bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 333: ZBP-89 downregulates histone deacetylase 3 (HDAC3) through inhibition of I kappa B in hepatocelluar carcinoma (HCC)
Authors: Lai Paul B. , Ye Cai-Guo , Liu Liping , He Ming-Liang , Ho Rocky , Chen George G. 
Published: May 2015

Abstract
Background
Histone deacetylase 3 (HDAC3) is frequently overexpressed in hepatocelluar carcinoma (HCC) and its inhibition enhances the efficacy of anti-HCC chemotherapy. ZBP-89 is known to induce apoptosis via an increase of pro-apoptotic Bak. But the relationship between ZBP-89 and HDAC3 is largely unknown.
Method
Human HCC cell lines PLC/PRF/5 and HepG2 were cultured in Minimum Essential Medium and treated with various agents to modulate NF-κB. These agents included CAY10576 and MG132 (which are inhibitors of I kappa B (IκB) degradation) as well as SN50 (an inhibitor of p65/p50 translocation). A xenograft tumor model was established by subcutaneous injection of HCC PLC/PRF/5 cells into nude mice and this model was used to confirm data obtained in HCC cell culture experiments. The expressions of relevant proteins were measured by Western blot or/and immunohistochemical staining.
Results
Our results showed that ZBP-89 reduced the expression of HDAC3 in HCC cells. ZBP-89 could form a complex with IκB and induce the phosphorylation of IκB, which inhibited IκB. Furthermore, ZBP-89-mediated HDAC3 reduction could be suppressed by IκB degradation inhibitors CAY10576 and MG132 but not NF-κB subunit p65/p50 translocation inhibitor SN50. These findings indicate that IκB decreases rather than increases the activity of NF-κB; and such may be involved in the ZBP-89-mediated HDAC3 reduction. In the HCC xenograft model, it was confirmed that the expression of HDAC3, measured by immunohistochemical staining and Western blot, was reduced in HCC with ZBP-89 overexpression, compared with the control. In contrast to HDAC3, ZBP-89 enhanced the expression of Bak.
Conclusion
ZBP-89 downregulates HDAC3 by decreasing IκB rather than elevating activity of NF-κB. This novel pathway identified helps us understand more the mechanism of ZBP-89-mediated inhibition of HCC.
Citation Format: Paul B. Lai, Cai-Guo Ye, Liping Liu, Ming-Liang He, Rocky Ho, George G. Chen. ZBP-89 downregulates histone deacetylase 3 (HDAC3) through inhibition of I kappa B in hepatocelluar carcinoma (HCC). [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 333. doi:10.1158/1538-7445.AM2014-333
Abstract 3330: HER2 overexpression induces membrane deformation that increases cell motility
Authors: Chung Inhee , Reichelt Mike , Dowbenko Donald , Mellman Ira , Sliwkowski Mark 
Published: May 2015

Abstract
Approximately 20% of breast cancers (BC) are characterized by the gene amplification and overexpression of HER2, a member of the ErbB/HER receptor family. While targeted therapies against HER2 effectively delay disease progression in this BC subtype, details of how overexpressed HER2s drive these tumors to malignancy are still unclear. To better understand this process, we investigated various cellular responses to HER2 overexpression in individual live cells. We developed novel single receptor diffusion analyses that determine the activation status of HER2 by diffusivity, to estimate average HER2 activity per single cell. Surprisingly, we found HER2 overexpression induces membrane deformation, which depends only on the HER2 density, but not the receptor activation status. Moreover, this membrane deformation lowers the available surface area for formation of focal adhesion sites, resulting in reduced cell adhesion and increased cell motility. These findings suggest there are signaling-independent roles of HER2 overexpression in disease progression of HER2 positive BCs.
Citation Format: Inhee Chung, Mike Reichelt, Donald Dowbenko, Ira Mellman, Mark Sliwkowski. HER2 overexpression induces membrane deformation that increases cell motility. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3330. doi:10.1158/1538-7445.AM2014-3330
Abstract 3331: CD24 promotes HER2 signaling pathways and CD24 inhibition sensitizes anti-HER2 therapy in breast cancer
Authors: Arima Yoshimi , Hosonaga Mari , Saya Hideyuki 
Published: May 2015

