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Search Results: 1 - 10 of 222203 matches for " Dennis C Sgroi "
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Re-evaluating early breast neoplasia
Sharon Moulis, Dennis C Sgroi
Breast Cancer Research , 2008, DOI: 10.1186/bcr1853
Abstract: Atypical ductal hyperplasia (ADH) and ductal carcinoma in situ (DCIS), the earliest neoplastic stages of human breast cancer progression, are characterized by a proliferation of epithelial cells that is confined within the basement membrane of the mammary ductal network [1]. ADH and DCIS represent a diverse group of tumors that are detected in women undergoing screening mammography, and it is believed that the detection of breast cancer in these early neoplastic stages is largely responsible for the recent trend toward improvement in breast cancer mortality worldwide. Historically, the pathological distinction between ADH and DCIS is largely morphological and is considered by some to be based upon the size and extent of the epithelial proliferation [2]. The classic model of breast cancer progression (Figure 1) is seen as a linear multi-step process manifesting itself as a sequence of pathologically defined stages in which molecular alterations within normal breast epithelium give rise to ADH, the first premalignant stage of breast cancer progression, upon which progressive molecular alterations give rise to DCIS, the second premalignant stage of breast cancer [3,4]. Additional molecular alterations in DCIS are thought to give rise to the malignant stages of invasive and metastatic carcinoma.Until recently, a significant impediment to a better understanding of breast cancer progression has been our inability to accurately interrogate the early neoplastic or premalignant stages of this process. However, over the past several years the successful application of combining highly specific tissue microdissection technologies with advanced high-throughput genomic and gene expression technologies has re-shaped our view of breast cancer progression. Instead of viewing breast cancer as a simple single linear pathway, recent molecular genetic evidence supports a multiple linear pathway model of progression.Loss of heterozygosity-based genomic studies of the premalignant stages
Gene expression profiling of the tumor microenvironment during breast cancer progression
Xiao-Jun Ma, Sonika Dahiya, Elizabeth Richardson, Mark Erlander, Dennis C Sgroi
Breast Cancer Research , 2009, DOI: 10.1186/bcr2222
Abstract: We combined laser capture microdissection and gene expression microarrays to analyze 14 patient-matched normal epithelium, normal stroma, tumor epithelium and tumor-associated stroma specimens. Differential gene expression and gene ontology analyses were performed.Tumor-associated stroma undergoes extensive gene expression changes during cancer progression, to a similar extent as that seen in the malignant epithelium. Highly upregulated genes in the tumor-associated stroma include constituents of the extracellular matrix and matrix metalloproteases, and cell-cycle-related genes. Decreased expression of cytoplasmic ribosomal proteins and increased expression of mitochondrial ribosomal proteins were observed in both the tumor epithelium and the stroma. The transition from preinvasive to invasive growth was accompanied by increased expression of several matrix metalloproteases (MMP2, MMP11 and MMP14). Furthermore, as observed in malignant epithelium, a gene expression signature of histological tumor grade also exists in the stroma, with high-grade tumors associated with increased expression of genes involved in immune response.Our results suggest that the tumor microenvironment participates in tumorigenesis even before tumor cells invade into stroma, and that it may play important roles in the transition from preinvasive to invasive growth. The immune cells in the tumor stroma may be exploited by the malignant epithelial cells in high-grade tumors for aggressive invasive growth.The tumor microenvironment or the stroma hosting the malignant breast epithelial cells is comprised of multiple cell types, including fibroblasts, myoepithelial cells, endothelial cells and various immune cells [1-4]. One prevailing view is that tumor-associated stroma is activated by the malignant epithelial cells to foster tumor growth – for example, by secreting growth factors, increasing angiogenesis, and facilitating cell migration, ultimately resulting in metastasis to remote organ sites [
