24 results on '"Crosariol M."'
Search Results
2. Cyclin D1 promotes androgen-dependent DNA damage repair in prostate cancer cells
- Author
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Casimiro M., Di Sante G., Ju X., Li Z., Chen K., Crosariol M., Yaman I., Gormley M., Meng H., Lisanti M., and Pestell R.
- Abstract
© 2016 American Association for Cancer Research.Therapy resistance and poor outcome in prostate cancer is associated with increased expression of cyclin D1. Androgens promoteDNAdouble-strand break repair to reduceDNAdamage, and cyclin D1 was also shown to enhance DNA damage repair (DDR). In this study, we investigated the significance of cyclin D1 in androgen-induced DDR using established prostate cancer cells and prostate tissues from cyclin D1 knockout mice. We demonstrate that endogenous cyclin D1 further diminished the dihydrotestosterone (DHT)-dependent reduction of γH2AX foci in vitro. We also show that cyclin D1 was required for the androgen-dependent DNA damage response both in vitro and in vivo. Furthermore, cyclin D1 was required for androgenenhanced DDR and radioresistance of prostate cancer cells. Moreover, microarray analysis of primary prostate epithelial cells from cyclin D1-deficient and wild-type mice demonstrated that most of the DHT-dependent gene expression changes are also cyclin D1 dependent. Collectively, our findings suggest that the hormonemediated recruitment of cyclin D1 to sites of DDR may facilitate the resistance of prostate cancer cells to DNA damage therapies and highlight the need to explore other therapeutic approaches in prostate cancer to prevent or overcome drug resistance.
- Published
- 2016
3. Abstract P5-06-09: Cyclin d1 binding to chromatin and the induction of chromosomal instability requires the fuzzy domain
- Author
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Pestell, RG, primary, Di Sante, G, additional, Di Rocco, A, additional, Pupo, C, additional, Crosariol, M, additional, Tompa, P, additional, Tantos, A, additional, Wang, C, additional, Yu, Z, additional, Vadlamudi, R, additional, Mann, M, additional, and Casimiro, MC, additional
- Published
- 2017
- Full Text
- View/download PDF
4. Kinase-independent role of cyclin D1 in chromosomal instability and mammary tumorigenesis
- Author
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Casimiro M., Di Sante G., Crosariol M., Loro E., Dampier W., Ertel A., Yu Z., Saria E., Papanikolaou A., Li Z., Wang C., Addya S., Lisanti M., Fortina P., Cardiff R., Tozeren A., Knudsen E., Arnold A., and Pestell R.
- Subjects
Breast cancer ,Cyclin D1 ,Chromosomal instability - Abstract
Cyclin D1 is an important molecular driver of human breast cancer but better understanding of its oncogenic mechanisms is needed, especially to enhance efforts in targeted therapeutics. Currently, pharmaceutical initiatives to inhibit cyclin D1 are focused on the catalytic component since the transforming capacity is thought to reside in the cyclin D1/CDK activity. We initiated the following study to directly test the oncogenic potential of catalytically inactive cyclin D1 in an in vivo mouse model that is relevant to breast cancer. Herein, transduction of cyclin D1-/- mouse embryonic fibroblasts (MEFs) with the kinase dead KE mutant of cyclin D1 led to aneuploidy, abnormalities in mitotic spindle formation, autosome amplification, and chromosomal instability (CIN) by gene expression profiling. Acute transgenic expression of either cyclin D1WT or cyclin D1KE in the mammary gland was sufficient to induce a high CIN score within 7 days. Sustained expression of cyclin D1KE induced mammary adenocarcinoma with similar kinetics to that of the wild-type cyclin D1. ChIP-Seq studies demonstrated recruitment of cyclin D1WT and cyclin D1KE to the genes governing CIN. We conclude that the CDK-activating function of cyclin D1 is not necessary to induce either chromosomal instability or mammary tumorigenesis.
- Published
- 2015
5. Abstract P5-07-06: Kinase-independent role of cyclin D1 in chromosomal instability and mammary tumorigenesis
- Author
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Pestell, RG, primary, Casimiro, MC, additional, Crosariol, M, additional, Loro, E, additional, Dampier, W, additional, Di Sante, G, additional, Ertel, A, additional, Yu, Z, additional, Saria, EA, additional, Papanikolaou, A, additional, Li, Z, additional, Wang, C, additional, Addya, S, additional, Lisanti, MP, additional, Fortina, P, additional, Tozeren, A, additional, Knudsen, ES, additional, and Arnold, A, additional
- Published
- 2013
- Full Text
- View/download PDF
6. Cyclins and Cell Cycle Control in Cancer and Disease
- Author
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Casimiro, M. C., primary, Crosariol, M., additional, Loro, E., additional, Li, Z., additional, and Pestell, R. G., additional
- Published
- 2012
- Full Text
- View/download PDF
7. Erratum: ChIP sequencing of cyclin D1 reveals a transcriptional role in chromosomal instability in mice (J Clin Invest. (2013) 123:5 (2332) 10.1172/JCI70042)
- Author
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Casimiro, M. C., Crosariol, M., Emanuele Loro, Ertel, A., Yu, Z., Dampier, W., Saria, E. A., Papanikolaou, A., Stanek, T. J., Li, Z., Wang, C., Fortina, P., Addya, S., Tozeren, A., Knudsen, E. S., Arnold, A., and Pestell, R. G.