Abstract
Human epidermal growth factor receptor 2 (HER2)-overexpressing breast cancers are treated with HER2-targeted agents such as trastuzumab and lapatinib, which suppress HER2-initiated activation of the phosphatidylinositol 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) cascades. CD24 is a glycosyl phosphatidylinositol (GPI)-anchored membrane protein and its overexpression is correlated with a poor prognosis in breast cancer patients. It has been reported that CD24 tends to be highly expressed in the HR-HER2+ breast cancer subgroup, which is negative for the hormone receptors (HRs) and positive for HER2. To determine the relationship between CD24 and HER2, we overexpressed HER2 in MDA-MB-231 breast cancer cells, which were negative for CD24 and HER2. We found that the expression of CD24 was increased by the overexpression of HER2. Flow cytometry analysis showed that the expression of CD24 was higher in the HER2-positive fraction than in the HER2-negative fraction. Conversely, in BT474 cells which express both CD24 and HER2, CD24 knockdown reduced the expression of HER2, while the knockdown of HER2 did not affect the expression of CD24. Furthermore, the knockdown of CD24 decreased the phosphorylation of Akt, which is known as a downstream molecule of PI3K and is related to cell survival. Accordingly, CD24 plays an important role in the regulation of the HER2-initiated signaling pathway. Based on these findings, we speculated that the expression of CD24 promotes a resistance to HER2-targeted therapies, leading to tumor progression in HER2-overexpressing cancers. We found that the knockdown of CD24 enhanced the sensitivity to lapatinib treatment. Consequently, we suggest using an anti-CD24 therapy to enhance the HER2-targeted therapy.
Citation Format: Yoshimi Arima, Mari Hosonaga, Hideyuki Saya. CD24 promotes HER2 signaling pathways and CD24 inhibition sensitizes anti-HER2 therapy in breast cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3331. doi:10.1158/1538-7445.AM2014-3331
Abstract 3334: The role of nuclear HER3 in breast cancer resistance
Authors: Tang Patrick Ming Kuen , Khoo Ui Soon , Harris Adrian L. , Kong Anthony 
Published: May 2015

Abstract
HER3 is reported to be overexpressed in 18-29% of human breast cancers and suggested to be a marker of reduced disease-specific survival in 4,406 patients with invasive breast carcinoma. Overexpression and subcellular localization of HER3 may be a negative predictive marker for targeted therapies, and HER3 status may play a role in the development of drug resistance and metastasis. Translocation of ERBB family members EGFR, HER2 and HER4 into nucleus for regulating gene transcription have been reported, but only a few studies about nuclear HER3 have been reported and the biological role of nuclear HER3 is still unknown. HER3 was detected in the nucleus of 57% in Japanese lung cancers, and has also been detected in the nuclei of prostate cancers and other cancer cell lines. A study suggested that nuclear HER3 by IHC is associated with favorable overall survival in 128 uveal melanoma patients. The potential mechanism of HER3 translocation and its role on drug resistance was intensively studied in the work. According to our observation, nuclear HER3 was found to be significantly increased in HER2-positive breast cancer cells SKBr3 during an EGFR-targeted therapy Iressa, and increased sub-band of HER3 was detected by Western blot in the Iressa-resistant SKBr3 cells. The Iressa-induced HER3 nuclear localization in SKBr3 and BT474 cells can be inhibited by the application of ADAM17 and gamma-secretase inhibitors or siRNA, the additional inhibitors can sensitize the cells to Iressa treatment which may be a new target for preventing HER3-mediated drug resistance. If the HER3 subcellular localization is important for cancer development and drug resistance, inhibitor for this pathway will enhance the efficiency of recent therapies on breast cancer.
Citation Format: Patrick Ming Kuen Tang, Ui Soon Khoo, Adrian L. Harris, Anthony Kong. The role of nuclear HER3 in breast cancer resistance. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3334. doi:10.1158/1538-7445.AM2014-3334
Abstract 3337: LRIG1 decreases cell proliferation and motility through downregulation of ErbB2 611-CTF
Authors: Cedano-Prieto Maria E. 
Published: May 2015

