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  • 1
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    Online Resource
    Breast Cancer Antiestrogen Resistance 3 (BCAR3) Promotes Cell Motility by Regulating Actin Cytoskeletal and Adhesion Remodeling in Invasive Breast Cancer Cells
    Public Library of Science (PLoS) ; 2013
    In:  PLoS ONE Vol. 8, No. 6 ( 2013-6-6), p. e65678-
    Details
    In: PLoS ONE, Public Library of Science (PLoS), Vol. 8, No. 6 ( 2013-6-6), p. e65678-
    Type of Medium: Online Resource
    ISSN: 1932-6203
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    DOI: 10.1371/journal.pone.0065678
    DOI: 10.1371/journal.pone.0065678.g001
    DOI: 10.1371/journal.pone.0065678.g002
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    DOI: 10.1371/journal.pone.0065678.s001
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    DOI: 10.1371/journal.pone.0065678.s007
    Language: English
    Publisher: Public Library of Science (PLoS)
    Publication Date: 2013
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  • 2
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    Abstract 3778: Breast Cancer Antiestrogen Resistance 3 (BCAR3) promotes cell motility by regulating actin cytoskeletal and adhesion remodeling in invasive breast cancer cells.
    American Association for Cancer Research (AACR) ; 2013
    In:  Cancer Research Vol. 73, No. 8_Supplement ( 2013-04-15), p. 3778-3778
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 73, No. 8_Supplement ( 2013-04-15), p. 3778-3778
    Abstract: Metastatic breast cancer is currently incurable and associated with a 5-year survival rate of only 23%. Thus it is critical to develop a better understanding of the molecular mechanisms that regulate metastasis and the underlying process of cell motility in order to improve patient survival. The adaptor molecule Breast Cancer Antiestrogen Resistance 3 (BCAR3) functions in cellular processes that contribute to cell motility. Previous work from our group has shown that elevated BCAR3 protein levels enhance breast cancer cell motility, while depletion of BCAR3 decreases cell motility and invasion in vitro. Here, we show BCAR3 controls membrane protrusion, Rac1 activity, and adhesion disassembly in invasive breast cancer cells in response to adhesion signals. Conversely, RhoA signaling pathways appear to predominate when BCAR3 is depleted from these cells, as evidenced by an increase in ROCK-mediated myosin light chain phosphorylation and the presence of stress fibers and large ROCK/mDia1-dependent focal adhesions. Thus, through its ability to tip the balance in favor of Rac1 signaling, BCAR3 functions as a positive regulator of cytoskeletal remodeling and adhesion turnover in invasive breast cancer cells, thereby promoting a more invasive, pro-migratory phenotype. Interestingly, we demonstrate that BCAR3 also controls actin cytoskeletal and adhesion remodeling in invasive breast cancer cells in response to epidermal growth factor. Considering that BCAR3 protein levels are elevated in advanced breast cancer cells lines, we propose that BCAR3 functions in the transition to advanced disease by triggering intracellular signaling events that are essential to the metastatic process. BCAR3 function is intimately linked to two other proteins, the adaptor molecule p130Cas (Cas) and the non-receptor tyrosine kinase c-Src. While BCAR3 protein levels have yet to be thoroughly assessed in human breast tumors, high expression of Cas and/or c-Src is associated with more aggressive breast cancer behaviors. Future work will determine whether this BCAR3/Cas/c-Src signaling network serves as a useful biomarker for invasive disease, and whether BCAR3 promotes breast tumor progression and metastasis in mouse models of human breast cancer. Citation Format: Ashley L. Wilson, Randy S. Schrecengost, Michael S. Guerrero, Keena S. Thomas, Amy H. Bouton. Breast Cancer Antiestrogen Resistance 3 (BCAR3) promotes cell motility by regulating actin cytoskeletal and adhesion remodeling in invasive breast cancer cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3778. doi:10.1158/1538-7445.AM2013-3778
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2013-3778
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2013
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    detail.hit.zdb_id: 410466-3
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  • 3
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    Breast Cancer Antiestrogen Resistance-3 Expression Regulates Breast Cancer Cell Migration through Promotion of p130Cas Membrane Localization and Membrane Ruffling
    American Association for Cancer Research (AACR) ; 2007
    In:  Cancer Research Vol. 67, No. 13 ( 2007-07-01), p. 6174-6182
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 67, No. 13 ( 2007-07-01), p. 6174-6182
    Abstract: Antiestrogens such as tamoxifen are widely used in the clinic to treat estrogen receptor–positive breast tumors. Resistance to tamoxifen can occur either de novo or develop over time in a large proportion of these tumors. Additionally, resistance is associated with enhanced motility and invasiveness in vitro. One molecule that has been implicated in tamoxifen resistance, breast cancer antiestrogen resistance-3 (BCAR3), has also been shown to regulate migration of fibroblasts. In this study, we investigated the role of BCAR3 in breast cancer cell migration and invasion. We found that BCAR3 was highly expressed in multiple breast cancer cell lines, where it associated with another protein, p130Cas (also known as breast cancer antiestrogen resistance-1; BCAR1), that plays a role in both tamoxifen resistance and cell motility. In cells with relatively low migratory potential, BCAR3 overexpression resulted in enhanced migration and colocalization with p130Cas at the cell membrane. Conversely, BCAR3 depletion from more aggressive breast cancer cell lines inhibited migration and invasion. This coincided with a relocalization of p130Cas away from the cell membrane and an attenuated response to epidermal growth factor stimulation that was characterized by a loss of membrane ruffles, decreased migration toward EGF, and disruption of p130Cas/Crk complexes. Based on these data, we propose that the spatial and temporal regulation of BCAR3/p130Cas interactions within the cell is important for controlling breast cancer cell motility. [Cancer Res 2007;67(13):6174–82]
