bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 592: HOXD10 suppresses mammary tumor growth and metastasis coincident with decreased CD11b+Gr1+ leukocyte infiltration and angiogenesis
Authors: Kachgal Suraj , Chen Amy , Sidani Mazen , Afghani Shahrzad , Boudreau Nancy J. 
Published: May 2015

Abstract
The tumor suppressor gene HOXD10 is frequently lost in breast cancer, and we have previously shown that restoring expression of this master transcriptional regulator can revert mammary tumor cells to a normal, polarized phenotype and inhibit their growth in nude mice (Carrio et al., Cancer Res., 2005). In addition, we showed that restoring HOXD10 also reduced VEGFA expression and decreased endothelial cell migration in vitro (Chen et al., Cancer Res., 2009). Considering the critical role of the immune system in mammary tumor progression and metastasis, we investigated whether Hoxd10 could also prevent breast tumor progression in an immunocompetent model. Metastatic 4T1 cell lines were transduced with Hoxd10 and were either orthotopically or intravenously injected into four to eight week old, female Balb/c mice. We observed a significant reduction in tumor burden at both primary at metastatic sites in tumors expressing Hoxd10. Immunohistochemical staining for CD31 of primary tumors expressing Hoxd10 revealed decreased angiogenesis. Flow cytometry and immunohistochemical staining also revealed a decrease in infiltrating Cd11b+Gr1+ leukocytes in Hoxd10-expressing tissues. Gene and protein analysis revealed that in addition to decreased VEGFA, HOXD10 also reduced expression of CCL2, a key chemokine linked to recruitment of Cd11B+Gr1+ leukocytes. Using an in vitro migration assay, we confirmed that the HOXD10-mediated reduction in CCL2 expression was directly linked to reduced recruitment of monocytes to tumor cells. Together, these data show that HOXD10 can stabilize the tumor microenvironment by coordinately reducing tumor cell growth, angiogenesis, leukocyte recruitment, and metastasis, and suggest a novel and comprehensive therapeutic approach to treat mammary tumors.
Citation Format: Suraj Kachgal, Amy Chen, Mazen Sidani, Shahrzad Afghani, Nancy J. Boudreau. HOXD10 suppresses mammary tumor growth and metastasis coincident with decreased CD11b+Gr1+ leukocyte infiltration and angiogenesis. [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 592. doi:10.1158/1538-7445.AM2014-592
Abstract 593: Rb association with Bax is regulated by phosphorylation
Authors: Antonucci Lisa , Egger Jacklynn V. , Krucher Nancy A. 
Published: May 2015

Abstract
The Retinoblastoma protein (Rb) is important in the control of cell proliferation and apoptosis. Its activity is controlled by reversible phosphorylation on several serine and threonine residues that mediate binding to various cellular proteins. The role of Rb phosphorylation in the control of apoptosis is largely unknown, although several apoptotic stimuli result in dephosphorylation of Rb. Our previous work identified Rb (threonine-821) dephosphorylation as required for induction of apoptosis caused by UV light and inhibitions of cyclin dependent kinases. These studies led to the identification of proteins that bind to Rb under apoptotic conditions. One such Rb binding protein is the pro-apoptotic protein Bax. Bax, a member of the Bcl-2 family, undergoes a conformational change during apoptosis that is associated with the permeabilization of the outer mitochondrial membrane. In this study, we examined the role of Rb phosphorylation in the regulation of binding to Bax. In MCF7 cells, by activating the phosphatase responsible for dephosphorylating Rb, PP1, apoptotic death is triggered. We utilize siRNA to block the expression of PNUTS (Phosphatase Nuclear Targeting Subunit) which causes Rb dephosphorylation, and cell death. We have found that Bax binds to Rb under normal cell conditions, but when Rb becomes dephosphorylated on specific amino acid sites, Bax dissociates from Rb. Our cell fractionation studies have shown that phosphorylated Rb co-localizes with the mitochondrial fraction. Further examination of the specific sites of Rb phosphorylation required for binding to Bax is underway.
Citation Format: Lisa Antonucci, Jacklynn V. Egger, Nancy A. Krucher. Rb association with Bax is regulated by phosphorylation. [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 593. doi:10.1158/1538-7445.AM2014-593
Abstract 594: DNAJB6a as tumor suppressor in esophageal squamous cell carcinoma
Authors: YU Valentine Zhuoyou , WONG Victor Chun Lam , CHAN Kwok Wah , LUNG Maria Li 
Published: May 2015