8. Cyclin D1 promotes androgen-dependent DNA damage repair in prostate cancer cells
- Author
-
Casimiro M., Di Sante G., Ju X., Li Z., Chen K., Crosariol M., Yaman I., Gormley M., Meng H., Lisanti M., Pestell R., Casimiro M., Di Sante G., Ju X., Li Z., Chen K., Crosariol M., Yaman I., Gormley M., Meng H., Lisanti M., and Pestell R.
- Abstract
© 2016 American Association for Cancer Research.Therapy resistance and poor outcome in prostate cancer is associated with increased expression of cyclin D1. Androgens promoteDNAdouble-strand break repair to reduceDNAdamage, and cyclin D1 was also shown to enhance DNA damage repair (DDR). In this study, we investigated the significance of cyclin D1 in androgen-induced DDR using established prostate cancer cells and prostate tissues from cyclin D1 knockout mice. We demonstrate that endogenous cyclin D1 further diminished the dihydrotestosterone (DHT)-dependent reduction of γH2AX foci in vitro. We also show that cyclin D1 was required for the androgen-dependent DNA damage response both in vitro and in vivo. Furthermore, cyclin D1 was required for androgenenhanced DDR and radioresistance of prostate cancer cells. Moreover, microarray analysis of primary prostate epithelial cells from cyclin D1-deficient and wild-type mice demonstrated that most of the DHT-dependent gene expression changes are also cyclin D1 dependent. Collectively, our findings suggest that the hormonemediated recruitment of cyclin D1 to sites of DDR may facilitate the resistance of prostate cancer cells to DNA damage therapies and highlight the need to explore other therapeutic approaches in prostate cancer to prevent or overcome drug resistance.
9. Cyclin D1 promotes androgen-dependent DNA damage repair in prostate cancer cells
- Author
-
Casimiro M., Di Sante G., Ju X., Li Z., Chen K., Crosariol M., Yaman I., Gormley M., Meng H., Lisanti M., Pestell R., Casimiro M., Di Sante G., Ju X., Li Z., Chen K., Crosariol M., Yaman I., Gormley M., Meng H., Lisanti M., and Pestell R.
- Abstract
© 2016 American Association for Cancer Research.Therapy resistance and poor outcome in prostate cancer is associated with increased expression of cyclin D1. Androgens promoteDNAdouble-strand break repair to reduceDNAdamage, and cyclin D1 was also shown to enhance DNA damage repair (DDR). In this study, we investigated the significance of cyclin D1 in androgen-induced DDR using established prostate cancer cells and prostate tissues from cyclin D1 knockout mice. We demonstrate that endogenous cyclin D1 further diminished the dihydrotestosterone (DHT)-dependent reduction of γH2AX foci in vitro. We also show that cyclin D1 was required for the androgen-dependent DNA damage response both in vitro and in vivo. Furthermore, cyclin D1 was required for androgenenhanced DDR and radioresistance of prostate cancer cells. Moreover, microarray analysis of primary prostate epithelial cells from cyclin D1-deficient and wild-type mice demonstrated that most of the DHT-dependent gene expression changes are also cyclin D1 dependent. Collectively, our findings suggest that the hormonemediated recruitment of cyclin D1 to sites of DDR may facilitate the resistance of prostate cancer cells to DNA damage therapies and highlight the need to explore other therapeutic approaches in prostate cancer to prevent or overcome drug resistance.
10. Kinase-independent role of cyclin D1 in chromosomal instability and mammary tumorigenesis
- Author
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Casimiro M., Di Sante G., Crosariol M., Loro E., Dampier W., Ertel A., Yu Z., Saria E., Papanikolaou A., Li Z., Wang C., Addya S., Lisanti M., Fortina P., Cardiff R., Tozeren A., Knudsen E., Arnold A., Pestell R., Casimiro M., Di Sante G., Crosariol M., Loro E., Dampier W., Ertel A., Yu Z., Saria E., Papanikolaou A., Li Z., Wang C., Addya S., Lisanti M., Fortina P., Cardiff R., Tozeren A., Knudsen E., Arnold A., and Pestell R.
- Abstract
Cyclin D1 is an important molecular driver of human breast cancer but better understanding of its oncogenic mechanisms is needed, especially to enhance efforts in targeted therapeutics. Currently, pharmaceutical initiatives to inhibit cyclin D1 are focused on the catalytic component since the transforming capacity is thought to reside in the cyclin D1/CDK activity. We initiated the following study to directly test the oncogenic potential of catalytically inactive cyclin D1 in an in vivo mouse model that is relevant to breast cancer. Herein, transduction of cyclin D1-/- mouse embryonic fibroblasts (MEFs) with the kinase dead KE mutant of cyclin D1 led to aneuploidy, abnormalities in mitotic spindle formation, autosome amplification, and chromosomal instability (CIN) by gene expression profiling. Acute transgenic expression of either cyclin D1WT or cyclin D1KE in the mammary gland was sufficient to induce a high CIN score within 7 days. Sustained expression of cyclin D1KE induced mammary adenocarcinoma with similar kinetics to that of the wild-type cyclin D1. ChIP-Seq studies demonstrated recruitment of cyclin D1WT and cyclin D1KE to the genes governing CIN. We conclude that the CDK-activating function of cyclin D1 is not necessary to induce either chromosomal instability or mammary tumorigenesis.
