31 results on '"Mu, Zhaomei"'
Search Results
2. Longitudinal Dynamics of Circulating Tumor Cells and Circulating Tumor DNA for Treatment Monitoring in Metastatic Breast Cancer
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Gerratana, Lorenzo, Davis, Andrew A., Zhang, Qiang, Basile, Debora, Rossi, Giovanna, Strickland, Kimberly, Franzoni, Alessandra, Allegri, Lorenzo, Mu, Zhaomei, Zhang, Youbin, Flaum, Lisa E., Damante, Giuseppe, Gradishar, William John, Platanias, Leonidas C., Behdad, Amir, Yang, Hushan, Puglisi, Fabio, and Cristofanilli, Massimo
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- 2021
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3. Prognostic values of cancer associated macrophage-like cells (CAML) enumeration in metastatic breast cancer
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Mu, Zhaomei, Wang, Chun, Ye, Zhong, Rossi, Giovanna, Sun, Carl, Li, Ling, Zhu, Zhu, Yang, Hushan, and Cristofanilli, Massimo
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- 2017
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4. Longitudinally collected CTCs and CTC-clusters and clinical outcomes of metastatic breast cancer
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Wang, Chun, Mu, Zhaomei, Chervoneva, Inna, Austin, Laura, Ye, Zhong, Rossi, Giovanna, Palazzo, Juan P., Sun, Carl, Abu-Khalaf, Maysa, Myers, Ronald E., Zhu, Zhu, Ba, Yanna, Li, Bingshan, Hou, Lifang, Cristofanilli, Massimo, and Yang, Hushan
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- 2017
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5. Prospective assessment of the prognostic value of circulating tumor cells and their clusters in patients with advanced-stage breast cancer
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Mu, Zhaomei, Wang, Chun, Ye, Zhong, Austin, Laura, Civan, Jesse, Hyslop, Terry, Palazzo, Juan P., Jaslow, Rebecca, Li, Bingshan, Myers, Ronald E., Jiang, Juntao, Xing, Jinliang, Yang, Hushan, and Cristofanilli, Massimo
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- 2015
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6. The effects of erythropoiesis-stimulating agents on the short-term and long-term survivals in metastatic breast cancer patients receiving chemotherapy: a SEER population-based study
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Lai, Yinzhi, Ye, Zhong, Civan, Jesse M., Wang, Chun, Cristofanilli, Massimo, Mu, Zhaomei, Austin, Laura, Palazzo, Juan P., Myers, Ronald E., and Yang, Hushan
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- 2015
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7. Presence of anaplastic lymphoma kinase in inflammatory breast cancer
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Robertson, Fredika M, Petricoin III, Emanuel F, Van Laere, Steven J, Bertucci, Francois, Chu, Khoi, Fernandez, Sandra V, Mu, Zhaomei, Alpaugh, Katherine, Pei, Jianming, Circo, Rita, Wulfkuhle, Julia, Ye, Zaiming, Boley, Kimberly M, Liu, Hui, Moraes, Ricardo, Zhang, Xuejun, DeMaria, Ruggero, Barsky, Sanford H, Sun, Guoxian, and Cristofanilli, Massimo
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- 2013
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8. Inflammatory breast cancer (IBC): clues for targeted therapies
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Fernandez, Sandra V., Robertson, Fredika M., Pei, Jianming, Aburto-Chumpitaz, Lucy, Mu, Zhaomei, Chu, Khoi, Alpaugh, R. K., Huang, Yong, Cao, Yu, Ye, Zaiming, Cai, Kathy Q., Boley, Kimberly M., Klein-Szanto, Andres J., Devarajan, Karthik, Addya, Sankar, and Cristofanilli, Massimo
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- 2013
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9. PKA knockdown enhances cell killing in response to radiation and androgen deprivation
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Hensley, Harvey H., Hannoun-Levi, Jean-Michel, Hachem, Paul, Mu, Zhaomei, Stoyanova, Radka, Khor, Li-Yan, Agrawal, Sudhir, and Pollack, Alan
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- 2011
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10. Antisense MDM2 Enhances the Response of Androgen Insensitive Human Prostate Cancer Cells to Androgen Deprivation In Vitro and In Vivo
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Mu, Zhaomei, Hachem, Paul, Hensley, Harvey, Stoyanova, Radka, Kwon, Hae Won, Hanlon, Alexandra L., Agrawal, Sudhir, and Pollack, Alan
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- 2008
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11. Antisense Bcl-2 Sensitizes Prostate Cancer Cells to Radiation
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Mu, Zhaomei, Hachem, Paul, and Pollack, Alan
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- 2005
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12. A Chromosome-centric HumanProteome Project (C-HPP) to Characterize the Sets of Proteins Encodedin Chromosome 17.