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-06-3455
    RVK:
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2007
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  • 4
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    Abstract 5135: Breast cancer antiestrogen resistance-3 influences breast cancer cell migration by regulating Rac and Rho GTPase signaling
    American Association for Cancer Research (AACR) ; 2010
    In:  Cancer Research Vol. 70, No. 8_Supplement ( 2010-04-15), p. 5135-5135
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 70, No. 8_Supplement ( 2010-04-15), p. 5135-5135
    Abstract: Breast Cancer Antiestrogen Resistance-3 (BCAR3) was initially identified as a gene whose expression confers resistance to endocrine therapy, such as the antiestrogen tamoxifen. However, work from our group as well as others implicate BCAR3 as a prominent regulator of cell migration and invasion. This is of interest because expression of BCAR3 is elevated in more aggressive breast cancer cell lines. In this study, we have taken both a gain-of-function and loss-of-function approach to determine the mechanism by which BCAR3 regulates cell migration and invasion. We found that overexpression of BCAR3 in less aggressive breast cancer cells resulted in enhanced cell migration and increased protrusive activity. Additionally, BCAR3 was co-localized at the cell membrane with an established scaffold protein, p130Cas (also known as BCAR1 or Cas). Conversely, siRNA-mediated depletion of BCAR3 in more aggressive breast cancer cells inhibited cell migration and decreased membrane protrusiveness, coincident with a significant reduction in Rac GTPase activity. This was accompanied by mislocalization of Cas and a decrease in Cas tyrosine phosphorylation. Loss of BCAR3 was also associated with stabilization of stress fibers, reduced adhesion turnover, and increased ROCK-dependent phosphorylation of myosin light chain, a major downstream target of Rho GTPase. Inhibition of ROCK in BCAR3-depleted cells disrupted stress fibers and restored membrane protrusions, confirming and indicating that the effect of BCAR3 depletion on stress fiber dynamics was dependent on ROCK. Furthermore, Cas localization to the cell periphery was restored and partial rescue of Cas tyrosine phosphorylation was observed. Taken together, these results suggest a model whereby BCAR3 expression influences cell migration and invasion by promoting Cas phosphorylation and Cas-mediated Rac activation, while negatively regulating Rho-mediated contractility. While the major mechanisms of BCAR3 as a critical regulator of breast cancer cell migration are addressed here, future studies will determine whether elevated BCAR3 expression promotes metastasis in animal models and is associated with clinical outcome in patients. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5135.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM10-5135
    RVK:
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2010
    detail.hit.zdb_id: 2036785-5
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  • 5
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    DIPG-15. CONCURRENT GB-13 (IL13.E13K-PE4E) IMPROVES THE EFFICACY OF RADIATION THERAPY IN DIFFUSE INTRINSIC PONTINE GLIOMA
    Oxford University Press (OUP) ; 2023
    In:  Neuro-Oncology Vol. 25, No. Supplement_1 ( 2023-06-12), p. i16-i16
    Details
    In: Neuro-Oncology, Oxford University Press (OUP), Vol. 25, No. Supplement_1 ( 2023-06-12), p. i16-i16
    Abstract: Diffuse midline glioma with H3 K27 alterations (DMG) is the most aggressive primary malignant brain tumor in the pediatric population. Radiation therapy (RT) is the standard-of-care; however, it has not demonstrated a significant improvement in overall survival or stalled disease progression, and children usually succumb to disease within 12-15 months of diagnosis. Consequently, finding efficient treatments for DMG remains one of the most critical unmet needs in modern neuro-oncology. Interleukin 13 receptor subunit alpha 2 (IL-13Rα2) is a cell-surface receptor upregulated in ~80% of DMG versus normal brain, posing a potentially promising therapeutic target. Immunotherapies harnessing IL-13Rα2 to selectively delivery cytotoxic payloads, such as pseudomonas exotoxin A (PE), to tumor cells have been previously demonstrated to be safe in DMG patients and efficacious in preclinical models of DMG with high IL-13Rα2 expression using convection-enhanced delivery (CED). Furthermore, there is evidence that PE-based therapies can sensitize cells to RT. In this study, we utilized in vitro and in vivo models of DMG to evaluate clinically-relevant combination treatments of RT and the IL-13/PE immunotoxin GB-13 (IL13.E13K-PE4E). GB-13 improved the effectiveness of low-dose RT in multiple DMG cell lines by promoting caspase activation, which boosted apoptotic cell death. Intratumoral administration of GB-13 via chronic CED decreased tumor burden and prolonged survival in both DMG patient-derived orthotopic xenograft and genetically engineered mouse models. When GB-13 and RT were administered concurrently, this impact became even more prominent, informing future preclinical and clinical investigation of a potentially efficacious therapeutic approach in a subset of DMG.