11. Kinase-independent role of cyclin D1 in chromosomal instability and mammary tumorigenesis
- Author
-
Casimiro M., Di Sante G., Crosariol M., Loro E., Dampier W., Ertel A., Yu Z., Saria E., Papanikolaou A., Li Z., Wang C., Addya S., Lisanti M., Fortina P., Cardiff R., Tozeren A., Knudsen E., Arnold A., Pestell R., Casimiro M., Di Sante G., Crosariol M., Loro E., Dampier W., Ertel A., Yu Z., Saria E., Papanikolaou A., Li Z., Wang C., Addya S., Lisanti M., Fortina P., Cardiff R., Tozeren A., Knudsen E., Arnold A., and Pestell R.
- Abstract
Cyclin D1 is an important molecular driver of human breast cancer but better understanding of its oncogenic mechanisms is needed, especially to enhance efforts in targeted therapeutics. Currently, pharmaceutical initiatives to inhibit cyclin D1 are focused on the catalytic component since the transforming capacity is thought to reside in the cyclin D1/CDK activity. We initiated the following study to directly test the oncogenic potential of catalytically inactive cyclin D1 in an in vivo mouse model that is relevant to breast cancer. Herein, transduction of cyclin D1-/- mouse embryonic fibroblasts (MEFs) with the kinase dead KE mutant of cyclin D1 led to aneuploidy, abnormalities in mitotic spindle formation, autosome amplification, and chromosomal instability (CIN) by gene expression profiling. Acute transgenic expression of either cyclin D1WT or cyclin D1KE in the mammary gland was sufficient to induce a high CIN score within 7 days. Sustained expression of cyclin D1KE induced mammary adenocarcinoma with similar kinetics to that of the wild-type cyclin D1. ChIP-Seq studies demonstrated recruitment of cyclin D1WT and cyclin D1KE to the genes governing CIN. We conclude that the CDK-activating function of cyclin D1 is not necessary to induce either chromosomal instability or mammary tumorigenesis.
12. A cyclin D1 intrinsically disordered domain accesses modified histone motifs to govern gene transcription.
- Author
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Jiao X, Di Sante G, Casimiro MC, Tantos A, Ashton AW, Li Z, Quach Y, Bhargava D, Di Rocco A, Pupo C, Crosariol M, Lazar T, Tompa P, Wang C, Yu Z, Zhang Z, Aldaaysi K, Vadlamudi R, Mann M, Skordalakes E, Kossenkov A, Du Y, and Pestell RG
- Abstract
The essential G
1 -cyclin, CCND1, is frequently overexpressed in cancer, contributing to tumorigenesis by driving cell-cycle progression. D-type cyclins are rate-limiting regulators of G1 -S progression in mammalian cells via their ability to bind and activate CDK4 and CDK6. In addition, cyclin D1 conveys kinase-independent transcriptional functions of cyclin D1. Here we report that cyclin D1 associates with H2BS14 via an intrinsically disordered domain (IDD). The same region of cyclin D1 was necessary for the induction of aneuploidy, induction of the DNA damage response, cyclin D1-mediated recruitment into chromatin, and CIN gene transcription. In response to DNA damage H2BS14 phosphorylation occurs, resulting in co-localization with γH2AX in DNA damage foci. Cyclin D1 ChIP seq and γH2AX ChIP seq revealed ~14% overlap. As the cyclin D1 IDD functioned independently of the CDK activity to drive CIN, the IDD domain may provide a rationale new target to complement CDK-extinction strategies., (© 2024. The Author(s).)- Published
- 2024
- Full Text
- View/download PDF
13. Adeno-Associated Virus Vector-Mediated Expression of Antirespiratory Syncytial Virus Antibody Prevents Infection in Mouse Airways.
- Author
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Tycko J, Adam VS, Crosariol M, Ohlstein J, Sanmiguel J, Tretiakova AP, Roy S, Worgall S, Wilson JM, and Limberis MP
- Subjects
- Animals, Antiviral Agents, Lung, Mice, Mice, Inbred BALB C, Palivizumab therapeutic use, Dependovirus genetics, Respiratory Syncytial Virus Infections drug therapy, Respiratory Syncytial Virus Infections prevention & control
- Abstract
Infants and older adults are especially vulnerable to infection by respiratory syncytial virus (RSV), which can cause significant illness and irreparable damage to the lower respiratory tract and for which an effective vaccine is not readily available. Palivizumab, a recombinant monoclonal antibody (mAb), is an approved therapeutic for RSV infection for use in high-risk infants only. Due to several logistical issues, including cost of goods and scale-up limitations, palivizumab is not approved for other populations that are vulnerable to severe RSV infections, such as older adults. In this study, we demonstrate that intranasal delivery of adeno-associated virus serotype 9 (AAV9) vector expressing palivizumab or motavizumab, a second-generation version of palivizumab, significantly reduced the viral load in the lungs of the BALB/c mouse model of RSV infection. Notably, we demonstrate that AAV9 vector-mediated prophylaxis against RSV was effective despite the presence of serum-circulating neutralizing AAV9 antibodies. These findings substantiate the feasibility of repeatedly administering AAV9 vector to the airway for seasonal prophylaxis against RSV, thereby expanding the application of vectored delivery of mAbs as an effective prophylaxis strategy against various airborne viruses.
