bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB-501: Role of HGF in epithelial-stromal cell interactions during progression from benign breast disease to ductal carcinoma in situ
Authors: Casbas-Hernandez Patricia , Troester Melissa A. , Perez Erick Roman , Sandhu Rupninder , Kirk Erin , D'arcy Monica , Rein Jessica 
Published: August 2012

Abstract
Role of HGF in epithelial-stromal cell interactions during progression from benign breast disease to ductal carcinoma in situ. Introduction: Tumor-stroma interactions create a ‘permissive microenvironment’ during cancer progression. Basal and luminal breast cancers (BC) have distinct tumor-stroma interactions, but few studies show how gene expression evolves in premalignant cells. We observed that hepatic fibrosis/HGF signaling is induced in basal-like microenvironments, and previous studies have demonstrated that overexpression of HGF is a predictor of breast cancer recurrence and survival. However it is not known whether HGF signaling is altered in early (premalignant and DCIS) lesions. Methods: To study tumor-stroma interactions during cancer progression, we cocultured breast fibroblasts with a panel of isogenic cell lines, the MCF10 series. The MCF10 series represents different stages of cancer progression (benign, atypical hyperplasia and ductal carcinoma in situ). RNA from cocultures was used to perform gene expression microarrays and proteins secreted into media were analyzed by antibody arrays. Differentially expressed genes were identified using supervised analysis, followed by gene ontology analysis. In addition, a signature of basal-like microenvironment was evaluated to test whether the stroma-epithelial interactions observed in basal-like cancers were also present in premalignant cells. Finally, HGF signaling was inhibited (using an HGF-antibody) to assess effects of this pathway on migration and gene expression. Results: Cocultures with MCF10DCIS express higher levels of RNA involved in immune response processes and connective tissue disorders, as reported previously for basal-like BC. In contrast, premalignant MCF10AT and MCF10A cells showed weak expression of these profiles. In cytokine arrays, striking overexpression of HGF was observed in both MCF10AT1 and MCF10DCIS cocultures relative to cocultures with the benign MCF10A cell line, with corresponding increases in c-MET levels. These changes correlated with increased migration, which was blocked by adding HGF-specific antibodies to the media. Conclusions: Inhibition of HGF alters stromal-epithelial interactions, rendering the premalignant microenvironment more similar to normal microenvironments. HGF signaling is necessary for stroma-induced migratory phenotypes in vitro and is induces widespread gene expression changes. Targeting HGF signaling in early carcinogenesis may have value in preventing progression of basal-like precursor lesions.
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 LB-501. doi:1538-7445.AM2012-LB-501
Abstract LB-506: Targeted integrations of fluorescent proteins into STAT3 and STAT1 Loci via ZFN mediated homologous recombination in human cancer cell lines provides a suitable and adequate model system for cell-based testing of new candidate drugs for human tumor treatment
Authors: Samsonov Andrey , Zhang Fan , Zhang Hongyi , Zenser Nathan , Fetter John , Malkov Dmitry 
Published: August 2012

