- Published
- 2001
- Full Text
- View/download PDF
34. p19ARF targets certain E2F species for degradation.
- Author
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Martelli F, Hamilton T, Silver DP, Sharpless NE, Bardeesy N, Rokas M, DePinho RA, Livingston DM, and Grossman SR
- Subjects
- Blotting, Northern, Blotting, Western, Cell Division, Cell Line, Cell Nucleolus metabolism, E2F Transcription Factors, E2F1 Transcription Factor, E2F3 Transcription Factor, E2F6 Transcription Factor, Humans, Hydrolysis, Protein Binding, Retinoblastoma-Binding Protein 1, Transcription Factor DP1, Tumor Suppressor Protein p14ARF, Tumor Suppressor Protein p53 metabolism, Carrier Proteins, Cell Cycle Proteins, DNA-Binding Proteins, Proteins metabolism, Transcription Factors metabolism
- Abstract
p19ARF suppresses the growth of cells lacking p53 through an unknown mechanism. p19ARF was found to complex with transcription factors E2F1, -2, and -3. Levels of endogenous or ectopically expressed E2F1, -2, and -3, but not E2F6, were reduced after synthesis of p19ARF, through a mechanism involving increased turnover. p19ARF-induced degradation of E2F1 depended on a functional proteasome, and E2F1 was relocalized to nucleoli when coexpressed with p19ARF. Consistent with reduced levels of E2F1 and E2F3, the proliferation of cells defective for p53 function was suppressed by p19ARF, and the effect was partially reversed by ectopic overexpression of E2F1. These results suggest a broader role for p19ARF as a tumor suppressor, in which targeting of certain E2F species may cooperate with stimulation of the p53 pathway to counteract oncogenic growth signals.
- Published
- 2001
- Full Text
- View/download PDF
35. Stable interaction between the products of the BRCA1 and BRCA2 tumor suppressor genes in mitotic and meiotic cells.
- Author
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Chen J, Silver DP, Walpita D, Cantor SB, Gazdar AF, Tomlinson G, Couch FJ, Weber BL, Ashley T, Livingston DM, and Scully R
- Subjects
- Antibodies, Monoclonal, BRCA1 Protein analysis, BRCA2 Protein, Breast Neoplasms genetics, Cell Line, Cell Nucleus ultrastructure, Chromosome Mapping, DNA Damage, DNA Repair, DNA Replication, DNA-Binding Proteins analysis, DNA-Binding Proteins genetics, Female, Humans, Meiosis, Mitosis, Neoplasm Proteins analysis, Ovarian Neoplasms genetics, Rad51 Recombinase, Transcription Factors analysis, Transfection, Tumor Cells, Cultured, Zygote cytology, BRCA1 Protein metabolism, Breast Neoplasms pathology, Genes, BRCA1, Genes, Tumor Suppressor, Neoplasm Proteins genetics, Neoplasm Proteins metabolism, Transcription Factors genetics, Transcription Factors metabolism
- Abstract
BRCA1 and BRCA2 account for most cases of familial, early onset breast and/or ovarian cancer and encode products that each interact with hRAD51. Results presented here show that BRCA1 and BRCA2 coexist in a biochemical complex and colocalize in subnuclear foci in somatic cells and on the axial elements of developing synaptonemal complexes. Like BRCA1 and RAD51, BRCA2 relocates to PCNA+ replication sites following exposure of S phase cells to hydroxyurea or UV irradiation. Thus, BRCA1 and BRCA2 participate, together, in a pathway(s) associated with the activation of double-strand break repair and/or homologous recombination. Dysfunction of this pathway may be a general phenomenon in the majority of cases of hereditary breast and/or ovarian cancer.