Abstract
The receptor ErbB2 is a membrane bound protein that controls important cell functions including cell cycle progression; deregulated expression of this protein is associated with the development of a variety of cancer types. Notably, ErbB2 over-expression is observed in approximately 25% of human breast tumors.
Trastuzumab, an FDA approved therapeutic currently used to treat ErbB2 positive breast cancer patients, is a monoclonal antibody that directly binds the ErbB2 extracellular domain. Unfortunately, only a fraction of patients treated with trastuzumab durably respond to the treatment. Moreover, patients that are treated long term with this antibody develop resistance. One of the proposed mechanisms of trastuzumab resistance is the expression of 611-CTF, a C-terminal fragment of ErbB2 which lacks most of its extracellular domain. Remarkably, 611-CTF is hyperactive and has been associated with increased cell migration, tumor progression and metastasis.
Currently nothing is known regarding mechanisms which lead to 611-CTF down-regulation. This represents a significant knowledge gap in our understanding of 611-CTF and receptor fragments in general. Since 611-CTF is associated with poor clinical outcome and therapeutic resistance, it is essential to clarify the mechanisms by which this ErbB2 fragment is regulated. This knowledge could ultimately lead to the development of new therapeutics which could improve the response rate of 611-CTF-positive breast cancer.
LRIG1 is a tumor suppressor that directly interacts with ErbB2 leading to receptor degradation. In this study we examined whether 611-CTF is susceptible to LRIG1-mediated down-regulation. We find that these proteins interact and that expression of LRIG1 is sufficient to decrease 611-CTF protein expression in three different cell lines. Furthermore, LRIG1 is capable of reducing 611-CTF-driven tumor cell proliferation and migration. Our results are unexpected because LRIG1 is thought to recognize its targets through mutual extracellular domain interactions and 611-CTF lacks a large portion of the ErbB2 extracellular domain.
Citation Format: Maria E. Cedano-Prieto. LRIG1 decreases cell proliferation and motility through downregulation of ErbB2 611-CTF. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3337. doi:10.1158/1538-7445.AM2014-3337
Abstract 3338: IGFBP2 promotes EGFR/STAT3 nuclear crosstalk in glioma
Authors: Chua YingXuan , Liu Yuexin , Hu Limei , Granberg Kirsi , Verploegen Maartje , Zhang Wei 
Published: May 2015

Abstract
Insulin-like growth factor binding protein 2 (IGFBP2) is a pleiotropic secreted protein that is overexpressed in various cancers including glioma. Extracellular IGFBP2 binds and modulates the activity of insulin growth factors I and II (IGFI and IGFII) while cytoplasmic IGFBP2 interacts with signaling pathways essential for cell proliferation and survival. The versatility of IGFBP2 as a secreted or cytoplasmic signaling effector is widely characterized; however, the functions of nuclear IGFBP2 remain largely unknown. Through genomic and functional analyses of glioma, we mechanistically elucidated the role of nuclear IGFBP2 and discovered a functional interaction of IGFBP2 with epidermal growth factor receptor (EGFR) and signal transducer and activator of transcription 3 (STAT3) proteins. Our findings established a signaling hierarchy of IGFBP2-EGFR-STAT3; IGFBP2 not only upregulates EGFR/STAT3 signaling activity, but also facilitates EGFR nuclear translocation and subsequent nuclear EGFR/STAT3 activity. Furthermore, mutation of the nuclear localization signal of IGFBP2 demonstrated that nuclear translocation of IGFBP2 is critical to promote the nuclear activity of EGFR. By identifying the role of IGFBP2 in perpetuating nuclear crosstalk between EGFR/STAT3, our study further reveals the importance of exploiting IGFBP2 as a target for glioma therapy.
Citation Format: YingXuan Chua, Yuexin Liu, Limei Hu, Kirsi Granberg, Maartje Verploegen, Wei Zhang. IGFBP2 promotes EGFR/STAT3 nuclear crosstalk in glioma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3338. doi:10.1158/1538-7445.AM2014-3338
Abstract 334: Mcl-1 protects prostate cancer cells from chemotherapy-induced DNA damage
Authors: Perez-Stable Carlos , Reiner Teresita , Pozas Alicia de las , Parrondo Ricardo 
Published: May 2015

