bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1015: Mammary stem cells increase late in embryogenesis, facilitating their characterization and revealing links to breast cancer
Authors: Spike Benjamin T. , Engle Dannielle D. , Lin Jennifer C. , La Justin , Cheung Samantha K. , Wahl Geoffrey M. 
Published: August 2012

Abstract
Parallels between embryonic development, stem cells, and cancer have long been recognized. The proliferative and invasive characteristics of the most lethal forms of breast cancer and their lack of differentiated characteristics resemble aspects of embryonic mammogenesis, raising the possibility that they share molecular mechanisms. We have identified, isolated and characterized a fetal mammary population with concentrated mammary stem cell activity and shown that it exhibits gene expression similarities to certain human breast cancer molecular subtypes. Limiting dilution transplantation analyses demonstrate that a robust increase in fetal mammary stem cell (fMaSC) activity is evident after embryonic day 16 (E16), coincident with invasion of the rudiment through the mesenchyme and into the fat pad precursor. Markers used to enrich adult MaSCs enabled isolation of a population at E18.5 that is highly enriched for fMaSCs and capable of serial transplantation in vivo and clonal, multilineage sphere formation in vitro. Genome-wide expression profiling and single cell analyses revealed candidate pathways in both the epithelial and stromal compartments with relevance to fMaSC activity and cancer. Notably, ErbB and FGF signaling were critical and synergistic for the in vitro growth of spheres derived from the fMaSC-enriched population, and fMaSCs expressed elevated ErbB2, 3, and 4 relative to adult MaSC enriched populations. We explored molecular links between fetal mammary development and cancer further by analyzing the expression of fetal gene signatures in archived breast cancer array data and in breast cancer cell lines. We identified gene expression modules correlating with certain cell lines, intrinsic breast cancer subtypes and clinical outcome. These studies advance the attractive hypothesis that regulatory pathways governing fMaSC function and embryonic mammogenesis that are deregulated in certain types of human cancer can be targeted in the development of new therapies and prognostic metrics.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1015. doi:1538-7445.AM2012-1015
Abstract 1018: Epithelial-to-mesenchymal transition (EMT) alters vesiculation of cancer cells expressing oncogenic epidermal growth factor receptor (EGFR): Implications for the aggressive, procoagulant and proangiogenic properties
Authors: Garnier Delphine , Milsom Chloe , Magnus Nathalie , Bentley Victoria , Lee Tae Hoon , Meehan Brian , Montermini Laura , Rak Janusz 
Published: August 2012

Abstract
Cancer cells release elevated amounts of membrane-derived organelles containing complex molecular cargo, and known as extracellular vesicles (EVs). This process (vesiculation) is implicated in intercellular communication, as well as in cancer invasion, metastasis, angiogenesis and activation of the coagulation system. We have previously demonstrated a link between oncogenic transformation mediated by mutant K-ras, epidermal growth factor receptor (EGFR) as well as other genetic lesions and the intensity of cancer cell vesiculation. In the present study we interrogate vesiculation during the superimposed processes of de-differentiation and epithelial-to-mesenchymal transition (EMT). In the EGFR-driven epidermoid cancer cell line A431, EMT can be induced by stimulation with EGFR ligands coupled with blockade of the E-cadherin. Of note, A431 cells express high levels of the