- Published
- 2021
- Full Text
- View/download PDF
14. Preclinical assessment of an optimized AAV-FVIII vector in mice and non-human primates for the treatment of hemophilia A.
- Author
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Elkouby L, Armour SM, Toso R, DiPietro M, Davidson RJ, Nguyen GN, Willet M, Kutza S, Silverberg J, Frick J, Crosariol M, Wang Y, Wang C, High KA, Sabatino DE, and Anguela XM
- Abstract
Extensive clinical data from liver-mediated gene therapy trials have shown that dose-dependent immune responses against the vector capsid may impair or even preclude transgene expression if not managed successfully with prompt immune suppression. The goal of this preclinical study was to generate an adeno-associated viral (AAV) vector capable of expressing therapeutic levels of B-domain deleted factor VIII (FVIII) at the lowest possible vector dose to minimize the potential Risk of a capsid-mediated immune response in the clinical setting. Here, we describe the studies that identified the investigational agent SPK-8011 , currently being evaluated in a phase 1/2 study (NCT03003533) in individuals with hemophilia A. In particular, the potency of our second-generation expression cassettes was evaluated in mice and in non-human primates using two different bioengineered capsids (AAV-Spark100 and AAV-Spark200). At 2 weeks after gene transfer, primates transduced with 2 × 10
12 vg/kg AAV-Spark100-FVIII or AAV-Spark200-FVIII expressed FVIII antigen levels of 13% ± 2% and 22% ± 6% of normal, respectively. Collectively, these preclinical results validate the feasibility of lowering the AAV capsid dose for a gene-based therapeutic approach for hemophilia A to a dose level orders of magnitude lower than the first-generation vectors in the clinic., Competing Interests: S.M.A., R.T., M.D., M.W., S.K., J.S., J.F., M.C., Y.W., C.W., L.E., K.A.H., and X.M.A. are current or former employees of Spark Therapeutics. K.A.H., X.M.A., L.E., and D.E.S. are inventors on issued and pending patents related to AAV viral vectors for which they have received royalty payments., (© 2021 The Authors.)- Published
- 2021
- Full Text
- View/download PDF
15. Hepatic expression of GAA results in enhanced enzyme bioavailability in mice and non-human primates.
- Author
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Costa-Verdera H, Collaud F, Riling CR, Sellier P, Nordin JML, Preston GM, Cagin U, Fabregue J, Barral S, Moya-Nilges M, Krijnse-Locker J, van Wittenberghe L, Daniele N, Gjata B, Cosette J, Abad C, Simon-Sola M, Charles S, Li M, Crosariol M, Antrilli T, Quinn WJ 3rd, Gross DA, Boyer O, Anguela XM, Armour SM, Colella P, Ronzitti G, and Mingozzi F
- Subjects
- Animals, Autophagy, Enzyme Replacement Therapy, Female, Glycogen Storage Disease Type II therapy, Liver enzymology, Male, Mice, alpha-Glucosidases genetics, Glycogen Storage Disease Type II enzymology, alpha-Glucosidases metabolism
- Abstract
Pompe disease (PD) is a severe neuromuscular disorder caused by deficiency of the lysosomal enzyme acid alpha-glucosidase (GAA). PD is currently treated with enzyme replacement therapy (ERT) with intravenous infusions of recombinant human GAA (rhGAA). Although the introduction of ERT represents a breakthrough in the management of PD, the approach suffers from several shortcomings. Here, we developed a mouse model of PD to compare the efficacy of hepatic gene transfer with adeno-associated virus (AAV) vectors expressing secretable GAA with long-term ERT. Liver expression of GAA results in enhanced pharmacokinetics and uptake of the enzyme in peripheral tissues compared to ERT. Combination of gene transfer with pharmacological chaperones boosts GAA bioavailability, resulting in improved rescue of the PD phenotype. Scale-up of hepatic gene transfer to non-human primates also successfully results in enzyme secretion in blood and uptake in key target tissues, supporting the ongoing clinical translation of the approach., (© 2021. The Author(s).)
- Published
- 2021
- Full Text
- View/download PDF
16. Adeno-Associated Virus Serotype 9-Expressed ZMapp in Mice Confers Protection Against Systemic and Airway-Acquired Ebola Virus Infection.