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Liu, Suli, Im, Hogune, Bairoch, Amos, Cristofanilli, Massimo, Chen, Rui, Deutsch, Eric W., Dalton, Stephen, Fenyo, David, Fanayan, Susan, Gates, Chris, Gaudet, Pascale, Hincapie, Marina, Hanash, Samir, Kim, Hoguen, Jeong, Seul-Ki, Lundberg, Emma, Mias, George, Menon, Rajasree, Mu, Zhaomei, and Nice, Edouard
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- 2013
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13. Antisense MDM2 sensitizes prostate cancer cells to androgen deprivation, radiation, and the combination
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Mu, Zhaomei, Hachem, Paul, Agrawal, Sudhir, and Pollack, Alan
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ANTISENSE DNA , *PROSTATE cancer , *APOPTOSIS , *DRUG therapy , *ANTIANDROGENS , *NUCLEOTIDES , *PROTEIN metabolism , *CELL lines , *COMBINED modality therapy , *COMPARATIVE studies , *RESEARCH methodology , *MEDICAL cooperation , *PROSTATE tumors , *PROTEINS , *RADIATION , *RESEARCH , *RESEARCH funding , *WESTERN immunoblotting , *EVALUATION research , *NUCLEAR proteins , *COLONY-forming units assay , *THERAPEUTICS - Abstract
: PurposeAntisense MDM2 (AS) sensitizes a variety of tumor cell types, including prostate cancer, to radiation and chemotherapy. We have previously described that AS enhances the apoptotic response to androgen deprivation (AD) and that this translates into a reduction in overall cell survival, as measured by clonogenic assay. Because AD + radiation (RT) is a key strategy for the treatment of men with high-risk prostate cancer, AS was tested for the ability to sensitize cells to the combination of AD+RT.: Methods and materialsLNCaP cells were cultured in vitro in either complete, androgen deprived (AD), or AD+R1881 (synthetic androgen) medium for 2–3 days before AS was administered. Radiation at 5 Gy was given 18–24 h later. Processing of the cells after RT was done at 3 h for Western blots, 24 and 48 h for trypan blue dye exclusion, 18 h for Annexin V staining by flow cytometric analysis, 18 h for Caspase 3+7 quantification by fluorometric assay, and immediately for clonogenic survival measured 12–14 days later. There were 18 treatment groups that were studied: lipofectin control, AS, antisense mismatch (ASM), AD, AD+R1881, and RT in all possible combinations. Statistical comparisons between groups were accomplished with one-way analysis of variance using the Bonferroni test, considering all 18 groups.: ResultsAS caused a reduction in MDM2 expression and an increase in p53 and p21 expression. Early cell death by trypan blue was found to be reflective of the apoptotic results by Annexin V and Caspase 3+7. AS caused a significant increase in apoptosis over the lipofectin control, AD, and RT controls. Apoptosis was further increased significantly by the addition of AD or RT to AS. When AS, AD, and RT were combined, there was a consistent increase in early cell death over AS+AD and AS+RT by all of the assay methods, although this increase was not significant. Overall cell death measured by clonogenic assay revealed synergistic cell killing of AS+RT beyond that of ASM+RT and RT alone, and AS+RT+AD beyond that of AS+RT, AS+RT+AD+R1881, ASM+RT+AD, and ASM+RT+AD+R1881.: ConclusionAS sensitizes cells to AD, RT, and AD+RT and shows promise in the treatment of the full range of patients with prostate cancer. AS has the potential to sensitize the primary tumor to AD+RT and metastasis to AD. [Copyright &y& Elsevier]
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- 2004
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14. A Phase I/II Study of the Investigational Drug Alisertib in Combination With Abiraterone and Prednisone for Patients With Metastatic Castration-Resistant Prostate Cancer Progressing on Abiraterone.
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Lin, Jianqing, Patel, Sheel A., Sama, Ashwin R., Hoffman‐Censits, Jean H., Kennedy, Brooke, Kilpatrick, Deborah, Ye, Zhong, Yang, Hushan, Mu, Zhaomei, Leiby, Benjamin, Lewis, Nancy, Cristofanilli, Massimo, and Kelly, William Kevin
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ANTINEOPLASTIC agents ,INVESTIGATIONAL drugs ,PROTEIN kinase inhibitors ,CLINICAL trials ,DOSE-effect relationship in pharmacology ,DRUG toxicity ,PATIENT safety ,PREDNISONE ,PROSTATE tumors ,TREATMENT effectiveness ,ABIRATERONE acetate ,THERAPEUTICS - Abstract
Background. We hypothesized that Aurora A kinase (AK) contributes to castrate resistance in prostate cancer (PCa) and that inhibiting AK with alisertib can resensitize PCa cells to androgen receptor (AR) inhibitor abiraterone. Methods. This was a phase I/II trial to determine the safety and efficacy of alisertib when given in combination with abiraterone plus prednisone (AP). Metastatic castration-resistant prostate cancer (mCRPC) patients were treated with dose escalation (alisertib at 30,40, and 50 mg orally b.i.d., days 1-7 every 21 days) per standard 3 + 3 design. Results. Nine of 43 planned subjects were enrolled. The maximum tolerated dose (MTD) was not reached, and the dose-limiting toxicities (DLTs) included neutropenic fever (1 of 9), neutropenia (1 of 9), fatigue with memory impairment (1 of 9), and diarrhea/mucositis (1 of 9). No prostate-specific antigen (PSA) decrease or circulating tumor cell (CTC) changes were observed during the study. Pharmaco-dynamically, adding alisertib did not affect total testosterone or dehydroepiandrosterone (DHEA) levels. There was some change in neuroendocrine markers after therapy. Mean duration on study was 2.5 months. The trial was terminated early. Conclusion. A tolerable dose of alisertib in combination with AP in mCRPC was not established in this study. There was no clear signal indicating that alisertib might be beneficial for patients with mCRPC progressing on abiraterone. [ABSTRACT FROM AUTHOR]
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- 2016
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15. Association of clinical outcomes in metastatic breast cancer patients with circulating tumour cell and circulating cell-free DNA.
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Ye, Zhong, Wang, Chun, Wan, Shaogui, Mu, Zhaomei, Zhang, Zhenchao, Abu-Khalaf, Maysa M., Fellin, Frederick M., Silver, Daniel P., Neupane, Manish, Jaslow, Rebecca J., Bhattacharya, Saveri, Tsangaris, Theodore N., Chervoneva, Inna, Berger, Adam, Austin, Laura, Palazzo, Juan P., Myers, Ronald E., Pancholy, Neha, Toorkey, Darayus, and Yao, Kaelan
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BREAST cancer prognosis , *BREAST tumor treatment , *BIOPSY , *BLOOD collection , *CANCER patients , *EXTRACELLULAR space , *FLUORIMETER , *LONGITUDINAL method , *METASTASIS , *NUCLEIC acids , *POLYMERASE chain reaction , *TUMOR markers , *TREATMENT effectiveness , *PROPORTIONAL hazards models , *DISEASE progression ,MORTALITY risk factors - Abstract
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. Highlights • Circulating tumour cell (CTC) or cell-free DNA (ccfDNA) associated with metastatic breast cancer (MBC) patient survivals. • Prognostic values of CTC and ccfDNA largely non-overlapping. • CTC and ccfDNA jointly associated with patient survival, especially overall survival. • Potential combined use of CTC and ccfDNA as liquid biopsy in MBC management. [ABSTRACT FROM AUTHOR]
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- 2019
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16. Antisense-MDM2 Sensitizes LNCaP Prostate Cancer Cells to Androgen Deprivation, Radiation, and the Combination In Vivo
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Stoyanova, Radka, Hachem, Paul, Hensley, Harvey, Khor, Li-Yan, Mu, Zhaomei, Hammond, M. Elizabeth H., Agrawal, Sudhir, and Pollack, Alan
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CANCER cells , *ANDROGENS , *ANTIGENS , *RADIOTHERAPY , *NUCLEOTIDES , *PROTEIN metabolism , *ANIMAL experimentation , *ANTHROPOMETRY , *CASTRATION , *CELL lines , *COMBINED modality therapy , *COMPARATIVE studies , *MAGNETIC resonance imaging , *RESEARCH methodology , *MEDICAL cooperation , *MICE , *PROSTATE tumors , *PROTEINS , *RADIATION , *RADIATION doses , *RESEARCH , *XENOGRAFTS , *PROSTATE-specific antigen , *EVALUATION research , *CHEMICAL inhibitors , *THERAPEUTICS - Abstract
Purpose: To test the effects of antisense (AS)-MDM2 alone and with androgen deprivation (AD), radiotherapy (RT), and AD + RT on wild-type LNCaP cells in an orthotopic in vivo model.Methods: Androgen-sensitive LNCaP cells were grown in the prostates of nude mice. Magnetic resonance imaging-based tumor volume and serum prostate-specific antigen (PSA) measurements were used to assess effects on tumor response. Tumor response was measured by biochemical and tumor volume failure definitions and doubling time estimates from fitted PSA and tumor volume growth curves. Expression of MDM2, p53, p21, and Ki-67 was quantified using immunohistochemical staining and image analysis of formalin-fixed tissue, analogous to methods used clinically.Results: Antisense-MDM2 significantly inhibited the growth of LNCaP tumors over the mismatch controls. The most significant increase in tumor growth delay and tumor doubling time was from AS-MDM2 + AD + RT, although the effect of AS-MDM2 + AD was substantial. Expression of MDM2 was significantly reduced by AS-MDM2 in the setting of RT.Conclusions: This is the first in vivo investigation of the effects of AS-MDM2 in an orthotopic model and the first to demonstrate incremental sensitization when added to AD and AD + RT. The results with AD underscore the potential to affect micrometastatic disease, which is probably responsible for treatment failure in 30-40% of men with high-risk disease. [ABSTRACT FROM AUTHOR]- Published
- 2007
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17. Junctional Adhesion Molecules in Cancer: A Paradigm for the Diverse Functions of Cell-Cell Interactions in Tumor Progression.