Abstract
Esophageal squamous cell carcinoma (ESCC) has an especially high incidence in China, with five-year survival rates in Hong Kong being of ∼14%. Functional impact and molecular mechanisms of DnaJ (Hsp40) homolog, subfamily B, member 6 (DNAJB6) in ESCC were examined. Tissue microarray (TMA) analysis was performed to investigate the clinical relevance of DNAJB6 in ESCC. In vivo and in vitro functional and molecular studies were performed to verify the TMA results and elucidate the mechanisms for DNAJB6 function. Nuclear but not cytoplasmic DNAJB6 staining was found to correlate significantly with survival in metastasis-free patients by Kaplan-Meier analysis. Expression of nuclear DNAJB6 was down-regulated in tumors compared to normal tissues. In ESCC cell lines, over-expression of the nuclear isoform (DNAJB6a) suppresses in vivo tumor growth in a localization-dependent manner. DNAJB6a over-expression suppresses G1/S transition through inhibiting the key oncogenic Akt signaling pathway and impairs proliferation, by recruiting protein phosphatase 2A through the N-terminal HPD motif. DNAJB6a silencing results in the opposite effect in both cancer cells and immortalized normal esophageal epithelial (NE) cells. DNAJB6a silencing in NE cells also results in senescence-like alterations. DNAJB6a also regulates Akt phosphorylation in other cancers. In summary, nuclear DNAJB6 staining is associated with survival in ESCC patients. DNAJB6a regulates AKT1 phosphorylation in ESCC to suppress tumorigenicity. DNAJB6a may be a useful biomarker for detecting early ESCC tumor initiation and its role in Akt signaling may yet provide opportunities for therapeutic intervention.
Note: This abstract was not presented at the meeting.
Citation Format: Valentine Zhuoyou YU, Victor Chun Lam WONG, Kwok Wah CHAN, Maria Li LUNG. DNAJB6a as tumor suppressor in esophageal squamous cell carcinoma. [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 594. doi:10.1158/1538-7445.AM2014-594
Abstract 595: Tumor suppressor SCUBE2 inhibits breast-cancer cell migration and invasion through the reversal of epithelial-mesenchymal transition
Authors: Lin Yuh-Charn , Lee Yi-Ching , Li Ling-Hui , Cheng Chien-Jui , Yang Ruey-Bing 
Published: May 2015

Abstract
Signal peptide-CUB-EGF domain-containing protein 2 (SCUBE2) belongs to a secreted and membrane-associated multi-domain SCUBE protein family. We previously demonstrated that SCUBE2 is a novel breast-tumor suppressor and could be a useful prognostic marker. However, the role of SCUBE2 in breast-cancer cell migration and invasion and how it is regulated during the epithelial-mesenchymal transition (EMT) remain undefined. In this study, we showed that ectopic SCUBE2 overexpression could enhance the formation of E-cadherin-containing adherens junctions by β-catenin-SOX-mediated induction of forkhead box A1 (a positive regulator of E-cadherin) and upregulation of E-cadherin, which in turn led to epithelial transition and inhibited migration and invasion of aggressive MDA-MB-231 breast-carcinoma cells. SCUBE2 expression was repressed together with that of E-cadherin in TGF-β-induced EMT; direct expression of SCUBE2 alone was sufficient to inhibit the TGF-β-induced EMT. Furthermore, quantitative DNA methylation, methylation-specific PCR, and chromatin immunoprecipitation analyses revealed that SCUBE2 expression was inactivated by DNA hypermethylation at the CpG islands by recruiting and binding DNA methyltransferase 1 during TGF-β-induced EMT. Together, our results suggest that SCUBE2 plays a key role in suppressing breast-carcinoma cell mobility and invasiveness by increasing the formation of the epithelial E-cadherin-containing adherens junctions to promote epithelial differentiation and drive the reversal of EMT.
Citation Format: Yuh-Charn Lin, Yi-Ching Lee, Ling-Hui Li, Chien-Jui Cheng, Ruey-Bing Yang. Tumor suppressor SCUBE2 inhibits breast-cancer cell migration and invasion through the reversal of epithelial-mesenchymal transition. [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 595. doi:10.1158/1538-7445.AM2014-595
Abstract 598: Forkhead transcription factor FOXF1 is a novel p53 target gene and regulates cancer cell migration and invasion
Authors: Tokino Takashi , Tamura Miyuki , Idogawa Masashi , Sasaki Yasushi 
Published: May 2015