- Author
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Limberis MP, Tretiakova A, Nambiar K, Wong G, Racine T, Crosariol M, Xiangguo Q, Kobinger G, and Wilson JM
- Subjects
- Animals, Antibodies, Monoclonal genetics, Disease Models, Animal, Female, Genetic Therapy methods, Hemorrhagic Fever, Ebola immunology, Immunologic Factors genetics, Mice, Inbred BALB C, Transduction, Genetic, Treatment Outcome, Antibodies, Monoclonal biosynthesis, Dependovirus genetics, Drug Carriers, Gene Expression, Hemorrhagic Fever, Ebola prevention & control, Immunologic Factors biosynthesis
- Abstract
Adeno-associated viral vectors can be used as a platform for delivering biological countermeasures against pandemic and biological threats. We show that vector delivery of two antibody components of the ZMapp product is effective in mice against systemic and airway challenge with a mouse-adapted strain of Ebola virus. This platform provides a generic manufacturing solution and overcomes some of the delivery challenges associated with repeated administration of the protective protein., (© The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.)
- Published
- 2016
- Full Text
- View/download PDF
17. Cyclin D1 Promotes Androgen-Dependent DNA Damage Repair in Prostate Cancer Cells.
- Author
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Casimiro MC, Di Sante G, Ju X, Li Z, Chen K, Crosariol M, Yaman I, Gormley M, Meng H, Lisanti MP, and Pestell RG
- Subjects
- Animals, Cell Line, Tumor, Cyclin D1 biosynthesis, Histones genetics, Histones metabolism, Humans, Male, Mice, Mice, Knockout, Neoplasms, Hormone-Dependent metabolism, Prostatic Neoplasms metabolism, Transfection, Cyclin D1 genetics, DNA Damage, DNA Repair, Dihydrotestosterone pharmacology, Neoplasms, Hormone-Dependent genetics, Prostatic Neoplasms genetics
- Abstract
Therapy resistance and poor outcome in prostate cancer is associated with increased expression of cyclin D1. Androgens promote DNA double-strand break repair to reduce DNA damage, and cyclin D1 was also shown to enhance DNA damage repair (DDR). In this study, we investigated the significance of cyclin D1 in androgen-induced DDR using established prostate cancer cells and prostate tissues from cyclin D1 knockout mice. We demonstrate that endogenous cyclin D1 further diminished the dihydrotestosterone (DHT)-dependent reduction of γH2AX foci in vitro. We also show that cyclin D1 was required for the androgen-dependent DNA damage response both in vitro and in vivo. Furthermore, cyclin D1 was required for androgen-enhanced DDR and radioresistance of prostate cancer cells. Moreover, microarray analysis of primary prostate epithelial cells from cyclin D1-deficient and wild-type mice demonstrated that most of the DHT-dependent gene expression changes are also cyclin D1 dependent. Collectively, our findings suggest that the hormone-mediated recruitment of cyclin D1 to sites of DDR may facilitate the resistance of prostate cancer cells to DNA damage therapies and highlight the need to explore other therapeutic approaches in prostate cancer to prevent or overcome drug resistance., (©2015 American Association for Cancer Research.)
- Published
- 2016
- Full Text
- View/download PDF
18. Kinase-independent role of cyclin D1 in chromosomal instability and mammary tumorigenesis.
- Author
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Casimiro MC, Di Sante G, Crosariol M, Loro E, Dampier W, Ertel A, Yu Z, Saria EA, Papanikolaou A, Li Z, Wang C, Addya S, Lisanti MP, Fortina P, Cardiff RD, Tozeren A, Knudsen ES, Arnold A, and Pestell RG
- Subjects
- Amino Acid Substitution, Aneuploidy, Animals, Catalytic Domain genetics, Cell Transformation, Neoplastic genetics, Cells, Cultured, Centrosome ultrastructure, Chromosomal Instability genetics, Cyclin D1 deficiency, Cyclin D1 genetics, Female, Fibroblasts, Genes, bcl-1, Humans, Mammary Tumor Virus, Mouse physiology, Mice, Mice, Knockout, Mice, Transgenic, Mutation, Piperazines pharmacology, Pyridines pharmacology, Recombinant Fusion Proteins metabolism, Spindle Apparatus ultrastructure, Transduction, Genetic, Adenocarcinoma genetics, Cyclin D1 physiology, Mammary Neoplasms, Experimental genetics
- Abstract
Cyclin D1 is an important molecular driver of human breast cancer but better understanding of its oncogenic mechanisms is needed, especially to enhance efforts in targeted therapeutics. Currently, pharmaceutical initiatives to inhibit cyclin D1 are focused on the catalytic component since the transforming capacity is thought to reside in the cyclin D1/CDK activity. We initiated the following study to directly test the oncogenic potential of catalytically inactive cyclin D1 in an in vivo mouse model that is relevant to breast cancer. Herein, transduction of cyclin D1(-/-) mouse embryonic fibroblasts (MEFs) with the kinase dead KE mutant of cyclin D1 led to aneuploidy, abnormalities in mitotic spindle formation, autosome amplification, and chromosomal instability (CIN) by gene expression profiling. Acute transgenic expression of either cyclin D1(WT) or cyclin D1(KE) in the mammary gland was sufficient to induce a high CIN score within 7 days. Sustained expression of cyclin D1(KE) induced mammary adenocarcinoma with similar kinetics to that of the wild-type cyclin D1. ChIP-Seq studies demonstrated recruitment of cyclin D1(WT) and cyclin D1(KE) to the genes governing CIN. We conclude that the CDK-activating function of cyclin D1 is not necessary to induce either chromosomal instability or mammary tumorigenesis.