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Lauko A, Mu Z, Gutmann DH, Naik UP, and Lathia JD
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- Apoptosis physiology, Breast Neoplasms etiology, Breast Neoplasms pathology, Breast Neoplasms physiopathology, Cell Adhesion physiology, Cell Movement physiology, Cell Proliferation physiology, Female, Humans, Junctional Adhesion Molecule A chemistry, Junctional Adhesion Molecules chemistry, Junctional Adhesion Molecules physiology, Neoplasm Invasiveness, Neoplasm Metastasis, Neoplasms physiopathology, Receptor, ErbB-2 metabolism, Structure-Activity Relationship, Tight Junctions, Tumor Microenvironment immunology, Tumor Suppressor Proteins physiology, Cell Communication physiology, Disease Progression, Junctional Adhesion Molecule A physiology, Junctional Adhesion Molecule C physiology, Neoplasms etiology, Neoplasms pathology
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Tight junction (TJ) proteins are essential for mediating interactions between adjacent cells and coordinating cellular and organ responses. Initial investigations into TJ proteins and junctional adhesion molecules (JAM) in cancer suggested a tumor-suppressive role where decreased expression led to increased metastasis. However, recent studies of the JAM family members JAM-A and JAM-C have expanded the roles of these proteins to include protumorigenic functions, including inhibition of apoptosis and promotion of proliferation, cancer stem cell biology, and epithelial-to-mesenchymal transition. JAM function by interacting with other proteins through three distinct molecular mechanisms: direct cell-cell interaction on adjacent cells, stabilization of adjacent cell surface receptors on the same cell, and interactions between JAM and cell surface receptors expressed on adjacent cells. Collectively, these diverse interactions contribute to both the pro- and antitumorigenic functions of JAM. In this review, we discuss these context-dependent functions of JAM in a variety of cancers and highlight key areas that remain poorly understood, including their potentially diverse intracellular signaling networks, their roles in the tumor microenvironment, and the consequences of posttranslational modifications on their function. These studies have implications in furthering our understanding of JAM in cancer and provide a paradigm for exploring additional roles of TJ proteins., (©2020 American Association for Cancer Research.)
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- 2020
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18. CCR5 Governs DNA Damage Repair and Breast Cancer Stem Cell Expansion.
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Jiao X, Velasco-Velázquez MA, Wang M, Li Z, Rui H, Peck AR, Korkola JE, Chen X, Xu S, DuHadaway JB, Guerrero-Rodriguez S, Addya S, Sicoli D, Mu Z, Zhang G, Stucky A, Zhang X, Cristofanilli M, Fatatis A, Gray JW, Zhong JF, Prendergast GC, and Pestell RG
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- Animals, Breast Neoplasms genetics, Cell Line, Tumor, Cell Proliferation genetics, Cell Transformation, Neoplastic genetics, Epithelial Cells metabolism, Female, Gene Expression Regulation, Neoplastic, Humans, Maraviroc pharmacology, Mice, Mice, Nude, Neoplasm Transplantation, Phosphatidylinositol 3-Kinases metabolism, Piperazines pharmacology, Pyrimidines pharmacology, Transplantation, Heterologous, Antineoplastic Agents pharmacology, Breast Neoplasms pathology, CCR5 Receptor Antagonists pharmacology, DNA Damage genetics, DNA Repair immunology, Neoplastic Stem Cells metabolism, Receptors, CCR5 metabolism
- Abstract
The functional significance of the chemokine receptor CCR5 in human breast cancer epithelial cells is poorly understood. Here, we report that CCR5 expression in human breast cancer correlates with poor outcome. CCR5
+ breast cancer epithelial cells formed mammospheres and initiated tumors with >60-fold greater efficiency in mice. Reintroduction of CCR5 expression into CCR5-negative breast cancer cells promoted tumor metastases and induced DNA repair gene expression and activity. CCR5 antagonists Maraviroc and Vicriviroc dramatically enhanced cell killing mediated by DNA-damaging chemotherapeutic agents. Single-cell analysis revealed CCR5 governs PI3K/Akt, ribosomal biogenesis, and cell survival signaling. As CCR5 augments DNA repair and is reexpressed selectively on cancerous, but not normal breast epithelial cells, CCR5 inhibitors may enhance the tumor-specific activities of DNA damage response-based treatments, allowing a dose reduction of standard chemotherapy and radiation. Significance: This study offers a preclinical rationale to reposition CCR5 inhibitors to improve the treatment of breast cancer, based on their ability to enhance the tumor-specific activities of DNA-damaging chemotherapies administered in that disease. Cancer Res; 78(7); 1657-71. ©2018 AACR ., (©2018 American Association for Cancer Research.)- Published
- 2018
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19. Cell-Free DNA and Circulating Tumor Cells: Comprehensive Liquid Biopsy Analysis in Advanced Breast Cancer.