Abstract
Mcl-1 (myeloid cell leukemia sequence 1 [Bcl2-related]) is predominantly localized in the cytoplasm and protects cells from apoptosis by blocking mitochondrial outer membrane permeabilization. There is evidence that nuclear localization of Mcl-1 has pleiotropic effects independent of apoptosis, including functional roles in DNA damage response. Mcl-1 is highly expressed in castration-resistant prostate cancer (CRPC), resulting in resistance to apoptosis and association with poor prognosis. The role of nuclear Mcl-1 in mediating sensitivity to chemotherapy-induced DNA damage and apoptotic cell death in prostate cancer (PCa) is not known. The novel antimitotic agent ENMD-1198 is a more stable and potent derivative of 2-methoxyestradiol (2ME2). We confirmed that 1198 was a more potent inhibitor of androgen-dependent LNCaP and castration-resistant DU145 and PC3 PCa cell viability compared to 2ME2 and induced apoptotic cell death in docetaxel-resistant PC3 cells that overexpress the multi-drug resistance protein (MDR). The ability of 1198 to increase the proteasomal-mediated degradation of Mcl-1 correlated with enhanced apoptotic cell death and shRNA knockdown of Mcl-1 further sensitized LNCaP and PC3 cells to 1198-mediated cell death. We then showed that the combination of 1198 with betulinic acid (BA, a plant-derived small molecule that can increase apoptosis specifically in cancer but not in normal cells) reduced nuclear Mcl-1, increased a pro-death Mcl-1 isoform, increased gamma histone 2AX (marker of DNA damage), and enhanced apoptotic cell death in human PC3 CRPC cells. In the TRAMP mouse model of PCa, the 1198 (75 mg/kg) + BA (10 mg/kg) combination significantly reduced PCa weights compared to 1198, BA alone, and vehicle controls. However, the reduced PCa weights between the 1198 + BA combination and BA alone was more associated with decreased Mcl-1 and increased gamma-H2AX (DNA damage) immunostaining compared to cleaved caspase-3 (apoptosis), CD31(angiogenesis), or Ki67 (proliferation). Furthermore, our results showed that blocking the DNA damage response signaling pathway with an ATM kinase (KU55933) or DNA-PK (NU7441) inhibitor lowered apoptotic cell death induced by the 1198 + BA combination in PC3 cells. Overall, our results demonstrate that nuclear Mcl-1 has an important role in protecting PCa cells from DNA damage and that agents such as 1198 and BA that reduce total/nuclear Mcl-1 and increase pro-death Mcl-1 isoforms will sensitize PCa cells to antimitotic DNA damaging agents.
Citation Format: Carlos Perez-Stable, Teresita Reiner, Alicia de las Pozas, Ricardo Parrondo. Mcl-1 protects prostate cancer cells from chemotherapy-induced DNA damage. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 334. doi:10.1158/1538-7445.AM2014-334
Abstract 3342: The p110β isoform of PI3K modulates response to growth factor receptor signaling in breast cancer cells irrespective of PTEN status
Authors: Bouley Stephanie J. , Dillon Lloye M. , Miller Todd W. 
Published: May 2015