- Published
- 2015
- Full Text
- View/download PDF
19. Adeno-associated virus 9-mediated airway expression of antibody protects old and immunodeficient mice against influenza virus.
- Author
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Adam VS, Crosariol M, Kumar S, Ge MQ, Czack SE, Roy S, Haczku A, Tretiakova A, Wilson JM, and Limberis MP
- Subjects
- Administration, Intranasal, Animals, Antibodies, Neutralizing genetics, Antibodies, Neutralizing immunology, Antibodies, Viral genetics, Dependovirus genetics, Disease Models, Animal, Female, Immunocompromised Host, Mice, Inbred BALB C, Mice, SCID, Survival Analysis, Treatment Outcome, Antibodies, Viral immunology, Biological Therapy methods, Dependovirus growth & development, Drug Carriers administration & dosage, Immunization, Passive methods, Influenza A Virus, H1N1 Subtype immunology, Orthomyxoviridae Infections prevention & control
- Abstract
Influenza causes serious and sometimes fatal disease in individuals at risk due to advanced age or immunodeficiencies. Despite progress in the development of seasonal influenza vaccines, vaccine efficacy in elderly and immunocompromised individuals remains low. We recently developed a passive immunization strategy using an adeno-associated virus (AAV) vector to deliver a neutralizing anti-influenza antibody at the site of infection, the nasal airways. Here we show that young, old, and immunodeficient (severe combined immunodeficient [SCID]) mice that were treated intranasally with AAV9 vector expressing a modified version of the broadly neutralizing anti-influenza antibody FI6 were protected and exhibited no signs of disease following an intranasal challenge with the mouse-adapted H1N1 influenza strain A/Puerto Rico/8/1934(H1N1) (PR8) (Mt. Sinai strain). Nonvaccinated mice succumbed to the PR8 challenge due to severe weight loss. We propose that airway-directed AAV9 passive immunization against airborne infectious agents may be beneficial in elderly and immunocompromised patients, for whom there still exists an unmet need for effective vaccination against influenza., (Copyright © 2014, American Society for Microbiology. All Rights Reserved.)
- Published
- 2014
- Full Text
- View/download PDF
20. Identification of a cyclin D1 network in prostate cancer that antagonizes epithelial-mesenchymal restraint.
- Author
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Ju X, Casimiro MC, Gormley M, Meng H, Jiao X, Katiyar S, Crosariol M, Chen K, Wang M, Quong AA, Lisanti MP, Ertel A, and Pestell RG
- Subjects
- Animals, Cell Line, Tumor, Cell Proliferation, Disease Progression, Disease-Free Survival, Gene Deletion, Humans, Male, Mice, Mice, Transgenic, Oligonucleotide Array Sequence Analysis, PTEN Phosphohydrolase metabolism, Prognosis, Recurrence, Signal Transduction, Treatment Outcome, Cyclin D1 physiology, Epithelial-Mesenchymal Transition, Gene Expression Regulation, Neoplastic, Prostatic Neoplasms metabolism
- Abstract
Improved clinical management of prostate cancer has been impeded by an inadequate understanding of molecular genetic elements governing tumor progression. Gene signatures have provided improved prognostic indicators of human prostate cancer. The TGF-β/BMP-SMAD4 signaling pathway, which induces epithelial-mesenchymal transition (EMT), is known to constrain prostate cancer progression induced by Pten deletion. Herein, cyclin D1 inactivation reduced cellular proliferation in the murine prostate in vivo and in isogenic oncogene-transformed prostate cancer cell lines. The in vivo cyclin D1-mediated molecular signature predicted poor outcome of recurrence-free survival for patients with prostate cancer (K-means HR, 3.75, P = 0.02) and demonstrated that endogenous cyclin D1 restrains TGF-β, Snail, Twist, and Goosecoid signaling. Endogenous cyclin D1 enhanced Wnt and ES cell gene expression and expanded a prostate stem cell population. In chromatin immunoprecipitation sequencing, cyclin D1 occupied genes governing stem cell expansion and induced their transcription. The coordination of EMT restraining and stem cell expanding gene expression by cyclin D1 in the prostate may contribute to its strong prognostic value for poor outcome in biochemical-free recurrence in human prostate cancer.
- Published
- 2014
- Full Text
- View/download PDF
21. Genetic ablation of Cav1 differentially affects melanoma tumor growth and metastasis in mice: role of Cav1 in Shh heterotypic signaling and transendothelial migration.