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Rossi G, Mu Z, Rademaker AW, Austin LK, Strickland KS, Costa RLB, Nagy RJ, Zagonel V, Taxter TJ, Behdad A, Wehbe FH, Platanias LC, Gradishar WJ, and Cristofanilli M
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- Breast Neoplasms blood, Breast Neoplasms mortality, Female, Humans, Immunohistochemistry, Kaplan-Meier Estimate, Liquid Biopsy methods, Neoplasm Metastasis, Neoplasm Staging, Neoplastic Cells, Circulating metabolism, Prognosis, Biomarkers, Tumor, Breast Neoplasms diagnosis, Breast Neoplasms genetics, Circulating Tumor DNA, Neoplastic Cells, Circulating pathology
- Abstract
Purpose: Liquid biopsy provides a real-time assessment of metastatic breast cancer (MBC). We evaluated the utility of combining circulating tumor cells (CTC) and circulating tumor DNA (ctDNA) to predict prognosis in MBC. Experimental Design: We conducted a retrospective study of 91 patients with locally advanced breast cancer and MBC. CTCs were enumerated by CellSearch; the plasma-based assay was performed utilizing Guardant360 and the survival analysis using Kaplan-Meier curves. Results: Eighty-four patients had stage IV cancer, and 7 patients had no metastases. Eighty patients had CTC analysis: median number 2 (0-5,612). Blood samples [232 of 277 (84%)] had mutations. The average ctDNA fraction was 4.5% (0-88.2%) and number of alterations 3 (0-27); the most commonly mutated genes were TP53 (52%), PIK3CA (40%), and ERBB2 (20%). At the time of analysis, 36 patients (39.6%) were dead. The median follow-up for CTCs was 9 months; for ctDNA, it was 9.9 months. For CTCs and ctDNA, respectively, progression-free survival (PFS) was 4.2 and 5.2 months and overall survival (OS) was 18.7 and 21.5 months. There was a statistically significant difference in PFS and OS for baseline CTCs < 5 versus CTCs ≥ 5 ( P = 0.021 and P = 0.0004, respectively); %ctDNA < 0.5 versus ≥ 0.5 ( P = 0.003 and P = 0.012); number of alterations < 2 versus ≥ 2 ( P = 0.059 borderline and P = 0.0015). A significant association by Fisher exact test was found between the number of alterations and the %ctDNA in the baseline sample ( P < 0.0001). Conclusions: The study demonstrated that liquid biopsy is an effective prognostic tool. Clin Cancer Res; 24(3); 560-8. ©2017 AACR ., (©2017 American Association for Cancer Research.)
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- 2018
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20. Detection of Activating Estrogen Receptor Gene ( ESR1 ) Mutations in Single Circulating Tumor Cells.
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Paolillo C, Mu Z, Rossi G, Schiewer MJ, Nguyen T, Austin L, Capoluongo E, Knudsen K, Cristofanilli M, and Fortina P
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- Adult, Aged, Biomarkers, Tumor, Cell Line, Tumor, Circulating Tumor DNA, DNA Mutational Analysis, Female, Humans, Liquid Biopsy, Male, Middle Aged, Neoplasm Metastasis, Neoplasm Staging, Neoplastic Cells, Circulating pathology, Proto-Oncogene Proteins B-raf genetics, Reproducibility of Results, Workflow, Estrogen Receptor alpha genetics, Mutation, Neoplasms diagnosis, Neoplasms genetics, Neoplastic Cells, Circulating metabolism
- Abstract
Purpose: Early detection is essential for treatment plans before onset of metastatic disease. Our purpose was to demonstrate feasibility to detect and monitor estrogen receptor 1 ( ESR1 ) gene mutations at the single circulating tumor cell (CTC) level in metastatic breast cancer (MBC). Experimental Design: We used a CTC molecular characterization approach to investigate heterogeneity of 14 hotspot mutations in ESR1 and their correlation with endocrine resistance. Combining the CellSearch and DEPArray technologies allowed recovery of 71 single CTCs and 12 WBC from 3 ER-positive MBC patients. Forty CTCs and 12 WBC were subjected to whole genome amplification by MALBAC and Sanger sequencing. Results: Among 3 selected patients, 2 had an ESR1 mutation (Y537). One showed two different ESR1 variants in a single CTC and another showed loss of heterozygosity. All mutations were detected in matched cell-free DNA (cfDNA). Furthermore, one had 2 serial blood samples analyzed and showed changes in both cfDNA and CTCs with emergence of mutations in ESR1 (Y537S and T570I), which has not been reported previously. Conclusions: CTCs are easily accessible biomarkers to monitor and better personalize management of patients with previously demonstrated ER-MBC who are progressing on endocrine therapy. We showed that single CTC analysis can yield important information on clonal heterogeneity and can be a source of discovery of novel and potential driver mutations. Finally, we also validate a workflow for liquid biopsy that will facilitate early detection of ESR1 mutations, the emergence of endocrine resistance and the choice of further target therapy. Clin Cancer Res; 23(20); 6086-93. ©2017 AACR ., (©2017 American Association for Cancer Research.)
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- 2017
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21. Detection and Characterization of Circulating Tumor Associated Cells in Metastatic Breast Cancer.