Abstract
p53 is an established tumor suppressor that can activate the transcription of multiple target genes. Recent evidence suggests that p53 may contribute to the regulation of cell invasion and migration. In this study, we show that the forkhead box transcription factor FOXF1 is a novel target of p53 because FOXF1 is upregulated by p53. We show that FOXF1 is induced upon DNA damage in a p53-dependent manner. Furthermore, we identified a response element located within the FOXF1 gene that is responsive to wild-type p53, TAp73 as well as TAp63. The ectopic expression of FOXF1 inhibited cancer cell invasion and migration, whereas the inactivation of FOXF1 stimulated cell invasion and migration. We also show that FOXF1 regulates the transcriptional activity of E-cadherin (CDH1) by acting on its FOXF1 consensus binding site located upstream of the E-cadherin gene. Collectively, our results show that FOXF1 is a p53 family target gene, and our data suggest that FOXF1 and p53 form a portion of a regulatory transcriptional network that appears to play an important role in cancer cell invasion and migration.
Citation Format: Takashi Tokino, Miyuki Tamura, Masashi Idogawa, Yasushi Sasaki. Forkhead transcription factor FOXF1 is a novel p53 target gene and regulates cancer cell migration and invasion. [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 598. doi:10.1158/1538-7445.AM2014-598
Abstract 599: Id4 acts as a tumor suppressor by inducing apoptosis and senescence in p53-dependent manner
Authors: Morton Derrick Jerone 
Published: May 2015

Abstract
The physiological mechanisms that can restore biological activity of mutant p53 is an area of high interest given that mutant p53 expression is observed in one third of prostate cancer and more than 50% of all cancers. Here we demonstrate that Id4 (inhibitor of differentiation-4) a dominant negative regulator of bHLH transcription factors can restore the mutant p53 transcriptional activity in prostate cancer cells. Id4 is highly expressed in the normal prostate and decreased in prostate cancer due to promoter hypermethylation. Prostate cancer cell lines: DU145 harbors mutant p53 also lack Id4 expression, and LNCaP cells with wild type p53 express Id4, whereas PC3 cells are null for p53 and express low levels of Id4. The p53 mutants (P223L and V274F) in DU145 cells are within the DNA binding domain and abrogate p53 transcriptional activity due structural de-stabilization and/or DNA interactions. Ectopic expression of Id4 in DU145 cells resulted in increased apoptosis and expression of BAX, PUMA and p21, the transcriptional targets of p53. DNA binding, p53 luciferase reporter studies and ChIP analysis demonstrated that mutant p53 gains Id4 dependent DNA binding and transcriptional activity in part due to CBP/p300 dependent acetylation of p53 at lysine 373. Loss of Id4 in LNCaP cells also abrogated wild type p53 DNA binding and transcriptional activity with concomitant loss of CBP/p300 requirement and decreased acetylation of p53. To further elucidate Id4 dependent restoration of biological activity of p53 we stably transfected p53-null cell line PC3, which has endogenous Id4 with mutant p53 mimicking DU145 cells. mRNA, protein levels and apoptosis assays were used to determine the effects on cell death and to determine if mutant p53 had the ability to transactivate upstream/downstream targets (MDM2, PUMA, and p21). Our results indicate that mutant p53 in PC3 cells were able to induce expression of downstream targets as well as effect biological processes such as apoptosis and cell cycle arrest. Also, post-translational modifications on residues lys320 and lys373 indicated activation of mutant p53. Collectively, based on our studies we demonstrate that Id4 promotes post-translational modifications of p53, which in turn regulates p53 transcriptional activity. NIH grant #R01CA128914
Citation Format: Derrick Jerone Morton. Id4 acts as a tumor suppressor by inducing apoptosis and senescence in p53-dependent manner. [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 599. doi:10.1158/1538-7445.AM2014-599
Abstract 600: Maternally expressed gene 3 (MEG3) as a tumor suppressor in nasopharyngeal carcinoma
Authors: Chak Wing P. , Tong Joanna Hung-Man , Lung Raymond Wai-Ming , Chan Yat Yee , Lo Kwok Wai , To Ka Fai 
Published: May 2015