Abstract
The class 1a phosphatidylinositol 3-kinases (PI3Ks) regulate cell growth, survival, and metabolism. These PI3Ks are heterodimeric lipid kinases composed of a p85 regulatory subunit and a p110 catalytic subunit (p110α, p110β, or p110δ). p110α and p110β play distinct roles in PI3K signaling in carcinoma cells. p110α is activated by growth factor receptor kinase signaling. In contrast, p110β was shown to play a role in insulin metabolic action, G protein-coupled receptor (GPCR) signaling, and oncogenic transformation. Cancer cells deficient in PTEN, the tumor suppressor phosphatase that antagonizes PI3K signaling, have been shown to be sensitized to pharmacological inhibitors of p110β. As a result, early clinical studies with p110β inhibitors are restricted to patients with PTEN-deficient cancers. However, analysis of data from the Genomics of Drug Sensitivity in Cancer database revealed that genetic lesions in PTEN or PIK3CA (encodes p110α) were significantly and independently associated with increased sensitivity to the p110β inhibitor AZD6284. Among 668 cancer cell lines, 96, 57, and 5 lines harbored alterations in PTEN, PIK3CA, or both, respectively. Among 61 cell lines with IC50 values ≤2 μM, only 25 harbored an alteration in PTEN and/or PIK3CA. Thus, a significant fraction of cancer cell lines (and tumors) without PTEN alterations are likely to be sensitive to p110β inhibition. To explore the role of p110β in PI3K signaling in ER+ breast cancer, we treated cells with the p110β inhibitor GSK2636771 and monitored effects on growth factor-induced activation of AKT and MEK/ERK. We found that p110β inhibition reduced basal pAKT and pERK levels in PTEN-deficient cells. Furthermore, p110β inhibition reduced insulin-like growth factor 1 (IGF-1)-induced pAKT levels and delayed the onset of AKT phosphorylation in both PTEN-deficient and PTEN-wild-type cells. In contrast, p110β inhibition sensitized both PTEN-wildtype and PTEN-deficient cells to heregulin stimulation. These results indicate that p110β desensitizes cells to IGF-1 stimulation and hyper-sensitizes them to heregulin stimulation and suggests that p110β regulates downstream AKT and MEK/ERK activation in response to growth factor receptor activation. Our findings advocate for the testing of p110β inhibitors in cell lines (and tumors) selected based on growth factor dependence and PTEN status.
Citation Format: Stephanie J. Bouley, Lloye M. Dillon, Todd W. Miller. The p110β isoform of PI3K modulates response to growth factor receptor signaling in breast cancer cells irrespective of PTEN status. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3342. doi:10.1158/1538-7445.AM2014-3342
Abstract 3344: Akt1 and Akt3 exert opposing roles in the regulation of vascular tumor growth
Authors: Phung Thuy L. , Xue Qi , Nhek Sokha , Gerald Damien , Perruzzi Carole , Ayyaswamy Sriram , Du Wa , Geeganage Sandaruwan , Benjamin Laura 
Published: May 2015

Abstract
Vascular tumors are endothelial cell neoplasms with a wide spectrum of clinical presentations, ranging from benign infantile hemangiomas in children to low-grade malignant hemangioendotheliomas and highly aggressive angiosarcomas in adults. To date, the cellular and molecular mechanisms leading to vascular tumor formation are poorly understood, and current therapies, particularly those for malignant vascular tumors, have not significantly improved the clinical outcome.
We examined the growth regulatory pathways in vascular tumors, and showed that human vascular tumors have increased Akt activation, and constitutive activation of Akt1 in endothelial cells is sufficient to drive de novo vascular tumor formation in a transgenic mouse model. Importantly, we have uncovered the opposing functions of Akt isoforms in this regulation, in which Akt1 promotes, whereas Akt3 inhibits tumor endothelial cell migration and growth in in vitro and in vivo tumor models. Consistent with these findings, we observed reduced levels of Akt3 expression in human vascular tumors. Mechanistically, Akt3 blocks tumor cell migration and growth by inhibiting p70 S6-Kinase (S6K) activation, and Akt3 does so in part by modulating the levels of Rictor, a component of the mammalian target of rapamycin complex-2. S6K in turn exerts negative feedback regulation on Akt3 expression. Moreover, vascular tumor cells with Akt3 knockdown have increased S6K signaling, and are sensitized to a novel S6K inhibitor. Our findings provide a new perspective on Akt signaling, in which there are “check-and-balance” functions by different Akt isoforms to modulate the overall Akt signaling output. These studies also highlight the potential clinical utility of treating malignant vascular tumors, such as angiosarcomas, with agents that effectively block the S6K pathway.
Citation Format: Thuy L. Phung, Qi Xue, Sokha Nhek, Damien Gerald, Carole Perruzzi, Sriram Ayyaswamy, Wa Du, Sandaruwan Geeganage, Laura Benjamin. Akt1 and Akt3 exert opposing roles in the regulation of vascular tumor growth. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3344. doi:10.1158/1538-7445.AM2014-3344