p66 Shc and tyrosine-phosphorylated Shc in primary breast tumors identify patients likely to relapse despite tamoxifen therapy
A Raymond Frackelton, Li Lu, Pamela A Davol, Robert Bagdasaryan, Laurie J Hafer, Dennis C Sgroi
Breast Cancer Research , 2006, DOI: 10.1186/bcr1631
Abstract: Immunohistochemical analyses of PY-Shc and p66 Shc were performed on archival primary breast cancer tumors from a population-based cohort (60 patients, 9 relapses) and, for validation, an independent external cohort (31 patients, 13 relapses) in which all patients received tamoxifen as a sole systemic adjuvant prior to relapse.By univariate and multivariate analyses, the Shc proteins were very strong and independent predictors of treatment failure in both the population-based cohort (interquartile hazard ratio = 8.3, 95% confidence interval [CI] 1.8 to 38, P = 0.007) and the validating cohort (interquartile relative risk = 12.1, 95% CI 1.7 to 86, P = 0.013).These results suggest that the levels of PY-Shc and p66 Shc proteins in primary tumors identify patients at high risk for relapsing despite treatment with tamoxifen and therefore with further validation may be useful in guiding clinicians to select alternative adjuvant treatment strategies.Tamoxifen, a partial estrogen receptor (ER) antagonist and the most widely prescribed drug for the treatment of ER-positive breast cancer, provides a 40% to 50% decrease in the rate of relapse in this group of patients [1]. The precise mechanism of tamoxifen action is unknown; however, binding of tamoxifen to the ER inhibits estradiol activation of the receptor and ER-dependent proliferation and promotes cellular apoptosis [2,3]. Despite the objective responses or disease stabilization achieved with tamoxifen treatment in more than 50% of patients with previously untreated metastatic breast cancer [4], nearly 100% of metastatic patients and up to 40% of patients receiving adjuvant tamoxifen will relapse and die [1]. Clearly, there is a need to identify those patients who are at increased risk of relapse even though tamoxifen therapy has been administered: such patients would be candidates for chemotherapy or alternative adjuvant therapies such as Herceptin? (Genentech, Inc., South San Francisco, CA, USA) and tyrosine kinase inh
Gene Expression Profiles of Beta-Cell Enriched Tissue Obtained by Laser Capture Microdissection from Subjects with Type 2 Diabetes
Lorella Marselli,Jeffrey Thorne,Sonika Dahiya,Dennis C. Sgroi,Arun Sharma,Susan Bonner-Weir,Piero Marchetti,Gordon C. Weir
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0011499
Abstract: Changes in gene expression in pancreatic beta-cells from type 2 diabetes (T2D) should provide insights into their abnormal insulin secretion and turnover.
Protective Unfolded Protein Response in Human Pancreatic Beta Cells Transplanted into Mice
Jeffrey Kennedy,Hitoshi Katsuta,Min-Ho Jung,Lorella Marselli,Allison B. Goldfine,Ulysses J. Balis,Dennis Sgroi,Susan Bonner-Weir,Gordon C. Weir
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0011211
Abstract: There is great interest about the possible contribution of ER stress to the apoptosis of pancreatic beta cells in the diabetic state and with islet transplantation.
Identification and Rational Redesign of Peptide Ligands to CRIP1, A Novel Biomarker for Cancers
Jihua Hao ,Adrian W. R. Serohijos ,Gail Newton,Gina Tassone,Zuncai Wang,Dennis C. Sgroi,Nikolay V. Dokholyan ,James P. Basilion
PLOS Computational Biology , 2008, DOI: 10.1371/journal.pcbi.1000138
Abstract: Cysteine-rich intestinal protein 1 (CRIP1) has been identified as a novel marker for early detection of cancers. Here we report on the use of phage display in combination with molecular modeling to identify a high-affinity ligand for CRIP1. Panning experiments using a circularized C7C phage library yielded several consensus sequences with modest binding affinities to purified CRIP1. Two sequence motifs, A1 and B5, having the highest affinities for CRIP1, were chosen for further study. With peptide structure information and the NMR structure of CRIP1, the higher-affinity A1 peptide was computationally redesigned, yielding a novel peptide, A1M, whose affinity was predicted to be much improved. Synthesis of the peptide and saturation and competitive binding studies demonstrated approximately a 10–28-fold improvement in the affinity of A1M compared to that of either A1 or B5 peptide. These techniques have broad application to the design of novel ligand peptides.