Abstract
Nasopharyngeal carcinoma (NPC) is a distinctive type of head and neck cancer arising from the nasopharynx. Although rarely occurring worldwide, the incidence and mortality rates of this tumor are remarkably high among Southern China including Hong Kong. The distinct geographical distribution highlights the significance of several etiologic factors in NPC tumorigenesis, including Epstein-Barr virus (EBV) infection, genetic predisposition and intake of preserved food. However, the understanding of NPC development is still unclear. In our previous genome-wide analysis, chromosome 14q32 has been suggested as a tumor suppressor region where loss of heterozygosity (LOH) was detected in &gt;80% of NPCs. Hence, some novel candidate genes involving in NPC development may be located within this region.
By microarray study in NPC samples, consistent down-regulation of a putative tumor suppressor gene, maternally expressed gene 3 (MEG3) within the 14q32 deletion region was identified. MEG3 is an imprinted gene with preferential maternal expression and encodes for a long non-coding RNA. The silenced expression of MEG3 gene in NPC cell lines and xenografts was further confirmed by quantitative RT-PCR. Subsequent DNA methylation analysis in a panel of NPC samples demonstrated that densely methylation at a CpG island on the MEG3 promoter region was observed in all tested NPC cell lines, xenografts and 50% of primary NPCs, while normal imprinting pattern was found in non-cancerous nasopharyngeal epithelium. Interestingly, the presence of demethylation agent in culture medium could successfully rescue MEG3 expression in available NPC cell lines, indicating that promoter hypermethylation is one of the mechanisms to control MEG3 expression. On the other hand, fluorescent in situ hybridization (FISH) also showed the loss of DNA copy number at chromosome 14q32 in 60% of primary NPCs, suggesting an alternative MEG3 regulation mechanism in NPC. In our functional studies, ectopic MEG3 expression in NPC cell lines could significantly inhibit cell propagation, colony and foci formation. A series of reporter assays further suggested that MEG3 might contribute to regulate both p53 and TGF-β signaling pathways.
In conclusion, we have found that MEG3 is a novel tumor suppressor gene in NPC. Further investigation the function of MEG3 in NPC pathogenesis may have potential implications to improve NPC treatment in the future.
Citation Format: Wing Po Chak, Joanna Hung-Man Tong, Raymond Wai-Ming Lung, Yat Yee Chan, Kwok Wai Lo, Ka Fai To. Maternally expressed gene 3 (MEG3) as a tumor suppressor in nasopharyngeal carcinoma. [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 600. doi:10.1158/1538-7445.AM2014-600
Abstract 603: TNFR1 is indispensable in the development of spontaneous lung squamous cell carcinomas
Authors: Xiao Zuoxiang , Willette-Brown Jami , Hu Yinling , Xi Sichuan 
Published: May 2015