Abstract
STAT3 which is a member of the family of signal transducers and activators of transcription is an oncogene and it is constitutively activated in numerous cancer cell lines and human cancers including breast, lung, head and neck, liver, and pancreas. Another STAT family member STAT1 possesses cancer-inhibitory properties and once activated may promote apoptosis in tumor cells. Thus STAT3 has been identified as a promising drug discovery target for many cancers. Ideally the potential inhibitors of STAT3 should be very selective and should not inactivate STAT1. To better address these cancer-research important genes, we tagged STAT3 and STAT1 loci with fluorescent protein (FP) sequences (RFP and GFP respectively) by targeted integration via Zinc-Finger Nuclease (ZFN) mediated homologous recombination in cancer derived cell lines. ZFN technology is a fast and reliable way to manipulate the genome in a targeted fashion. ZFNs are synthetic proteins engineered to bind DNA at a sequence-specific location and create a double strand break (www.compozrzfn.com). The cell's natural machinery repairs the break in one of two ways: non-homologous end joining or homologous recombination. Utilizing the homologous recombination pathway that ZFNs induce, we successfully inserted the FP transgenes into the desired target locations - at the N-terminus of the STAT3 locus and at the C-terminus of the STAT1 locus. Three cell lines were created, two with the single STAT tagged and a third with both STATs tagged. Integration resulted in endogenous expression of fluorescent STAT3 and STAT1 chimeric fusion proteins in the A549 cell lines. Functional analyses of knock-in cell lines indicated that both STAT3 and STAT1 native gene regulation is conserved resulting in normal levels of protein expression and preservation of protein function. When stimulated with IL-6 or INF-γ, A549 cells showed fast and robust nuclear translocation of RFP-STAT3 or STAT1-GFP respectively. Cell pre-incubation with a known specific STAT3 inhibitors showed that STAT1-GFP, INF-γ-induced translocation was not impaired. Thus, these cell lines provide a simple and convenient method for high-content screening and pre-clinical testing of potential STAT3 inhibitors while ensuring that the STAT1 pathway is not affected. This approach of zfn-tagging endogenous genes could be applied to other cancer targets.
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 LB-506. doi:1538-7445.AM2012-LB-506
Abstract LB-516: PDZ-RhoGEF promotes glioblastoma cell invasion, proliferation and survival
Authors: Kwiatkowska Aneta , Dong Zhiwan , Paulino Vincent M. , Tran Nhan L. , Ruggieri Rosamaria , Symons Marc H. 
Published: August 2012

Abstract
Invasion of glioblastoma cells into the surrounding brain parenchyma is a critical parameter of this disease as it hampers complete surgical resection of the tumor mass. Glioblastoma tumors are highly proliferative and resistant to radio- and chemo-therapy, thereby leading to tumor recurrence. Rho family members have been shown to control both the invasive and proliferative behavior of tumor cells. Rho GTPases are activated by guanine nucleotide exchange factors (GEFs). In this study we focused on PDZ-RhoGEF, as its role in glioblastoma is not known. It has been shown that invading glioblastoma cells need contractile force to squeeze their nucleus through narrow spaces that are characteristic of the brain parenchyma (Beadle et al, Mol. Biol. Cell (2008) 19: 3357). We found that depletion of PDZ-RhoGEF in U87 and SNB19 glioblastoma cells strongly inhibits cell migration across a small (3 μm) pore size filter, a process which necessitates nuclear squeezing. PDZ-RhoGEF depletion also inhibits cell migration across a larger (8 μm) pore size filter, albeit to a lesser extent than in the squeezing assay. Interestingly, cells lacking PDZ-RhoGEF display multi-lobed lamellae, suggesting a defect in cell polarization. In addition, PDZ-RhoGEF depletion strongly inhibits glioblastoma cell invasion into ex vivo brain slices. In vitro studies have demonstrated that PDZ-RhoGEF can act on both RhoA and RhoC. The roles of these GTPases in the invasive behavior of glioblastoma have not been reported to date. Interestingly, we found that depletion of RhoC strongly inhibits brain slice invasion and nuclear squeezing, whereas depletion of RhoA has no significant effect on these functions. Thus, taken together, these data suggest that PDZ-RhoGEF largely acts by activating RhoC to stimulate glioma cell invasion. Our preliminary data also indicate that PDZ-RhoGEF mediates glioma cell proliferation and survival. In conclusion, our findings suggest that PDZ-RhoGEF is a potential therapeutic target for glioma therapy.
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 LB-516. doi:1538-7445.AM2012-LB-516
Abstract LB-519: Chemotaxis of acute promyelocytic leukemia cells toward CXCL12 is involved in ATRA syndrome and the requirement of chemotherapy during Induction therapy with ATRA
Authors: Gotoh Akihiko , Aota Yasuo , Miyazawa Keisuke , Kizaki Masahiro , Ohyashiki Kazuma 
Published: August 2012