- Author
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Capozza F, Trimmer C, Castello-Cros R, Katiyar S, Whitaker-Menezes D, Follenzi A, Crosariol M, Llaverias G, Sotgia F, Pestell RG, and Lisanti MP
- Subjects
- Animals, Caveolin 1 genetics, Caveolin 1 metabolism, Caveolin 2 deficiency, Caveolin 2 metabolism, Cell Growth Processes genetics, Coculture Techniques, Cytokines metabolism, Female, Fibroblasts metabolism, Fibroblasts pathology, Human Umbilical Vein Endothelial Cells metabolism, Human Umbilical Vein Endothelial Cells pathology, Humans, Lung Neoplasms genetics, Lung Neoplasms metabolism, Lung Neoplasms secondary, Melanoma, Experimental genetics, Melanoma, Experimental metabolism, Mice, Mice, Inbred C57BL, Mice, Knockout, Mice, Nude, Neoplasm Metastasis, Caveolin 1 deficiency, Cell Movement genetics, Hedgehog Proteins metabolism, Melanoma, Experimental pathology
- Abstract
Both cell-autonomous and non-cell-autonomous factors contribute to tumor growth and metastasis of melanoma. The function of caveolin-1 (Cav1), a multifunctional scaffold protein known to modulate several biologic processes in both normal tissue and cancer, has been recently investigated in melanoma cancer cells, but its role in the melanoma microenvironment remains largely unexplored. Here, we show that orthotopic implantation of B16F10 melanoma cells in the skin of Cav1KO mice increases tumor growth, and co-injection of Cav1-deficient dermal fibroblasts with melanoma cells is sufficient to recapitulate the tumor phenotype observed in Cav1KO mice. Using indirect coculture experiments with fibroblasts and melanoma cells combined with cytokine analysis, we found that Cav1-deficient fibroblasts promoted the growth of melanoma cells via enhanced paracrine cytokine signaling. Specifically, Cav1-deficient fibroblasts displayed increased ShhN expression, which heterotypically enhanced the Shh signaling pathway in melanoma cells. In contrast to primary tumor growth, the ability of B16F10 melanoma cells to form lung metastases was significantly reduced in Cav1KO mice. This phenotype was associated mechanistically with the inability of melanoma cells to adhere to and to transmigrate through a monolayer of endothelial cells lacking Cav1. Together, our findings show that Cav1 may regulate different mechanisms during primary melanoma tumor growth and metastatic dissemination., (©2012 AACR)
- Published
- 2012
- Full Text
- View/download PDF
22. ChIP sequencing of cyclin D1 reveals a transcriptional role in chromosomal instability in mice.
- Author
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Casimiro MC, Crosariol M, Loro E, Ertel A, Yu Z, Dampier W, Saria EA, Papanikolaou A, Stanek TJ, Li Z, Wang C, Fortina P, Addya S, Tozeren A, Knudsen ES, Arnold A, and Pestell RG
- Subjects
- Animals, Binding Sites, Breast Neoplasms genetics, Cell Line, Tumor, Chromatin Immunoprecipitation, Chromosome Aberrations, Female, Fibroblasts metabolism, Gene Expression Regulation, Neoplastic, Genome-Wide Association Study, Humans, Karyotyping, Mice, Mice, Transgenic, Transcription, Genetic, Chromosomal Instability, Cyclin D1 genetics
- Abstract
Chromosomal instability (CIN) in tumors is characterized by chromosomal abnormalities and an altered gene expression signature; however, the mechanism of CIN is poorly understood. CCND1 (which encodes cyclin D1) is overexpressed in human malignancies and has been shown to play a direct role in transcriptional regulation. Here, we used genome-wide ChIP sequencing and found that the DNA-bound form of cyclin D1 occupied the regulatory region of genes governing chromosomal integrity and mitochondrial biogenesis. Adding cyclin D1 back to Ccnd1(-/-) mouse embryonic fibroblasts resulted in CIN gene regulatory region occupancy by the DNA-bound form of cyclin D1 and induction of CIN gene expression. Furthermore, increased chromosomal aberrations, aneuploidy, and centrosome abnormalities were observed in the cyclin D1-rescued cells by spectral karyotyping and immunofluorescence. To assess cyclin D1 effects in vivo, we generated transgenic mice with acute and continuous mammary gland-targeted cyclin D1 expression. These transgenic mice presented with increased tumor prevalence and signature CIN gene profiles. Additionally, interrogation of gene expression from 2,254 human breast tumors revealed that cyclin D1 expression correlated with CIN in luminal B breast cancer. These data suggest that cyclin D1 contributes to CIN and tumorigenesis by directly regulating a transcriptional program that governs chromosomal stability.