Abstract
We recently reported that kinase-dead IKKα knockin mice, in which an ATP binding site of IKKα, Lys 44 was replaced by alanine (IkkαKA/KA), develop spontaneous lung SCCs that were closely associated with lung inflammatory microenvironment. This mouse model resembles human lung SCCs, sheds light on the mechanisms underlying lung malignancy development, and identifies targets for therapy of lung SCCs (Xiao et al. Cancer Cell 23(4):527-40, 2013). To further elucidate what and how the inflammatory stimuli contribute to the tumorigenesis, we generated bitransgenic mice harboring IkkαKA/KA and tnfrsf1-/- (KALTFR). It was identified that the KALTFR mice display lung tumor-free even the lung inflammations are still severe, while almost all of the littermate IkkαKA/KA mice developed lung SCCs. Interestingly, we found a noticeably increased TNFR1 expression in the lung SCCs of IkkαKA/KA mice compared to normal lung tissues. It has also been detected that the TNFR1 expressions are significantly higher in both transcript and protein levels in human lung SCCs with the compare to their adjacent tissues. These findings indicate that TNFR1 may play a crucial role in the development of lung SCC in either IkkαKA/KA mice or humans. Further investigation demonstrated that TNFR1 is a critical factor to regulate nuclear transcriptional factors and oncogenes including C-Myc, through one bromodomain (BRD) proteins- containing complex. These findings broaden our understanding about how inflammatory microenvironment contributes to tumorigenesis through TNFα-TNFRs engagements.
Citation Format: Zuoxiang Xiao, Jami Willette-Brown, Yinling Hu, Sichuan Xi. TNFR1 is indispensable in the development of spontaneous lung squamous cell carcinomas. [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 603. doi:10.1158/1538-7445.AM2014-603
Abstract 611: Co-targeting the PI3K and androgen receptor signal pathways in castration resistant prostate cancer
Authors: Velasco Marco A. De , Kura Yurie , Ando Naomi , Fukushima Emiko , Hatanaka Yuji , Yamamoto Yutaka , Shimizu Nobutaka , Yoshimura Kazuhiro , Nozawa Masahiro , Yoshikawa Kazuhiro , Nishio Kazuto , Uemura Hirotsugu 
Published: May 2015

Abstract
PTEN-deficient castration-naïve prostate tumors respond well to PI3K pathway inhibition, however, treatment response is largely ineffective in castration-resistant prostate cancer (CRPC). Reciprocal feedback regulation between the PI3K and androgen receptor (AR) signaling pathways helps maintain survival. We hypothesized that combined PI3K and AR pathway inhibition would improve the therapeutic outcome. Using an in vivo model of prostate cancer, we assessed the rational therapeutic combination of the mTOR inhibitor, everolimus, and the anti-androgen, chlormadinone acetate (CA), in PTEN deficient tumors. Treatment efficacy was examined in conditional PTEN-mutant mice that developed CRPC after surgical castration. Drug efficacy was evaluated by comparing differences in tumor burden, inhibition of tumor cell proliferation and induction of apoptosis. Treatment-specific responses were measured by downstream PI3K signal molecules, nuclear translocation of AR and activation of compensatory signaling pathways. Mice treated with everolimus or CA alone did not show a significant reduction in tumor burden compared to controls, however, the combination of everolimus and CA significantly inhibited tumor burden. Combination therapy also significantly inhibited cellular proliferation and increased apoptosis. PI3K pathway activation was effectively suppressed by everolimus as measured the levels of phosphorylated S6. No significant differences were noted in the nuclear translocation of the AR between control and treatment groups. Mice treated with the combination therapy demonstrated suppression of MAPK pathway activation. Interestingly, all treatments resulted in an increase of STAT3 activation. In summary, our findings show that AR re-challenge can sensitize CRPC to PI3K inhibition. This study provides a rationale for the developing combination therapies for CRPC by co-targeting the AR and PI3K signal transduction pathways.
Citation Format: Marco A. De Velasco, Yurie Kura, Naomi Ando, Emiko Fukushima, Yuji Hatanaka, Yutaka Yamamoto, Nobutaka Shimizu, Kazuhiro Yoshimura, Masahiro Nozawa, Kazuhiro Yoshikawa, Kazuto Nishio, Hirotsugu Uemura. Co-targeting the PI3K and androgen receptor signal pathways in castration resistant prostate 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 611. doi:10.1158/1538-7445.AM2014-611