Induction of Stable Drug Resistance in Human Breast Cancer Cells Using a Combinatorial Zinc Finger Transcription Factor Library
Jeongeun Lee, Andrew S. Hirsh, Ben S. Wittner, Morgan L. Maeder, Rajasekhar Singavarapu, Magdalena Lang, Sailajah Janarthanan, Ultan McDermott, Vijay Yajnik, Sridhar Ramaswamy, J. Keith Joung, Dennis C. Sgroi
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0021112
Abstract: Combinatorial libraries of artificial zinc-finger transcription factors (ZF-TFs) provide a robust tool for inducing and understanding various functional components of the cancer phenotype. Herein, we utilized combinatorial ZF-TF library technology to better understand how breast cancer cells acquire resistance to fulvestrant, a clinically important anti-endocrine therapeutic agent. From a diverse collection of nearly 400,000 different ZF-TFs, we isolated six ZF-TF library members capable of inducing stable, long-term anti-endocrine drug-resistance in two independent estrogen receptor-positive breast cancer cell lines. Comparative gene expression profile analysis of the six different ZF-TF-transduced breast cancer cell lines revealed five distinct clusters of differentially expressed genes. One cluster was shared among all 6 ZF-TF-transduced cell lines and therefore constituted a common fulvestrant-resistant gene expression signature. Pathway enrichment-analysis of this common fulvestrant resistant signature also revealed significant overlap with gene sets associated with an estrogen receptor-negative-like state and with gene sets associated with drug resistance to different classes of breast cancer anti-endocrine therapeutic agents. Enrichment-analysis of the four remaining unique gene clusters revealed overlap with myb-regulated genes. Finally, we also demonstrated that the common fulvestrant-resistant signature is associated with poor prognosis by interrogating five independent, publicly available human breast cancer gene expression datasets. Our results demonstrate that artificial ZF-TF libraries can be used successfully to induce stable drug-resistance in human cancer cell lines and to identify a gene expression signature that is associated with a clinically relevant drug-resistance phenotype.
Estrogen receptor positive breast cancers in BRCA1 mutation carriers: clinical risk factors and pathologic features
Nadine Tung, Yihong Wang, Laura C Collins, Jennifer Kaplan, Hailun Li, Rebecca Gelman, Amy H Comander, Bridget Gallagher, Katharina Fetten, Karen Krag, Kathryn A Stoeckert, Robert D Legare, Dennis Sgroi, Paula D Ryan, Judy E Garber, Stuart J Schnitt
Breast Cancer Research , 2010, DOI: 10.1186/bcr2478
Abstract: Clinical characteristics of BRCA1 carriers with 58 ER+ and 114 ER- first invasive breast cancers were compared. Pathologic features of BRCA1 ER+ cancers were compared to those of BRCA1 ER- cancers and to age-matched ER+ sporadic cancers.BRCA1 carriers aged ≥ 50 at diagnosis of first invasive breast cancer were more likely to have an ER+ cancer compared to those aged < 50 (57% vs 29%, P = 0.005). ER+ BRCA1 cancers were less likely than ER- BRCA1 cancers to have "BRCA-associated" features such as high mitotic activity, geographic necrosis/fibrotic focus, and pushing margins (RR 0.06, 0.22, 0.24; P < 0.001, 0.02, 0.03 respectively). When compared to sporadic ER+ cancers, ER+ BRCA1 cancers were more often of invasive ductal type (RR 2.4, P = 0.03), with a high mitotic rate (RR 5.0, P = 0.006) and absent or mild lymphocytic infiltrate (RR 10.2, P = 0.04).BRCA1 carriers who are older at first breast cancer diagnosis are more likely to have ER+ tumors than younger BRCA1 carriers. These ER+ cancers appear pathologically "intermediate" between ER- BRCA1 cancers and ER+ sporadic breast cancers raising the possibility that either some ER+ BRCA1 cancers are incidental or that there is a unique mechanism by which these cancers develop.Most breast cancers that occur in women with germline BRCA1 mutations are estrogen receptor-negative (ER-) and typically lack expression of