Abstract
We previously reported that treatment of acute promyelocytic leukemia (APL) cells with all-trans retinoic acid (ATRA) in vitro increases the directed migration towards CXCL12. Here we report the clinical significance of this phenomenon. Bone marrow cells were corrected from 13 de-novo APL patients after obtaining informed consent. Flow-cytometric analysis revealed that all cases expressed CXCR4, the receptor of CXCL12. The CXCR4 expression was enhanced after 24 hour treatment with ATRA in vitro. Chemotaxis analysis using Boyden chamber demonstrated that the directed migration towards CXCL12 increased 1.03 to 4.16 (median 1.65) times in ATRA-treated APL cells as compared to non-treated cells. Four out of 13 APL patients developed ATRA syndrome during induction therapy with ATRA. The chemotaxis towards CXCL12 was enhanced in these four patients (p&lt;0.01). Six cases required chemotherapy with IDR and Ara-C during induction therapy with ATRA. The significant increase in chemotaxis toward CXCL12 was also observed in these patients as compared with those who achieved CR by the induction therapy with ATRA alone (p&lt;0.01). Interestingly, the ability of chemotaxis of APL cells appeared to be more well correlated with the occurrence of ATRA syndrome and the requirement of additional chemotherapy during ATRA treatment as compared with other well known predictable factors such as the APL cell number or white blood cell number in the peripheral blood, and the expression level of CXCR4. To investigate the possible mechanism of the chemotaxis, we used APL cell lines such as ATRA-sensitive NB4 cells and ATRA-resistant UF-1 cells as well as primary APL cells. An inhibitory antibody against CXCR4 and pertussis toxin effectively suppressed chemotaxis of APL cells toward CXCL12. Chemotaxis assay using selective signaling inhibitors demonstrated that activation of phospholipase C but not MAP kinase was strongly involved in the directed migration towards CXCL12 in APL cells. Additionally, the Akt-PI3-kinse pathway was partly participated in this chemotaxis. These results suggest that chemotaxis ability of APL cells toward CXCL12 is involved in the pathogenesis of ATRA syndrome and the requirement of chemotherapy during induction therapy with ATRA. Furthermore, specific signal targeted-therapy might contribute to prevent ATRA syndrome and/or avid administration of excessive chemotherapeutic agents.
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 LB-519. doi:1538-7445.AM2012-LB-519
Abstract LB-55: The European Cancer Patient Coalition speaks with a single voice for all cancer patients
Authors: Kossler Ingrid 
Published: August 2012

Abstract
Established in 2003, The European Cancer Patient Coalition is the voice of the European cancer patient community, uniquely representing the interests of all cancer patient groups from the major to the rarer cancers. ECPC is an independent, non-profit “umbrella” organization based in Brussels close to the European institutions, governed by an elected Board of seven members most of whom must be cancer patients, survivors or carers. ECPC maintains close links with EU institutions (Commission, Parliament, Council, and European Medicines Agency). ECPC monitors political development at EU level, identifies those which could impact the field of oncology, informs its member societies and supports European health issues. Priority Areas- • Influence EU policy that has an impact on the prevention, detection and treatment of cancer. • Reach out to national level to support ECPC members in their capacity building efforts on the national level • Build strategic partnerships with key cancer stakeholders to create mutual benefit One of ECPC's key priorities is to make cancer a priority for action on the European health policy agenda. With its policy activities, ECPC aims to effect change in legislative or regulatory policies to help optimize cancer prevention, detection, treatment and care throughout Europe. The policies also need to ensure that gaps within and between Member States are identified and eradicated, and that best practice is shared.
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 LB-55. doi:1538-7445.AM2012-LB-55
Abstract LB-57: Susan G. Komen for the Cure- A global breast cancer movement
Authors: Halarewicz Lee 
Published: August 2012