    Type of Medium: Online Resource
    ISSN: 1522-8517 , 1523-5866
    URL: Article
    DOI: 10.1093/neuonc/noad073.062
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2023
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  • 6
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    IL-13Rα2 Status Predicts GB-13 (IL13.E13K-PE4E) Efficacy in High-Grade Glioma
    MDPI AG ; 2022
    In:  Pharmaceutics Vol. 14, No. 5 ( 2022-04-24), p. 922-
    Details
    In: Pharmaceutics, MDPI AG, Vol. 14, No. 5 ( 2022-04-24), p. 922-
    Abstract: High-grade gliomas (HGG) are devastating diseases in children and adults. In the pediatric population, diffuse midline gliomas (DMG) harboring H3K27 alterations are the most aggressive primary malignant brain tumors. With no effective therapies available, children typically succumb to disease within one year of diagnosis. In adults, glioblastoma (GBM) remains largely intractable, with a median survival of approximately 14 months despite standard clinical care of radiation and temozolomide. Therefore, effective therapies for these tumors remain one of the most urgent and unmet needs in modern medicine. Interleukin 13 receptor subunit alpha 2 (IL-13Rα2) is a cell-surface transmembrane protein upregulated in many HGGs, including DMG and adult GBM, posing a potentially promising therapeutic target for these tumors. In this study, we investigated the pharmacological effects of GB-13 (also known as IL13.E13K-PE4E), a novel peptide–toxin conjugate that contains a targeting moiety designed to bind IL-13Rα2 with high specificity and a point-mutant cytotoxic domain derived from Pseudomonas exotoxin A. Glioma cell lines demonstrated a spectrum of IL-13Rα2 expression at both the transcript and protein level. Anti-tumor effects of GB-13 strongly correlated with IL-13Rα2 expression and were reflected in apoptosis induction and decreased cell proliferation in vitro. Direct intratumoral administration of GB-13 via convection-enhanced delivery (CED) significantly decreased tumor burden and resulted in prolonged survival in IL-13Rα2-upregulated orthotopic xenograft models of HGG. In summary, administration of GB-13 demonstrated a promising pharmacological response in HGG models both in vitro and in vivo in a manner strongly associated with IL-13Rα2 expression, underscoring the potential of this IL-13Rα2-targeted therapy in a subset of HGG with increased IL-13Rα2 levels.