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Mu Z, Benali-Furet N, Uzan G, Znaty A, Ye Z, Paolillo C, Wang C, Austin L, Rossi G, Fortina P, Yang H, and Cristofanilli M
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- Biomarkers, Tumor metabolism, Breast Neoplasms diagnosis, Breast Neoplasms metabolism, DNA Mutational Analysis, Epithelial-Mesenchymal Transition, Estrogen Receptor alpha genetics, Estrogen Receptor alpha metabolism, Female, Humans, Microscopy, Fluorescence, Mutation, Neoplasm Metastasis, Neoplasm Staging, Tumor Suppressor Protein p53 genetics, Tumor Suppressor Protein p53 metabolism, Breast Neoplasms pathology, Neoplastic Cells, Circulating metabolism
- Abstract
The availability of blood-based diagnostic testing using a non-invasive technique holds promise for real-time monitoring of disease progression and treatment selection. Circulating tumor cells (CTCs) have been used as a prognostic biomarker for the metastatic breast cancer (MBC). The molecular characterization of CTCs is fundamental to the phenotypic identification of malignant cells and description of the relevant genetic alterations that may change according to disease progression and therapy resistance. However, the molecular characterization of CTCs remains a challenge because of the rarity and heterogeneity of CTCs and technological difficulties in the enrichment, isolation and molecular characterization of CTCs. In this pilot study, we evaluated circulating tumor associated cells in one blood draw by size exclusion technology and cytological analysis. Among 30 prospectively enrolled MBC patients, CTCs, circulating tumor cell clusters (CTC clusters), CTCs of epithelial-mesenchymal transition (EMT) and cancer associated macrophage-like cells (CAMLs) were detected and analyzed. For molecular characterization of CTCs, size-exclusion method for CTC enrichment was tested in combination with DEPArray™ technology, which allows the recovery of single CTCs or pools of CTCs as a pure CTC sample for mutation analysis. Genomic mutations of TP53 and ESR1 were analyzed by targeted sequencing on isolated 7 CTCs from a patient with MBC. The results of genomic analysis showed heterozygous TP53 R248W mutation from one single CTC and pools of three CTCs, and homozygous TP53 R248W mutation from one single CTC and pools of two CTCs. Wild-type ESR1 was detected in the same isolated CTCs. The results of this study reveal that size-exclusion method can be used to enrich and identify circulating tumor associated cells, and enriched CTCs were characterized for genetic alterations in MBC patients, respectively., Competing Interests: The authors declare no conflict of interest.
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- 2016
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22. Edelfosine Promotes Apoptosis in Androgen-Deprived Prostate Tumors by Increasing ATF3 and Inhibiting Androgen Receptor Activity.
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Udayakumar TS, Stoyanova R, Shareef MM, Mu Z, Philip S, Burnstein KL, and Pollack A
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- Androgen Antagonists pharmacology, Animals, Apoptosis, Cell Line, Tumor, Cell Proliferation drug effects, Cell Survival drug effects, Drug Synergism, Gene Expression Regulation, Neoplastic drug effects, Humans, Male, Mice, Neoplasm Transplantation, Phospholipid Ethers pharmacology, Promoter Regions, Genetic drug effects, Prostatic Neoplasms genetics, Prostatic Neoplasms metabolism, Proto-Oncogene Proteins c-akt metabolism, Receptors, Androgen metabolism, Signal Transduction drug effects, Up-Regulation, Xenograft Model Antitumor Assays, Activating Transcription Factor 3 metabolism, Androgen Antagonists administration & dosage, Phospholipid Ethers administration & dosage, Prostatic Neoplasms drug therapy, Receptors, Androgen genetics
- Abstract
Edelfosine is a synthetic alkyl-lysophospholipid that possesses significant antitumor activity in several human tumor models. Here, we investigated the effects of edelfosine combined with androgen deprivation (AD) in LNCaP and VCaP human prostate cancer cells. This treatment regimen greatly decreased cell proliferation compared with single agent or AD alone, resulting in higher levels of apoptosis in LNCaP compared with VCaP cells. Edelfosine caused a dose-dependent decrease in AKT activity, but did not affect the expression of total AKT in either cell line. Furthermore, edelfosine treatment inhibited the expression of androgen receptor (AR) and was associated with an increase in activating transcription factor 3 (ATF3) expression levels, a stress response gene and a negative regulator of AR transactivation. ATF3 binds to AR after edelfosine + AD and represses the transcriptional activation of AR as demonstrated by PSA promoter studies. Knockdown of ATF3 using siRNA-ATF3 reversed the inhibition of PSA promoter activity, suggesting that the growth inhibition effect of edelfosine was ATF3 dependent. Moreover, expression of AR variant 7 (ARv7) and TMPRSS2-ERG fusion gene were greatly inhibited after combined treatment with AD and edelfosine in VCaP cells. In vivo experiments using an orthotopic LNCaP model confirmed the antitumor effects of edelfosine + AD over the individual treatments. A significant decrease in tumor volume and PSA levels was observed when edelfosine and AD were combined, compared with edelfosine alone. Edelfosine shows promise in combination with AD for the treatment of prostate cancer patients. Mol Cancer Ther; 15(6); 1353-63. ©2016 AACR., (©2016 American Association for Cancer Research.)
- Published
- 2016
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23. Arterial Blood, Rather Than Venous Blood, is a Better Source for Circulating Melanoma Cells.
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Terai M, Mu Z, Eschelman DJ, Gonsalves CF, Kageyama K, Chervoneva I, Orloff M, Weight R, Mastrangelo MJ, Cristofanilli M, and Sato T
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- Adult, Aged, Female, Humans, Male, Melanoma therapy, Middle Aged, Neoplasm Metastasis, Tumor Burden, Melanoma blood, Melanoma diagnosis, Neoplastic Cells, Circulating pathology
- Abstract
Background: CTCs provide prognostic information and their application is under investigation in multiple tumor types. Of the multiple variables inherent in any such process, none is more important to outcome than the appropriateness of the sample source. To address this question, we investigated CTCs in paired peripheral venous and arterial blood specimens obtained from stage IV uveal melanoma patients., Methods: Blood specimens were obtained from both common femoral arteries and antecubital veins in 17 uveal melanoma patients with multiple hepatic metastases for CTC measurements., Finding: CTCs were detectable with greater frequency (100%) and in larger numbers (median 5, range 1 to 168) in all arterial blood specimens than in venous samples (52.9%; median 1, range 0 to 8). Patients with hepatic as well as extra-hepatic metastasis showed higher number of arterial CTCs, compared to patients with liver-only metastasis (p = 0.003). There was no significant association between the number of arterial CTCs and the tumor burden within the liver in patients who had liver-only metastases., Interpretation: Our data indicate that arterial blood specimens might be a better source of circulating uveal melanoma cells. Although less conveniently processed, perhaps arterial blood should be evaluated as sample source for measurement of CTCs.
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- 2015
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24. CTC enumeration and characterization: moving toward personalized medicine.
- Author
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Toss A, Mu Z, Fernandez S, and Cristofanilli M
- Abstract
The primary cause of tumor-related death in breast cancer (BC) is still represented by distant metastasization. The dissemination of tumor cells from the primary tumor to distant sites through bloodstream cannot be early detected by standard imaging methods. The enumeration of circulating tumor cells (CTCs) represents an effective prognostic and predictive biomarker, which is able to monitor efficacy of adjuvant therapies, detect early development of (micro)metastases and at last, assess therapeutic responses of advanced disease earlier than traditional imaging methods. Moreover, since repeated tissue biopsies are invasive, costly and not always feasible, the assessment of tumor characteristics on CTCs, by a peripheral blood sample as a 'liquid biopsy', represents an attractive opportunity. The implementation of molecular and genomic characterization of CTCs could contribute to improve the treatment selection and thus, to move toward more personalized treatments. This review describes the current state of the art on CTC detection strategies, the evidence to demonstrate their clinical validity, and their potential impact for both future clinical trial design and, decision-making process in our daily practice.