Abstract
Twenty-two Northeast Ohio counties comprise the Northeast Ohio Affiliate for which I volunteer. The Northeast Ohio Affiliate is dedicated to combating breast cancer at every front. Up to 75% of the Affiliate's net income goes toward funding grants to local hospitals and community organizations that provide breast health education and breast cancer screening and treatment programs for medically underserved women. The Affiliate is the only community resource in the Northeast Ohio region positioned to impact the core issues in ways significant enough to improve breast cancer screening rates, which will ultimately lead to a reduction in late stage diagnosis The remaining net income (a minimum of 25%) the Northeast Ohio Affiliate raises supports the national Komen Grants Program, which funds groundbreaking breast cancer research, meritorious awards and educational and scientific programs around the world. The impact of Komen's research investments is evident in every major advance in breast cancer over the past 25 years. Advocate participation in peer review is extended to involvement in many of these ongoing research projects and to other scientific activities through the Advocates in Science program. The Komen Advocates in Science (AIS) program is an inclusive community of dedicated volunteer advocates in scientific breast cancer research. We are brought together and sponsored by Komen to foster excellence in research advocacy and spur greater advocate engagement in research related activities. As an AIS Research Advocate, I participate in a variety of scientific activities to ensure that the unique and valuable perspectives of cancer survivors and others affected by cancer are integrated into scientific dialogue and decisions affecting our progress toward ending breast cancer. Advocates bring a real-world understanding of what most impacts those affected by breast cancer, and they also bring an urgency to find cures and more effective prevention, diagnosis and treatment. Additionally, AIS members engage in ongoing education to enhance our advocacy skills and expand our scientific knowledge.
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 LB-57. doi:1538-7445.AM2012-LB-57
Abstract LB-60: Long-term use of hormone therapy and breast cancer incidence and mortality
Authors: Chen Wendy Y. , Willett Walter C. , Hankinson Susan E. , Rosner Bernard A. ,   Nurses Health Study Group
Published: August 2012

Abstract
Background: The risk of breast cancer associated with longer-term use of both estrogen (ET) or estrogen + progesterone (E+P) hormone therapy (HT) cannot be determine from existing randomized controlled trials. Methods: The Nurses’ Health Study included 121,700 female registered nurses aged 30-55 in 1976 who have been followed with biennial questionnaires to medication use, risk factors and cancer incidence. Only postmenopausal women were included in this analysis. The main outcome was incidence of invasive breast cancer. We additionally evaluated the risk of fatal breast cancer (breast cancer diagnosis that resulted in breast cancer death). Results: During 1.57 million person-years of follow-up from 1980 through 2008, 5631 incident invasive breast cancers were diagnosed and 884 died of breast cancer. Breast cancer risk increased with duration of current E+P use without evidence for a plateau (e.g. RR 1.88 (95% CI 1.64-2.16) for 10-14.9 years and RR 2.35 (95% CI 1.90-2.92) for 15-19.9 years of use). More than 10 years of current ET use was also associated with increased breast cancer risk (RR 1.22 (95% CI 1.06-1.40) for 10-14.9 years and RR 1.43 (95% CI 1.22-1.68) for 15-19.9 years of use). Past E+P was also weakly associated with breast cancer risk. When the population was restricted to the same entry criteria as the Women's Health Initiative trial, we also observed a non-significant deceased risk of breast cancer HT with current ET use similar in magnitude to that seen in the trial (RR 0.61 (95% CI 0.63-1.05) for &lt; 5 years and RR 0.93 (95% CI 0.76-1.14) for 5-9.9 years), but still observed an increased risk with current ET users of 15-19.9 years (RR 1.30 (95% CI 1.07-1.59). Effects were stronger for ER positive tumors and among thinner women. Results were similar when limited to women who underwent regular screening. Although breast cancer incidence was increased in these groups, there was no increase in the risk of fatal breast cancer with either E+P or ET use (RR 1.05 (95% CI 0.67-1.68) and RR 1.08 (0.80-1.46) for 10-19.9 years of current use respectively). Conclusions: Both past and current E + P users and current long-term ET users were at increased breast cancer risk. We did not observe an increase in fatal breast cancer with HT use.
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 LB-60. doi:1538-7445.AM2012-LB-60
Abstract SY10-04: Delineating cellular targets of transformation in breast cancer
Authors: Fu Nai Yang , Vaillant François , Lindeman Geoffrey J. , Visvader Jane E. 
Published: August 2012