progesterone receptor (PR) and human epidermal growth factor receptor (HER) 2 overexpression (so-called 'triple-negative' breast cancers) [1-8]. These BRCA1-associated ER-tumors are most often high-grade invasive ductal carcinomas with a high mitotic rate that frequently exhibit other characteristic pathologic features including a prominent lymphocytic infiltrate, pushing or circumscribed margins, and geographic areas of necrosis or a central fibrotic focus [3,9,10]. In addition, these tumors often express 'basal' biomarkers and most cluster within the 'basal-like' group in gene expression profiling studies [7,
Sequencing of Candidate Chromosome Instability Genes in Endometrial Cancers Reveals Somatic Mutations in ESCO1, CHTF18, and MRE11A
Jessica C. Price, Lana M. Pollock, Meghan L. Rudd, Sarah K. Fogoros, Hassan Mohamed, Christin L. Hanigan, Matthieu Le Gallo, NIH Intramural Sequencing Center (NISC) Comparative Sequencing Program, Suiyuan Zhang, Pedro Cruz, Praveen F. Cherukuri, Nancy F. Hansen, Kirk J. McManus, Andrew K. Godwin, Dennis C. Sgroi, James C. Mullikin, Maria J. Merino, Philip Hieter, Daphne W. Bell
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0063313
Abstract: Most endometrial cancers can be classified histologically as endometrioid, serous, or clear cell. Non-endometrioid endometrial cancers (NEECs; serous and clear cell) are the most clinically aggressive of the three major histotypes and are characterized by aneuploidy, a feature of chromosome instability. The genetic alterations that underlie chromosome instability in endometrial cancer are poorly understood. In the present study, we used Sanger sequencing to search for nucleotide variants in the coding exons and splice junctions of 21 candidate chromosome instability genes, including 19 genes implicated in sister chromatid cohesion, from 24 primary, microsatellite-stable NEECs. Somatic mutations were verified by sequencing matched normal DNAs. We subsequently resequenced mutated genes from 41 additional NEECs as well as 42 endometrioid ECs (EECs). We uncovered nonsynonymous somatic mutations in ESCO1, CHTF18, and MRE11A in, respectively, 3.7% (4 of 107), 1.9% (2 of 107), and 1.9% (2 of 107) of endometrial tumors. Overall, 7.7% (5 of 65) of NEECs and 2.4% (1 of 42) of EECs had somatically mutated one or more of the three genes. A subset of mutations are predicted to impact protein function. The co-occurrence of somatic mutations in ESCO1 and CHTF18 was statistically significant (P = 0.0011, two-tailed Fisher's exact test). This is the first report of somatic mutations within ESCO1 and CHTF18 in endometrial tumors and of MRE11A mutations in microsatellite-stable endometrial tumors. Our findings warrant future studies to determine whether these mutations are driver events that contribute to the pathogenesis of endometrial cancer.
Prevalence and predictors of loss of wild type BRCA1 in estrogen receptor positive and negative BRCA1-associated breast cancers
Nadine Tung, Alexander Miron, Stuart J Schnitt, Shiva Gautam, Katharina Fetten, Jennifer Kaplan, Yosuf Yassin, Ayodele Buraimoh, Ji-Young Kim, Attila M Szász, Ruiyang Tian, Zhigang C Wang, Laura C Collins, Jane Brock, Karen Krag, Robert D Legare, Dennis Sgroi, Paula D Ryan, Daniel P Silver, Judy E Garber, Andrea L Richardson
Breast Cancer Research , 2010, DOI: 10.1186/bcr2776
Abstract: 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.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 ∞).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.Sixty-four to 90% of breast cancers that occur in BRCA1 mutation carriers (BRCA1 carriers) are estrogen receptor-negative (ER-), progesterone receptor-negative (PR-) and lack HER2 protein overexpression and gene amplification, so called "triple negative" breast cancers [1-8]. These BRCA1-associated ER- tumors typically demonstrate characteristic pathologic features which include high grade ductal histology, a high mitotic rate, a prominent lymphocytic infiltrate
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