- Published
- 1998
- Full Text
- View/download PDF
36. Localization, interaction, and RNA binding properties of the V(D)J recombination-activating proteins RAG1 and RAG2.
- Author
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Spanopoulou E, Cortes P, Shih C, Huang CM, Silver DP, Svec P, and Baltimore D
- Subjects
- 3T3 Cells, Animals, Binding Sites, Cell Nucleus metabolism, Gene Deletion, Gene Transfer Techniques, Mice, Proteins genetics, DNA-Binding Proteins, Homeodomain Proteins, Proteins metabolism, RNA metabolism, T-Lymphocytes metabolism
- Abstract
The RAG1 and RAG2 gene products are indispensable for activating somatic rearrangement of antigen receptor gene segments. The two proteins form a stable complex in primary thymocytes as well as when expressed in adherent cells. In both cell types, most cells localize RAG proteins at the periphery of the nucleus. However, when overexpressed in fibroblast cells, RAG1 is found largely in the nucleolus. Nucleolar localization of RAG1 is mediated by several domains containing stretches of basic amino acids, indicating that RAG1 has affinity for RNA or ssDNA. The RAG1 interacting proteins SRP1 and Rch1 directly bind to the nuclear localization signals of RAG1, which mediate the nuclear and nucleolar translocation of the protein. RAG1 appears to have a binary structure, each half containing multiple regions that can act as NLSs, binding sites for the SRP1/Rch1 family, and RNA binding domains.
- Published
- 1995
- Full Text
- View/download PDF
37. Functional immunoglobulin transgenes guide ordered B-cell differentiation in Rag-1-deficient mice.
- Author
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Spanopoulou E, Roman CA, Corcoran LM, Schlissel MS, Silver DP, Nemazee D, Nussenzweig MC, Shinton SA, Hardy RR, and Baltimore D
- Subjects
- Animals, B-Lymphocytes cytology, Bone Marrow Cells, Cell Differentiation, Clonal Deletion, Gene Rearrangement, B-Lymphocyte, Gene Targeting, Genetic Complementation Test, H-2 Antigens immunology, Immunoglobulin kappa-Chains genetics, Immunoglobulin mu-Chains genetics, Mice, Mice, Inbred C57BL, Mice, Transgenic, Proteins genetics, T-Lymphocytes immunology, B-Lymphocytes immunology, Genes, Immunoglobulin, Genes, RAG-1, Homeodomain Proteins, Proteins physiology, Receptors, Antigen, B-Cell genetics
- Abstract
We have examined the regulatory role of the individual components of the immunoglobulin antigen receptor in B-cell development by transgenic complementation of Rag-1 deficient (Rag-1-) mice. Complementation with a membrane mu heavy chain (mu HC) gene allows progression of developmentally arrested Rag-1- pro-B-cells to the small pre-B cell stage, whereas the introduction of independently integrated mu HC and kappa light chain (kappa LC) transgenes promotes the appearance of peripheral lymphocytes which, however, remain unresponsive to external stimuli. Complete reconstitution of the B-cell lineage and the emergence of functionally nature Rag-1- peripheral B cells is achieved by the introduction of cointegrated heavy and light chain transgenes encoding an anti-H-2k antibody. This experimental system demonstrates the competence of the mu HC and kappa LC to direct and regulate the sequential stages of B-cell differentiation, defines the time at which negative selection of self-reactive B cells occurs, and shows that elimination of these cells occurs equally well in the absence of Rag-1 as in its presence. These data also support the hypothesis that Rag-1 directly participates in the V(D)J recombination process.
- Published
- 1994
- Full Text
- View/download PDF
38. Dispensable sequence motifs in the RAG-1 and RAG-2 genes for plasmid V(D)J recombination.
- Author
-
Silver DP, Spanopoulou E, Mulligan RC, and Baltimore D
- Subjects
- 3T3 Cells, Animals, Cell Line, Immunoglobulin Variable Region genetics, Mice, Mutation, Plasmids, Proteins chemistry, Proteins physiology, Retroviridae genetics, Structure-Activity Relationship, DNA-Binding Proteins, Genes, Immunoglobulin, Genes, RAG-1, Homeodomain Proteins, Immunoglobulin Joining Region genetics, Proteins genetics, Recombination, Genetic
- Abstract
As a probe of whether RAG-1 and RAG-2 gene products activate other genes or form part of the recombinase itself, certain mutants of the RAG genes were assayed for their ability to activate variable-diversity-joining region [V(D)J] recombination in a plasmid substrate in fibroblasts. The results indicate that the N-terminal one-third of RAG-1, including a zinc-finger-like domain, and an acidic domain of RAG-2 are dispensable for activating V(D)J recombination in a fibroblast, although they contribute quantitatively. In contrast, deletion of the C-terminal segment of RAG-1, which has homology to a topoisomerase-like protein from yeast, abolished recombination activation. These results do not support the hypothesis that the RAG gene products are transcription factors and suggest the possibility that they are parts of the recombination machinery.
- Published
- 1993
- Full Text
- View/download PDF
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