- Published
- 2014
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25. AZD8931, an equipotent, reversible inhibitor of signaling by epidermal growth factor receptor (EGFR), HER2, and HER3: preclinical activity in HER2 non-amplified inflammatory breast cancer models.
- Author
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Mu Z, Klinowska T, Dong X, Foster E, Womack C, Fernandez SV, and Cristofanilli M
- Subjects
- Animals, Antineoplastic Agents therapeutic use, Apoptosis drug effects, Cell Line, Tumor, ErbB Receptors antagonists & inhibitors, Female, Gene Amplification, Humans, Inflammatory Breast Neoplasms metabolism, Mice, Mice, SCID, Quinazolines therapeutic use, Receptor, ErbB-2 genetics, Signal Transduction, Tumor Burden drug effects, Xenograft Model Antitumor Assays, Antineoplastic Agents pharmacology, ErbB Receptors metabolism, Inflammatory Breast Neoplasms drug therapy, Quinazolines pharmacology, Receptor, ErbB-2 metabolism, Receptor, ErbB-3 metabolism
- Abstract
Introduction: Epidermal growth factor receptor (EGFR) overexpression has been associated with prognostic and predictive value in inflammatory breast cancer (IBC). Epidermal growth factor receptor 2 (HER2) overexpression is observed at a higher rate in IBC compared with noninflammatory breast cancer. Current clinically available anti-HER2 therapies are effective only in patients with HER2 amplified breast cancer, including IBC. AZD8931 is a novel small-molecule equipotent inhibitor of EGFR, HER2, and HER3 signaling. In this study, we investigated the antitumor activity of AZD8931 alone or in combination with paclitaxel using preclinical models of EGFR-overexpressed and HER2 non-amplified IBC cells., Methods: Two IBC cell lines SUM149 and FC-IBC-02 derived from pleural effusion of an IBC patient were used in this study. Cell growth and apoptotic cell death were examined in vitro. For the in vivo tumor growth studies, IBC cells were orthotopically transplanted into the mammary fat pads of immunodeficient mice. AZD8931 was given by daily oral gavage at doses of 25 mg/kg, 5 days/week for 4 weeks. Paclitaxel was subcutaneously injected twice weekly., Results: AZD8931 significantly suppressed cell growth of IBC cells and induced apoptosis of human IBC cells in vitro. Significantly, we showed that AZD8931 monotherapy inhibited xenograft growth and the combination of paclitaxel + AZD8931 was demonstrably more effective than paclitaxel or AZD8931 alone treatment at delaying tumor growth in vivo in orthotopic IBC models., Conclusion: AZD8931 single agent and in combination with paclitaxel demonstrated signal inhibition and antitumor activity in EGFR-overexpressed and HER2 non-amplified IBC models. These results suggest that AZD8931 may provide a novel therapeutic strategy for the treatment of IBC patients with HER2 non-amplified tumors.
- Published
- 2014
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26. EZH2 knockdown suppresses the growth and invasion of human inflammatory breast cancer cells.
- Author
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Mu Z, Li H, Fernandez SV, Alpaugh KR, Zhang R, and Cristofanilli M
- Subjects
- Animals, Cell Growth Processes physiology, Enhancer of Zeste Homolog 2 Protein, Female, Gene Knockdown Techniques, Humans, Inflammatory Breast Neoplasms pathology, Lentivirus Infections genetics, Lentivirus Infections metabolism, Mice, Mice, SCID, Neoplastic Stem Cells metabolism, Polycomb Repressive Complex 2 genetics, Spheroids, Cellular, Survival Analysis, Inflammatory Breast Neoplasms genetics, Polycomb Repressive Complex 2 metabolism
- Abstract
Introduction: Inflammatory breast cancer (IBC) is the most metastatic variant of breast cancer with the poorest survival in all types of breast cancer patients and presently therapeutic targets for IBC are very limited. Enhancer of zeste homolog 2 (EZH2) is frequently expressed in human IBC and its expression positively correlates with worse clinical outcome. However, the molecular basis for EZH2 promoting IBC has not been explored. Here, we investigated the functional role of EZH2 in IBC cells by examining the effects of its knockdown on the formation of tumor spheroids and invasion of these cells in vitro and in vivo in an orthotopic xenograft model., Methods: SUM149 and a new IBC cell line-FC-IBC-02 derived from pleural effusion fluid of an IBC patient were used in this study. Specific knockdown of EZH2 was performed using short hairpin RNA (shRNA) specific to the human EZH2 gene. Cell growth and the formation of tumor spheroids were examined in vitro. The effects of EZH2 knockdown on IBC cell migration and invasion were examined by a Boyden chamber assay. For the in vivo tumor growth studies, IBC cells were orthotopically transplanted into the mammary fat pads of immunodeficient mice., Results: The results showed that EZH2 is expressed at higher levels in human IBC cell lines compared with normal human mammary epithelial cells, and the knockdown of EZH2 expression significantly suppressed cell growth and tumor spheroid formation of human IBC cells in vitro. In addition, EZH2 knockdown inhibited the migration and invasion of IBC cells. Significantly, EZH2 knockdown suppressed the angiogenesis and tumor growth of IBC cells in vivo., Conclusions: Our results provide direct evidence that EZH2 is critical for the formation of tumor spheroids and invasion of human IBC cells and could be a potential target for developing novel therapeutic strategies for human IBC.
- Published
- 2013
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27. Genome wide proteomics of ERBB2 and EGFR and other oncogenic pathways in inflammatory breast cancer.