Tissue Factor (TF) receptor which renders them procoagulant, and is required for the efficient tumor initiation and proangiogenic signalling. A431 cells emit heterogeneous population of EVs, including subsets containing TF, and EGFR. We observed that induction of EMT in A431 cells is associated with a global increase in vesiculation, as revealed by nanoparticle tracking analysis (NTA/Nanosight). At the same time, EGFR and TF are relocated from the plasma membrane to distinct subcellular microdomains, and this change is associated with a rearrangement in the proteome of EVs emitted by cancer cells, including a significant increase in TF content. Tumor cell-derived, TF-containing EVs are readily taken up by endothelial cells and trigger their procoagulant conversion and angiogenic responses. While forming tumors in vivo A431 cells spontaneously undergo multilineage differentiation and generate EMT-like subpopulations, which release into the circulation a subset of EVs with a distinct molecular signature. Thus, EMT-like processes not only modulate intrinsic cellular properties (cell shape, differentiation), but also trigger a shift in cellular vesiculation that may be detected in EV preparations isolated from peripheral blood. Moreover, EVs that emanate from cancer cells upon their entry into the EMT pathway may acquire the ability to modify the extracellular and vascular milieu, and possibly facilitate tumor initiation, invasion and metastasis.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1018. doi:1538-7445.AM2012-1018
Abstract 1034: Upregulation of Ezh2 expression correlates with higher tumor proliferation and grade in non-Hodgkin's B- and T-cell lymphoma
Authors: Al-Kader Lamia Abd , Oka Takashi , Takata Katsuyoshi , Sun Xu , Sato Hiaki , Murakami Ichiro , Kimura Hiroshi , Otte Arie P. , Yoshino Tadashi 
Published: August 2012

Abstract
Polycomb group (PcG) proteins are involved in regulation of hematopoiesis, which include two main members Ezh2 and Bmi-1. Reports on their expression levels in different subtypes of malignant lymphoma and role in lymphomagensis and tumor progression are rather limited. To address this issue, we analyzed a total of 197 patient samples including 10 samples of Hodgkin lymphoma (HL), 109 of B-cell lymphoma (BCL) and 78 of T-cell lymphoma (TCL) by immunohistochemistry. The results showed overall expression in HL, BCL and TCL to be 90%, 56.9% and 84.6% for Ezh2 and 90%, 82.5% and 84.6% for Bmi-1 respectively. Among BCL, highest Ezh2 positivity was seen in Burkitt's lymphoma (BL) followed by high-grade follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL). In TCL, Ezh2 expression was observed in all subtypes and seemed more homogenous. Difference in its expression between aggressive and indolent subtypes of BCL was statistically significant (p= 0.000∼0.010). On the other hand, Bmi-1 was rather more consistently expressed in both BCL and TCL up to 100% in 7 subtypes. Difference in its expression between aggressive and indolent subtypes was statistically insignificant. Ki67 showed strong positive correlation with Ezh2 in BCL (Correlation coefficient (Co) =0.983, p= 0.000) and moderate correlation in TCL (Co=0 .629, p= 0.000). This correlation could not be detected in case of Bmi1. These data suggest that out of the two Polycomb group (PcG) proteins, only Ezh2 correlates with tumor proliferation and signals a more aggressive nature.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1034. doi:1538-7445.AM2012-1034
Abstract 1041: Epigenetic regulation of BRAF-HDAC complex in presence of trichostatin A, 5-aza-2′-deoxycytidine and cisplatin in ovarian cancer
Authors: Meng Fanliang , Zhong Mei , Sun Guigin , Yu Yanhong , Brewer Molly A. 