Abstract
To understand relationships between the mammary epithelia, ‘cells of origin’ and cancer stem cells in breast tumors, it is necessary to dissect the normal mammary epithelial hierarchy. We have isolated discrete populations of mouse and human mammary epithelial cells on the basis of cell-surface markers and identified cell subsets that are highly enriched for mammary stem (MaSC), luminal progenitor and mature luminal cells. Analysis of different mouse models of mammary tumorigenesis using syngeneic transplantation assays and interrogation of molecular profiles has revealed potential ‘cells of origin’ in preneoplastic tissue and the presence of a definitive cancer stem cell subset in different mouse mammary tumors. Cell lineage tracing studies in the mouse provide the current gold standard for identifying cells of origin. Towards this end, we have constructed a series of transgenic mice harboring lineage-specific gene regulatory regions (180 kB) that can be used to direct the expression of specific mammary oncogenes to discrete epithelial cell types. This will allow us to address the contribution of ‘cells of origin’ and the nature of the oncogene itself to mouse mammary tumorigenesis.
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 SY10-04. doi:1538-7445.AM2012-SY10-04
Abstract SY20-01: CHD5: Chromosome engineering, chromatin dynamics and cancer
Authors: Mills Alea A. 
Published: August 2012

Abstract
Although 1p36 loss has been documented for decades and a variety of malignancies have this particular lesion, the tumor suppressor mapping to this genomic interval had not been identified. Using chromosome engineering to create models with gain and loss of the region of the mouse genome corresponding to human 1p36, we pinpointed a potent tumor suppressive interval, identified Chromodomain Helicase DNA-binding domain protein 5 (CHD5) as the causative gene in the region, elucidated molecular pathways induced by CHD5, and demonstrated that CHD5 is frequently deleted in human cancer. The discovery of CHD5 as a tumor suppressor has had a major impact in the cancer field. Indeed, it is now appreciated that CHD5 is mutated in cancers of the breast, ovary, colon, and prostate, as well as in melanoma, glioma, and neuroblastoma. Furthermore, CHD5 status is a prognostic indicator of patient survival following anti-cancer therapy.
Still, the mechanism by which CHD5 exerts its tumor suppressive role is barely understood. CHD5 belongs to the CHD family of SWI-SNF-like ATP dependent-chromatin remodeling proteins; however, the role of CHD5 in modulating chromatin dynamics has not been reported. Here, we show that CHD5's tumor suppressive function is dependent on its tandem plant homeodomains (PHDs)—modules that in several other chromatin-remodeling proteins regulate transcription by binding to specific covalent modifications on histone tails. Each of the two PHDs of CHD5 preferentially bind unmethylated H3K4 (H3K4me0), an interaction abrogated by methylation of H3K4 but unaffected by modification of H3K9. Consistent with its binding specificity in vitro, genome-wide ChIP-sequencing indicates that CHD5 binds loci lacking highly methylated H3K4 marks in vivo. Both loss- and gain-of-function studies reveal that CHD5 modulates transcription, and furthermore, that CHD5 is a potent inhibitor of cellular proliferation. Mutation of residues within the PHDs of CHD5 that abolish H3K4me0 binding effectively abrogate the ability of CHD5 to modulate expression of target genes as well as to inhibit proliferation, leading to tumorigenesis in vivo.
These findings identify CHD5 as a member of a newly appreciated class of H3K4me0-binding PHD containing proteins and reveal a critical role for this interaction in facilitating CHD5's cellular function, providing new insight into the molecular mechanism responsible for the tumor suppressive role of CHD5.
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 SY20-01. doi:1538-7445.AM2012-SY20-01