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Zhang EY, Cristofanilli M, Robertson F, Reuben JM, Mu Z, Beavis RC, Im H, Snyder M, Hofree M, Ideker T, Omenn GS, Fanayan S, Jeong SK, Paik YK, Zhang AF, Wu SL, and Hancock WS
- Subjects
- Breast Neoplasms metabolism, Breast Neoplasms pathology, Cell Line, Tumor, ErbB Receptors metabolism, Female, Gene Expression Profiling, Genome-Wide Association Study, Humans, Inflammation, Molecular Sequence Annotation, Neoplasm Proteins metabolism, Proteomics, RNA, Messenger metabolism, Receptor, ErbB-2 metabolism, Signal Transduction, Breast Neoplasms genetics, ErbB Receptors genetics, Gene Expression Regulation, Neoplastic, Neoplasm Proteins genetics, RNA, Messenger genetics, Receptor, ErbB-2 genetics
- Abstract
In this study we selected three breast cancer cell lines (SKBR3, SUM149 and SUM190) with different oncogene expression levels involved in ERBB2 and EGFR signaling pathways as a model system for the evaluation of selective integration of subsets of transcriptomic and proteomic data. We assessed the oncogene status with reads per kilobase per million mapped reads (RPKM) values for ERBB2 (14.4, 400, and 300 for SUM149, SUM190, and SKBR3, respectively) and for EGFR (60.1, not detected, and 1.4 for the same 3 cell lines). We then used RNA-Seq data to identify those oncogenes with significant transcript levels in these cell lines (total 31) and interrogated the corresponding proteomics data sets for proteins with significant interaction values with these oncogenes. The number of observed interactors for each oncogene showed a significant range, e.g., 4.2% (JAK1) to 27.3% (MYC). The percentage is measured as a fraction of the total protein interactions in a given data set vs total interactors for that oncogene in STRING (Search Tool for the Retrieval of Interacting Genes/Proteins, version 9.0) and I2D (Interologous Interaction Database, version 1.95). This approach allowed us to focus on 4 main oncogenes, ERBB2, EGFR, MYC, and GRB2, for pathway analysis. We used bioinformatics sites GeneGo, PathwayCommons and NCI receptor signaling networks to identify pathways that contained the four main oncogenes and had good coverage in the transcriptomic and proteomic data sets as well as a significant number of oncogene interactors. The four pathways identified were ERBB signaling, EGFR1 signaling, integrin outside-in signaling, and validated targets of C-MYC transcriptional activation. The greater dynamic range of the RNA-Seq values allowed the use of transcript ratios to correlate observed protein values with the relative levels of the ERBB2 and EGFR transcripts in each of the four pathways. This provided us with potential proteomic signatures for the SUM149 and 190 cell lines, growth factor receptor-bound protein 7 (GRB7), Crk-like protein (CRKL) and Catenin delta-1 (CTNND1) for ERBB signaling; caveolin 1 (CAV1), plectin (PLEC) for EGFR signaling; filamin A (FLNA) and actinin alpha1 (ACTN1) (associated with high levels of EGFR transcript) for integrin signalings; branched chain amino-acid transaminase 1 (BCAT1), carbamoyl-phosphate synthetase (CAD), nucleolin (NCL) (high levels of EGFR transcript); transferrin receptor (TFRC), metadherin (MTDH) (high levels of ERBB2 transcript) for MYC signaling; S100-A2 protein (S100A2), caveolin 1 (CAV1), Serpin B5 (SERPINB5), stratifin (SFN), PYD and CARD domain containing (PYCARD), and EPH receptor A2 (EPHA2) for PI3K signaling, p53 subpathway. Future studies of inflammatory breast cancer (IBC), from which the cell lines were derived, will be used to explore the significance of these observations.
- Published
- 2013
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28. A chromosome-centric human proteome project (C-HPP) to characterize the sets of proteins encoded in chromosome 17.
- Author
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Liu S, Im H, Bairoch A, Cristofanilli M, Chen R, Deutsch EW, Dalton S, Fenyo D, Fanayan S, Gates C, Gaudet P, Hincapie M, Hanash S, Kim H, Jeong SK, Lundberg E, Mias G, Menon R, Mu Z, Nice E, Paik YK, Uhlen M, Wells L, Wu SL, Yan F, Zhang F, Zhang Y, Snyder M, Omenn GS, Beavis RC, and Hancock WS
- Subjects
- Amino Acid Sequence, Databases, Protein, Gene Expression, Human Genome Project, Humans, Chromosomes, Human, Pair 17 genetics, Chromosomes, Human, Pair 17 metabolism, Genome, Human, Proteins classification, Proteins genetics, Proteins metabolism, Proteomics
- Abstract
We report progress assembling the parts list for chromosome 17 and illustrate the various processes that we have developed to integrate available data from diverse genomic and proteomic knowledge bases. As primary resources, we have used GPMDB, neXtProt, PeptideAtlas, Human Protein Atlas (HPA), and GeneCards. All sites share the common resource of Ensembl for the genome modeling information. We have defined the chromosome 17 parts list with the following information: 1169 protein-coding genes, the numbers of proteins confidently identified by various experimental approaches as documented in GPMDB, neXtProt, PeptideAtlas, and HPA, examples of typical data sets obtained by RNASeq and proteomic studies of epithelial derived tumor cell lines (disease proteome) and a normal proteome (peripheral mononuclear cells), reported evidence of post-translational modifications, and examples of alternative splice variants (ASVs). We have constructed a list of the 59 "missing" proteins as well as 201 proteins that have inconclusive mass spectrometric (MS) identifications. In this report we have defined a process to establish a baseline for the incorporation of new evidence on protein identification and characterization as well as related information from transcriptome analyses. This initial list of "missing" proteins that will guide the selection of appropriate samples for discovery studies as well as antibody reagents. Also we have illustrated the significant diversity of protein variants (including post-translational modifications, PTMs) using regions on chromosome 17 that contain important oncogenes. We emphasize the need for mandated deposition of proteomics data in public databases, the further development of improved PTM, ASV, and single nucleotide variant (SNV) databases, and the construction of Web sites that can integrate and regularly update such information. In addition, we describe the distribution of both clustered and scattered sets of protein families on the chromosome. Since chromosome 17 is rich in cancer-associated genes, we have focused the clustering of cancer-associated genes in such genomic regions and have used the ERBB2 amplicon as an example of the value of a proteogenomic approach in which one integrates transcriptomic with proteomic information and captures evidence of coexpression through coordinated regulation.
- Published
- 2013
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29. MR-guided pulsed high intensity focused ultrasound enhancement of docetaxel combined with radiotherapy for prostate cancer treatment.