Published: August 2012

Abstract
Objective: To investigate the regulation of the subunits of BRAF-HDAC complex, a gene transcription repression complex, which regulates the interaction of histone methylation, histone acetylation, DNA methylation and DNA repair in response to chemotherapy in ovarian cancer cell lines with different treatment strategies. We hypothesized that combining different epigenetic modifiers with low dose Cisplatin would result in an optimal therapeutic regime for ovarian cancer. Materials and Methods: Two epigenetic modifiers Trichostatin A (TSA), a histone deacetylase inhibitor and 5-aza-2′- deoxycytidine (Decitabine), a demethylating agent were evaluated in different doses alone and in combination with Cisplatin on the expression of subunits of BRAF-HDAC complex, histone methylation, acetylation and the associated pathways affected. Three cell lines, A2780, Hey and SKOV3 were used. Spheroids were grown in serum free medium and injected IP in SCID mice. Western blots confirmed protein expression. Results: Different combinations of TSA, Decitabine and low dose Cisplatin significantly inhibited the expression of the subunits LSD1 and CoREST in the BRAF-HDAC complex, two proteins which together demethylate H3K4 and H3K9. The BRAF-HDAC complex cofactor subunit BRAF35 was also significantly suppressed by the combination treatment. The BRAF-HDAC complex subunit repressor increased significantly after combined treatment. indicating that the combination of TSA, Decitabine and Cisplatin suppresses the expression of H3K4 and H3K9 methylation and increases the expression of Histone H3 lys9/14 and Histone H4 ser1/lys5/lys8/lys12 acetylation. Along with these methylation and acetylation changes, we found a decrease in epithelial-mesenchymal transition, cancer cell proliferation, chemoresistance and pluripotency. Spheroid formation was decreased in vitro and there was no tumor formation in SCID mice in presence of these epigenetic modifiers and low dose Cisplatin. Conclusions: The combination of epigenetic modifiers and low dose Cisplatin can regulate and modify the expression of subunits of BRAF-HDAC complex, resulting in decreased expression of tri- and di- methylated H3K4 and H3K9 and increased acetylation of Histone H3 and H4, subsequently modifying the tumor biology and tumorigenicity of these ovarian cancer cell lines. Further investigation of these mechanisms could provide the development of more effective and less toxic treatment for ovarian cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1041. doi:1538-7445.AM2012-1041
Abstract 1055: Enhancer of Zeste Homologue 2 (EZH2) may relate to progression of intra and extrahepatic cholangiocarcinoma
Authors: Nakagawa Shigeki , Okabe HIrohisa , Beppu Toru , Kuroki Hideyuki , Mima Kousuke , Hayashi Hiromitu , Imai Katsunori , Nitta Hidetoshi , Nakahara Osamu , Ikuta Yoshiaki , Chikamoto Akira , Ishiko Takatoshi , Takamori Hiroshi , Baba Hideo 
Published: August 2012

Abstract
[Background and Aims]Enhancer of Zeste Homolog 2 (EZH2) is one of the polycomb proteins and involved in the progress of several solid tumors by methylating histone3 Lysin27 (H3K27) and silencing various genes. However, the role of EZH2 in cholangiocarcinoma has not been clarified. In this study, we investigated the significance of EZH2 expression in intrahepatic and extrahepatic cholangiocarcinoma progression.[Patients and Methods]Fourty-seven intrahepatic cholangiocarcinoma (ICC) patients and 45 extrahepatic cholangiocarcinoma (ECC) patients treated with curative resection from 1993 to 2010 were enrolled. We examined the EZH2 expression by immunohistochemistry, and relationship between EZH2 expression and clinicopathological factors, such as gender, age, CA19-9, tumor diameter, tumor number, histological vascular invasion, differentiation, lymph node metastasis and prognosis. To assess whether EZH2 relates to angiogenesis and tumor growth, Ki67 expression and microvessel density (MVD) using CD34 were also examined by immunohistochemistry. EZH2 expression was investigated eight cholangiocarcinoma cell lines. Using small interfering RNA against EZH2, the influence of EZH2 knock-down on cholangiocarcinoma cell proliferation and invasion was studied in vitro. [Results]In ICC, 24 