- Published
- 2012
- Full Text
- View/download PDF
23. Cell fate determination factor Dachshund reprograms breast cancer stem cell function.
- Author
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Wu K, Jiao X, Li Z, Katiyar S, Casimiro MC, Yang W, Zhang Q, Willmarth NE, Chepelev I, Crosariol M, Wei Z, Hu J, Zhao K, and Pestell RG
- Subjects
- ARNTL Transcription Factors genetics, Animals, Biomarkers, Tumor genetics, Breast Neoplasms genetics, Breast Neoplasms pathology, CD24 Antigen genetics, CD24 Antigen metabolism, Cell Line, Tumor, Eye Proteins genetics, Female, Genome-Wide Association Study, Homeodomain Proteins genetics, Homeodomain Proteins metabolism, Humans, Hyaluronan Receptors genetics, Hyaluronan Receptors metabolism, Kruppel-Like Factor 4, Kruppel-Like Transcription Factors genetics, Kruppel-Like Transcription Factors metabolism, Mice, Mice, Nude, Nanog Homeobox Protein, Neoplasm Transplantation, Neoplastic Stem Cells pathology, Octamer Transcription Factor-3 genetics, Octamer Transcription Factor-3 metabolism, Promoter Regions, Genetic genetics, Proto-Oncogene Proteins c-myc genetics, Proto-Oncogene Proteins c-myc metabolism, RNA-Binding Proteins genetics, RNA-Binding Proteins metabolism, SOXB1 Transcription Factors genetics, SOXB1 Transcription Factors metabolism, Transcription Factors genetics, ARNTL Transcription Factors metabolism, Biomarkers, Tumor metabolism, Breast Neoplasms metabolism, Cell Dedifferentiation, Eye Proteins metabolism, Neoplastic Stem Cells metabolism, Transcription Factors metabolism
- Abstract
The cell fate determination factor Dachshund was cloned as a dominant inhibitor of the hyperactive epidermal growth factor receptor ellipse. The expression of Dachshund is lost in human breast cancer associated with poor prognosis. Breast tumor-initiating cells (TIC) may contribute to tumor progression and therapy resistance. Here, endogenous DACH1 was reduced in breast cancer cell lines with high expression of TIC markers and in patient samples of the basal breast cancer phenotype. Re-expression of DACH1 reduced new tumor formation in serial transplantations in vivo, reduced mammosphere formation, and reduced the proportion of CD44(high)/CD24(low) breast tumor cells. Conversely, lentiviral shRNA to DACH1 increased the breast (B)TIC population. Genome-wide expression studies of mammary tumors demonstrated DACH1 repressed a molecular signature associated with stem cells (SOX2, Nanog, and KLF4) and genome-wide ChIP-seq analysis identified DACH1 binding to the promoter of the Nanog, KLF4, and Lin28 genes. KLF4/c-Myc and Oct4/Sox2 antagonized DACH1 repression of BTIC. Mechanistic studies demonstrated DACH1 directly repressed the Nanog and Sox2 promoters via a conserved domain. Endogenous DACH1 regulates BTIC in vitro and in vivo.
- Published
- 2011
- Full Text
- View/download PDF
24. MicroRNA expression profiling of male breast cancer.
- Author
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Fassan M, Baffa R, Palazzo JP, Lloyd J, Crosariol M, Liu CG, Volinia S, Alder H, Rugge M, Croce CM, and Rosenberg A
- Subjects
- Adenocarcinoma chemistry, Adenocarcinoma diagnosis, Breast Neoplasms chemistry, Breast Neoplasms diagnosis, Breast Neoplasms genetics, Breast Neoplasms, Male chemistry, Breast Neoplasms, Male diagnosis, Cell Transformation, Neoplastic genetics, Diagnosis, Differential, Female, Genetic Association Studies, Gynecomastia diagnosis, Gynecomastia genetics, Gynecomastia metabolism, Homeodomain Proteins genetics, Humans, Male, MicroRNAs biosynthesis, MicroRNAs physiology, Neoplasm Proteins genetics, RNA, Neoplasm biosynthesis, Reverse Transcriptase Polymerase Chain Reaction, Sex Characteristics, Transcription Factors genetics, Vascular Endothelial Growth Factor A genetics, Adenocarcinoma genetics, Breast Neoplasms, Male genetics, Gene Expression Profiling, Gene Expression Regulation, Neoplastic genetics, Genome-Wide Association Study, MicroRNAs genetics, RNA, Neoplasm genetics
- Abstract
Introduction: MicroRNAs (miRNAs) are a class of small noncoding RNAs that control gene expression by targeting mRNAs and triggering either translation repression or RNA degradation. Their aberrant expression may be involved in human diseases, including cancer. To test the hypothesis that there is a specific miRNA expression signature which characterizes male breast cancers, we performed miRNA microarray analysis in a series of male breast cancers and compared them with cases of male gynecomastia and female breast cancers., Methods: Paraffin blocks were obtained at the Department of Pathology of Thomas Jefferson University from 28 male patients including 23 breast cancers and five cases of male gynecomastia, and from 10 female ductal breast carcinomas. The RNA harvested was hybridized to miRNA microarrays (~1,100 miRNA probes, including 326 human and 249 mouse miRNA genes, spotted in duplicate). To further support the microarray data, an immunohistochemical analysis for two specific miRNA gene targets (HOXD10 and VEGF) was performed in a small series of male breast carcinoma and gynecomastia samples., Results: We identified a male breast cancer miRNA signature composed of a large portion of underexpressed miRNAs. In particular, 17 miRNAs with increased expression and 26 miRNAs with decreased expression were identified in male breast cancer compared with gynecomastia. Among these miRNAs, some had well-characterized cancer development association and some showed a deregulation in cancer specimens similar to the one previously observed in the published signatures of female breast cancer. Comparing male with female breast cancer miRNA expression signatures, 17 significantly deregulated miRNAs were observed (four overexpressed and 13 underexpressed in male breast cancers). The HOXD10 and VEGF gene immunohistochemical expression significantly follows the corresponding miRNA deregulation., Conclusions: Our results suggest that specific miRNAs may be directly involved in male breast cancer development and that they may represent a novel diagnostic tool in the characterization of specific cancer gene targets.
- Published
- 2009
- Full Text
- View/download PDF
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