- Author
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Mu Z, Ma CM, Chen X, Cvetkovic D, Pollack A, and Chen L
- Subjects
- Animals, Biological Transport, Cell Line, Tumor, Combined Modality Therapy, Docetaxel, Humans, Male, Mice, Prostatic Neoplasms metabolism, Prostatic Neoplasms pathology, Taxoids metabolism, Taxoids therapeutic use, Treatment Outcome, Tumor Burden drug effects, Tumor Burden radiation effects, Xenograft Model Antitumor Assays, High-Intensity Focused Ultrasound Ablation, Magnetic Resonance Imaging, Prostatic Neoplasms drug therapy, Prostatic Neoplasms radiotherapy, Surgery, Computer-Assisted, Taxoids pharmacology
- Abstract
The purpose of this study is to evaluate the efficacy of the enhancement of docetaxel by pulsed focused ultrasound (pFUS) in combination with radiotherapy (RT) for treatment of prostate cancer in vivo. LNCaP cells were grown in the prostates of male nude mice. When the tumors reached a designated volume by MRI, tumor bearing mice were randomly divided into seven groups (n = 5): (1) pFUS alone; (2) RT alone; (3) docetaxel alone; (4) docetaxel + pFUS; (5) docetaxel + RT; (6) docetaxel + pFUS + RT, and (7) control. MR-guided pFUS treatment was performed using a focused ultrasound treatment system (InSightec ExAblate 2000) with a 1.5T GE MR scanner. Animals were treated once with pFUS, docetaxel, RT or their combinations. Docetaxel was given by i.v. injection at 5 mg kg(-1) before pFUS. RT was given 2 Gy after pFUS. Animals were euthanized 4 weeks after treatment. Tumor volumes were measured on MRI at 1 and 4 weeks post-treatment. Results showed that triple combination therapies of docetaxel, pFUS and RT provided the most significant tumor growth inhibition among all groups, which may have potential for the treatment of prostate cancer due to an improved therapeutic ratio.
- Published
- 2012
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30. MR-guided focused ultrasound: enhancement of intratumoral uptake of [³H]-docetaxel in vivo.
- Author
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Chen L, Mu Z, Hachem P, Ma CM, Wallentine A, and Pollack A
- Subjects
- Animals, Antineoplastic Agents pharmacology, Antineoplastic Agents therapeutic use, Biological Transport, Capillary Permeability, Cell Line, Tumor, Docetaxel, Humans, Male, Mice, Prostatic Neoplasms diagnosis, Prostatic Neoplasms drug therapy, Taxoids pharmacology, Taxoids therapeutic use, Temperature, Thermometers, Time Factors, Tritium, Xenograft Model Antitumor Assays, Antineoplastic Agents pharmacokinetics, Magnetic Resonance Imaging, Prostatic Neoplasms metabolism, Prostatic Neoplasms therapy, Taxoids pharmacokinetics, Ultrasonic Therapy methods
- Abstract
The purpose of this study is to quantify the enhancement of [³H]-docetaxel in implanted prostate tumors treated with MR-guided pulsed focused ultrasound (MRgFUS). Human prostate cancer, LNCaP cells in 25 µl, were implanted into the prostates of male nude mice. The tumor growth was directly monitored on MRI. When the tumor reached a designated size, MRgFUS treatment was performed using a focused ultrasound treatment system (InSightec ExAblate 2000) with a 1.5 T GE MR scanner. The tumor-bearing animals were randomly divided into three groups: group 1, MRgFUS treatment + [³H]-docetaxel; group 2, [³H]-docetaxel only and group 3, as a control. Animals in group 1 were treated with MRgFUS non-invasively. Immediately after the treatment, the animals received a single dose of tail vein injection of docetaxel at 15 mg kg⁻¹ mixed with [³H]-docetaxel at 50 uCi kg⁻¹ in a total volume of 150 µl. Animals in group 2 were treated the same as in group one, however without MRgFUS treatment. Animals in group 3 were treated as a control. Animals were sacrificed 30 min after i.v. injections regardless of whether or not they received focused ultrasound. Tumors were removed and processed. The radioactivity of [³H]-docetaxel in the tumor tissue was quantitatively measured by a liquid scintillation counter. Our study showed that all animals tolerated the MRgFUS treatment well. Our data showed increased (³H-docetaxel concentration in the tumor in the MRgFUS-treated group (1079 ± 132 cmp/75 mg) versus those without MRgFUS treatment (524 ± 201 cmp/75 mg) with P = 0.037.
- Published
- 2010
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31. Antisense MDM2 oligonucleotides restore the apoptotic response of prostate cancer cells to androgen deprivation.
- Author
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Mu Z, Hachem P, Agrawal S, and Pollack A
- Subjects
- Blotting, Western, Cell Survival, Gene Expression Profiling, Humans, Male, Nuclear Proteins pharmacology, Proto-Oncogene Proteins pharmacology, Proto-Oncogene Proteins c-mdm2, Proto-Oncogene Proteins p21(ras) biosynthesis, Tumor Cells, Cultured, Tumor Stem Cell Assay, Tumor Suppressor Protein p53 biosynthesis, Zinc Fingers, Androgen Antagonists pharmacology, Apoptosis drug effects, Nuclear Proteins biosynthesis, Nuclear Proteins genetics, Oligonucleotides, Antisense pharmacology, Prostatic Neoplasms pathology, Proto-Oncogene Proteins biosynthesis, Proto-Oncogene Proteins genetics
- Abstract
Background: Early in the malignant transformation of prostate epithelial cells, the apoptotic response to androgen deprivation (AD) is lost and the principle response is a slowing of cell growth. In this study, we tested whether interruption of MDM2 function using antisense MDM2 oligonucleotide (AS) affects the apoptotic response of prostate cancer cells to AD., Methods: Wild type LNCaP cells and MDM2-overexpressing (LNCaP-MST) cells were treated with AS alone or in combination with AD. Protein levels of MDM2, p53, and p21 were determined by Western blotting. Cell viability was measure by trypan blue staining. Apoptotic cell death was confirmed by cell morphological changes, annexin V/propidium iodide staining and caspase-3 + 7 activity. Overall cell survival was quantified by clonogenic assay., Results: AS inhibited MDM2 expression to a greater extent in LNCaP cells, as compared to LNCaP-MST cells. AS enhanced the expression of p53 and p21 in both cell lines. The growth inhibitory and cell death effects of AS + AD were generally greater than AS alone in LNCaP cells. Treatment of LNCaP cells with AS + AD for 72 hr caused a significant increase in cell death (66%) over AD alone (13%), AS alone (33%), or AD + AS + R1881 (34% with synthetic androgen replacement) that was attributable mainly to apoptosis. Clonogenic survival reflected the same pattern., Conclusions: Our results suggest that the apoptotic response of prostate cancer to AD is strongly influenced by MDM2 expression. Antisense MDM2 has broad potential as a therapeutic agent to sensitize prostate cancer cells to AD therapy by enhancing apoptotic cell death., (Copyright 2004 Wiley-Liss, Inc.)
- Published
- 2004
- Full Text
- View/download PDF
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