patients (51.0%) shows a high expression of EZH2 when the cutoff value was determined to be 10%. The EZH2 high expression is significantly correlated with tumor diameter &gt; 3.5cm (P=0.0113) and MVD score (P=0.039). The high EZH2 expression group showed significantly worse overall survival (p=0.045). In ECC, 19 patients(42.2%) showed a high EZH2 expression. The EZH2 high expression is significantly correlated with positive lymph node metastasis (p=0.0469), high Ki67 expression (P=0.0017). The high EZH2 expression group showed significantly worse overall survival (P=0.0261). All of the eight cholangiocarcinoma cell lines expressed EZH2 in a various level. When we knock down the expression of EZH2 in RBE cells, the expression of H3K27 was reduced and cell growth decreased. However, EZH2 down-regulation didn't affect cell invasion.[Conclusion]EZH2 may relate to the progression of intra and extrahepatic cholangiocarcinoma.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1055. doi:1538-7445.AM2012-1055
Abstract 1056: Deregulated HDAC9 expression in breast cancer is associated with basal molecular subtype
Authors: Linares Aurélien , Lapierre Marion , Boulahtouf Abdel , Rodriguez Carmen , Orsetti Béatrice , Balaguer Patrick , Maudelonde Thierry , Cavailles Vincent , Boulle Nathalie 
Published: August 2012

Abstract
Estrogens play a pivotal role in the etiology of breast cancer. Estrogen receptor (ER) activity is finely regulated by various transcriptional regulatory complexes including histone acetyl transferases (HAT) and histone deacetylases (HDACs). Previous studies have underlined the potential role of some HDACs in breast tumor progression and their interactions with estrogen signalling. However, expression of the various class I, II and IV HDACs in breast tumors has not been systematically analysed. In this study, we performed a careful analysis of HDACs 1 to 11 expression in five breast cancer cell lines expressing (MCF7, ZR75, T47D) or not (MDA231, MDA436) ERα. HDAC4, HDAC11 and more strikingly HDAC9 were found to be differentially expressed in ERα+ and ERα- cells. HDAC9 mRNA levels were further measured in a panel of 14 breast tumor cell lines expressing or not ERα and classified as luminal, basal A and basal B. This showed that the difference in HDAC9 expression was more related to the luminal or basal characteristics of the breast tumor cells than to ERα expression, with basal cells harboring significantly higher HDAC9 mRNA levels than luminal ones. Comparison of mRNA levels of total HDAC9 with those of the longest HDAC9 isoforms (variants 1, 4 and 5) and the HDAC9ΔCD isoform, lacking the catalytic deacetylase domain (also known as MITR), showed a similar pattern of distribution among luminal, basal A and basal B cells. In basal cells, HDAC9 overexpression was not linked to gain in HDAC9 gene copy number but mainly to higher rates of gene transcription together with enhanced HDAC9 mRNA stability. Based on cDNA array data, the same differential expression was detected in patients’ tumors as significant higher levels of HDAC9 mRNA were measured in ERα negative and basal breast tumors as compared to ERα expressing and luminal ones respectively, suggesting the biological relevance of the results obtained using breast cancer cell lines. In contrast to luminal cells harboring very low or no detectable levels of HDAC9 protein, a 95 kDa HDAC9 protein isoform was detected in basal breast cancer cells, with a predominant and diffuse nuclear distribution as shown by immunofluorescence. Altogether, our results indicate that class IIa HDAC9 is overexpressed at the mRNA and protein levels in the most agressive breast tumors of basal phenotype. The role of this specific HDAC in breast carcinogenesis and ER signaling will be further analysed and described using mammary tumor cell models harboring HDAC9 overexpression or HDAC9 silencing.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1056. doi:1538-7445.AM2012-1056
Abstract 1061: EZH2 expression in different subtypes of human breast cancer
Authors: Khramtsova Galina F. , Islam Abul B.M.M.K. , Khramtsov Andrey I. , Lyman Phoebe , Chuanhong Liao , Jene-Sanz Alba , Sveen Walmy E. , Huo Dezheng , Lopez-Bigas Nuria , Benevolenskaya Elizaveta V. , Olopade Olufunmilayo I. 