    Type of Medium: Online Resource
    ISSN: 1999-4923
    URL: Article
    DOI: 10.3390/pharmaceutics14050922
    Language: English
    Publisher: MDPI AG
    Publication Date: 2022
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    SSG: 15,3
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  • 7
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    Pathways to tamoxifen resistance
    Elsevier BV ; 2007
    In:  Cancer Letters Vol. 256, No. 1 ( 2007-10), p. 1-24
    Details
    In: Cancer Letters, Elsevier BV, Vol. 256, No. 1 ( 2007-10), p. 1-24
    Type of Medium: Online Resource
    ISSN: 0304-3835
    URL: Article
    DOI: 10.1016/j.canlet.2007.03.016
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2007
    detail.hit.zdb_id: 195674-7
    detail.hit.zdb_id: 2004212-7
    SSG: 12
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  • 8
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    A Novel Association between p130Cas and Resistance to the Chemotherapeutic Drug Adriamycin in Human Breast Cancer Cells
    American Association for Cancer Research (AACR) ; 2008
    In:  Cancer Research Vol. 68, No. 21 ( 2008-11-01), p. 8796-8804
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 68, No. 21 ( 2008-11-01), p. 8796-8804
    Abstract: Resistance to chemotherapy remains a major obstacle for the treatment of breast cancer. Understanding the molecular mechanism(s) of resistance is crucial for the development of new effective therapies to treat this disease. This study examines the putative role of p130Cas (Cas) in resistance to the cytotoxic agent Adriamycin. High expression of Cas in primary breast tumors is associated with the failure to respond to the antiestrogen tamoxifen and poor prognosis, highlighting the potential clinical importance of this molecule. Here, we show a novel association between Cas and resistance to Adriamycin. We show that Cas overexpression renders MCF-7 breast cancer cells less sensitive to the growth inhibitory and proapoptotic effects of Adriamycin. The catalytic activity of the nonreceptor tyrosine kinase c-Src, but not the epidermal growth factor receptor, is critical for Cas-mediated protection from Adriamycin-induced death. The phosphorylation of Akt and extracellular signal-regulated kinase 1/2 (ERK1/2) is elevated in Cas-overexpressing cells treated with Adriamycin, whereas expression of the proapoptotic protein Bak is decreased. Conversely, Cas depletion in the more resistant T47D and MDA-MB-231 cell lines increases sensitivity to Adriamycin. Based on these data, we propose that Cas activates growth and survival pathways regulated by c-Src, Akt, and ERK1/2 that lead to the inhibition of mitochondrial-mediated apoptosis in the presence of Adriamycin. Because Cas is frequently expressed at high levels in breast cancers, these findings raise the possibility of resensitizing Cas-overexpressing tumors to chemotherapy through perturbation of Cas signaling pathways. [Cancer Res 2008;68(21):8796–804]
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-08-2426
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2008
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 9
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    BCAR3 Regulates Src/p130Cas Association, Src Kinase Activity, and Breast Cancer Adhesion Signaling
    Elsevier BV ; 2010
    In:  Journal of Biological Chemistry Vol. 285, No. 4 ( 2010-01), p. 2309-2317
    Details
    In: Journal of Biological Chemistry, Elsevier BV, Vol. 285, No. 4 ( 2010-01), p. 2309-2317
    Type of Medium: Online Resource
    ISSN: 0021-9258
    URL: Article
    DOI: 10.1074/jbc.M109.046631
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2010
    detail.hit.zdb_id: 2141744-1
    detail.hit.zdb_id: 1474604-9
    SSG: 12
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  • 10
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    The use of gamma-irradiation and ultraviolet-irradiation in the preparation of human melanoma cells for use in autologous whole-cell vaccines
    Springer Science and Business Media LLC ; 2008
    In:  BMC Cancer Vol. 8, No. 1 ( 2008-12)
    Details
    In: BMC Cancer, Springer Science and Business Media LLC, Vol. 8, No. 1 ( 2008-12)
    Abstract: Human cancer vaccines incorporating autologous tumor cells carry a risk of implantation and subsequent metastasis of viable tumor cells into the patient who is being treated. Despite the fact that the melanoma cell preparations used in a recent vaccine trial (Mel37) were gamma-irradiated (200 Gy), approximately 25% of the preparations failed quality control release criteria which required that the irradiated cells incorporate 3 H-thymidine at no more than 5% the level seen in the non-irradiated cells. We have, therefore, investigated ultraviolet (UV)-irradiation as a possible adjunct to, or replacement for gamma-irradiation. Methods Melanoma cells were gamma- and/or UV-irradiated. 3 H-thymidine uptake was used to assess proliferation of the treated and untreated cells. Caspase-3 activity and DNA fragmentation were measured as indicators of apoptosis. Immunohistochemistry and Western blot analysis was used to assess antigen expression. Results UV-irradiation, either alone or in combination with gamma-irradiation, proved to be extremely effective in controlling the proliferation of melanoma cells. In contrast to gamma-irradiation, UV-irradiation was also capable of inducing significant levels of apoptosis. UV-irradiation, but not gamma-irradiation, was associated with the loss of tyrosinase expression. Neither form of radiation affected the expression of gp100, MART-1/MelanA, or S100. Conclusion These results indicate that UV-irradiation may increase the safety of autologous melanoma vaccines, although it may do so at the expense of altering the antigenic profile of the irradiated tumor cells.
    Type of Medium: Online Resource
    ISSN: 1471-2407
    URL: Article
    DOI: 10.1186/1471-2407-8-360
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2008
    detail.hit.zdb_id: 2041352-X
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