Published: August 2012

Abstract
Introduction: Cancer is characterized by aberrant patterns of expression of multiple genes believed to be due to not only genetic but also epigenetic changes. The epigenetic changes are communicated through chemical modifications, including modifications of histone proteins. For each histone, multiple histone-modifying enzymes have been discovered in mammals. We found that the expression of genes with histone modifications was highly predictable from the level of expression of the corresponding histone-modifying enzyme. Specifically, expression of genes displaying histone H3 K27 methylation was dependent on EZH2 expression. Method: We analyzed breast cancer tissue arrays for EZH2 expression. Tissue microarrays were constructed from 95 histologically confirmed breast cancer samples. To identify breast cancer subtypes, the tissues were evaluated for the expression of ER, PR, HER2, CK5/6 and EGFR. Staining with vimentin served as a control to monitor the quality of tissue fixation in archival tumors. Breast cancer subtypes were defined as luminal A (ER+ and/or PR+, HER2-), luminal B (ER+ and/or PR+, HER2+), basal-like (ER-, PR-, HER2-, CK5/6+, and/or EGFR+), HER2+/ER- (HER2+, ER-, PR-), and unclassified (negative for all five markers). EZH2 expression was measured by staining using an anti- EZH2 antibody (Invitrogen, cat. #18-7395). Staining quantification was performed independently by two pathologists. Results: The mean age of the patients was 56 years old (SD=15.6). 63.7% of the patients had estrogen receptor positive tumors, 50.6% had progesterone receptor positive tumors, and 21.2% had HER2+ tumors. The distribution of breast cancer subtypes is luminal A (58.9%), luminal B (6.3%), HER2+/ER- (4.2%), basal-like (28.5%), unclassified (2.1%). A majority of the patients had high grade tumors (46.0% grade II and 47.1% grade III). High EZH2 expression was associated with Her2+ and basal-like tumors (P&lt;0.0001). Conclusion: In this cohort, high expression of EZH2 was associated with the most aggressive breast cancer phenotypes and likely reflects increased expression of histone modifying proteins in the tumors. Supported by Grants: NIH R01CA138631 (E.V.B.), R01 CA142996 and P50 CA125183 (O.I.O).
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1061. doi:1538-7445.AM2012-1061
Abstract 1072: The FGF18/FGFR4 amplicon: Novel therapeutic biomarkers for ovarian cancer
Authors: Wei Wei , Mohapatra Gayatry , Birrer Michael J. 
Published: August 2012

Abstract
Epithelial ovarian cancer is the fifth leading cause of cancer-related death among women and has the highest case-fatality rate among gynecologic cancers. High throughput genomic technologies have been instrumental in identifying new biomarkers and potential novel therapeutic targets for ovarian cancer. However, comprehensive functional validation studies on both the biological and clinical levels are needed to better understand the mechanistic basis for these biomarkers and realize their clinical significance and application. Fibroblast growth factor 18 (FGF18) has been recently identified as an aberrantly expressed gene within an expression signature predicting poor rate of survival in patients with advanced stage serous ovarian cancers. In addition, genomic amplification of both FGF18 and FGFR4 has been shown to predict for poor overall survival among women with advanced stage high grade serous ovarian cancers. siRNA mediated knock-down of FGFR4 abolishes FGF18 induced phosphorylation of FRS2 and ERK1/2 in ovarian cancer cells, indicating the FGF18 signaling is at least partially conferred by FGFR4 in ovarian cancer cells. However, the exact role of FGF18/FGFR4 in the clinicopathologic properties of ovarian cancer has not been determined. Preliminary studies by ectopic FGF18 overexpression or recombinant FGF18 treatment demonstrate that FGF18 promotes the in vitro migration and invasion of both ovarian cancer cells and endothelial cells. In SCID mice xenograft models, FGF18 expression in ovarian cancer cells results in increased tumor formation. Microarray analysis identified up-regulation of a large number of proinflammatory cytokines by FGF18 which may mediate the increases in angiogenesis and infiltration of macrophages seen in FGF18 expressing xenografts. Pathway analysis further demonstrated participation of NF-κB signaling in FGF18 mediated cytokine production. Conversely, knock-down of FGF18 in ovarian cancer cells reduces the in vitro migration; inhibits the production of cytokines and impairs the in vivo tumorigenicity in SCID mice xenograft model. Taken together, FGF18/FGFR4 axis may play an important role in ovarian cancer pathogenesis and may serve as a novel therapeutic target.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1072. doi:1538-7445.AM2012-1072