bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2296: Identification of novel nuclear receptor targets in estrogen receptor negative breast cancer
Authors: Covington Kyle R. , Gu Guowei , Tsimelzon Anna , Hilsenbeck Susan , Brown Powel , Change Jenny , Osborne C Kent , Xu Jianming , O'Malley Bert , Mangelsdorf David , Minna John , Fuqua Suzanne 
Published: June 2012

Abstract
Introduction: Estrogen receptor (ER)-negative breast cancer has a particularly poor prognosis, and there are limited targeted agents for this subtype.
Aims and Methods: To identify nuclear receptor (NR) targets, we did microarray analysis of 227 ER-negative tumors as assessed by immunohistochemistry, and performed hierarchical clustering using 41 NRs, and prediction analysis of microarrays (PAM) across the clustered groups. Cell lines were matched to identified groups using previously published data. Clinical correlations were made using previously published breast cancer datasets.
Results and Conclusion: The 41 NRs clustered the tumors into 5 distinct groups. We found that the androgen receptor (AR) was the highest ranked discriminator of these groups followed by ERα. Group 1 (14% of the tumors) was characterized by elevated ERRα and RXR expression. Group 2 (9%) was characterized by higher expression of the orphan receptor NURR1. Group 3 was the largest group (37%), and showed high level expression of PPARα. Group 4 (16%) expressed higher levels of PPARγ. Group 5 (24%) demonstrated particularly high relative expression of AR, and also showed higher expression of ERα and ERRα. We used previously published microarray data to match cell lines to the NR groups using the scoring matrix developed in the PAM analysis. These cell lines are currently being tested for response to NR agonists and antagonists in growth (MTT, soft-agar, mammosphere) and apoptotic assays. We used a previously published microarray data set with long-term follow up information to identify potential differences in outcomes for the different NR subtypes. While we found no significant differences between the groups, the sample size was quite low for each subtype (n∼15 per group).
In summary, we have identified several novel ER-negative tumor groups by different expression level of NRs which may contribute to the prediction of breast cancer molecular subtypes.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2296. doi:10.1158/1538-7445.AM2011-2296
Abstract 2297: ERβ agonists reduce letrozole resistant breast cancer cell growth and diminish aromatase expression and activity
Authors: Ganapathy Manonmani , Nair Hareesh Babu , Kirma Nameer B. , Krishnegowda Naveen Kumar , Vadlamudi Ratna Kumar , Kurmayagari Kusuma , Tagliaferri Mary , Cohen Isaac , Tekmal Rajeshwar Rao 
Published: June 2012

Abstract
Aromatase inhibitors (AI) have shown efficacy against estrogen receptor (ER) positive breast cancer; however, development of resistance to AI is a major concern. The need to develop therapeutic agents that overcome AI resistance is urgent. We investigated whether synthetic and natural selective ERβ agonists restored sensitivity to AI and anti-estrogens in hormone resistant breast cancer cells. Our data suggest that ERβ agonists such as DPN (a synthetic compound) and plant derived Nyasol, Liquiritigenin, and MF101 (Menerba) ERβ agonists may restore sensitivity against resistance by the current drugs. Natural ERβ agonists in combination with AI reduced cell proliferation in MCF7/ARO (overexpressing aromatase), MCF7/HER2 (overexpressing Her2/neu) LTLT-Ca (letrozole resistant), MCF7/TAM (tamoxifen resistant), SKBR3, and T47D breast cancer cells by 70 % to 90% when compared with DPN/AI combination. Our Western blot and RT-PCR analyses showed that combination treatment with natural ERβ agonist in combination with AI resulted in decreased levels of ERα, Cyclin D1, TNF-α, IL-6 and increased ERβ levels in LTLT-Ca and MCF7/ARO cells. In addition, aromatase expression and activity were decreased due to ERβ agonists/AI combination treatment. The activity of aromatase promoter 1.3, which is activated in breast cancer, was found to be down regulated with Nyasol, Liquiritigenin and MF101 combinations with AI when compared to single compounds in various breast cancer cells. Decreased promoter 1.3 activity is consistent with the combination-treatment decrease in the expression of inflammatory cytokines known to induce this promoter (e.g., IL-6). Our data suggest that inhibition of aromatase expression/activity by natural ERβ agonists (in combination with AI) may be a factor in overcoming AI-resistant breast cancer cell growth by these drugs. Our data also suggest that modulation of inflammatory cytokines may be factors by which ERβ agonists may influence aromatase expression and sensitizing AI-resistant breast cancer to AI therapy. Further work is required to understand the mechanistic aspects of this regulation and to advance natural ERβ agonists to the clinical treatment of AI-resistant breast cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2297. doi:10.1158/1538-7445.AM2011-2297
Abstract 23: Prognostic significance of vitamin D receptor polymorphisms in head and neck squamous cell carcinoma
Authors: Hama Takanori , Norizoe Chihiro , Yuza Yuki , Suda Toshihito , Kato Takakuni , Moriyama Hiroshi , Urashima Mitsuyoshi 
Published: June 2012

Abstract
Objective Many studies demonstrate associations between UVB rays and a lower risk of developing various cancers, implying that UVB rays induce vitamin D synthesis, which suppresses growth and induces differentiation/apoptosis of cancer. In patients with non-small-cell lung cancer, vitamin D receptor (VDR) polymorphisms and haplotypes are reported to be associated with survival. We hypothesized that a similar association would be observed in other type of cancers. In this study, we focused on head and neck squamous-cell carcinoma (HNSCC).
Methods DNA was extracted from the frozen tumor and the VDR polymorphisms (Cdx2, FokI and BsmI) in 97 patients with HNSCC were genotyped by sequencing. Disease-free survival was compared between VDR polymorphisms using Kaplan-Meier survival with log-rank tests and using the Cox proportional hazard model adjusted for age, gender, primary tumor site, and postoperative stages. Adjusted hazard ratios (AHR) and 95% confidence intervals (95% CI) were determined.
Results Tumor recurrence occurred in 41/97 (42%) patients during a median follow-up of 603 days. Genotype frequencies of the VDR polymorphisms were as follows: FokI: C/C, 39 (40%); C/T, 48 (50%); TT, 10 (10%); for Cdx2: G/G, 16 (17%); G/A, 41 (42%); A/A, 40 (41%) Bsm I: A/A, 5 (5.2%); A/G, 16 (16.5%); and G/G, 76 (78.3%). The FokI T/T genotype was associated with poor prognosis: median survival for T/T was 265 days compared with 959 days for C/C or C/T (log-rank: P=0.015; AHR, 2.65; 95% CI, 1.18 to 5.96; P=0.018). In contrast, Cdx2 and BsmI showed no significant association with survival. The G-T (Cdx2-FokI) haplotype was associated with worse disease-free survival compared with other haplotypes: median disease-free survival for G-T was 238 days compared with 959 days for other haplotypes (log-rank: P=0.0008; AHR, 6.67; 95% CI, 2.23 to 20.0; P=0.001).
Conclusion These results suggest that VDR polymorphisms and haplotypes may be associated with prognosis of patients with HNSCC.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 23. doi:10.1158/1538-7445.AM2011-23
Abstract 2308: Selective targeting of HeLa cervical cancer cells using folate receptor targeting drug loaded PLGA-lipid hybrid nanoparticles
Authors: Sandoval Sergio , Liberman Alex , Yang Jian , Aschemeyer Sharraya , Alfaro Jesus G. , Zhang Liangfang , Trogler William C. , Kummel Andrew C. 
Published: June 2012

Abstract
The response rate of breast cancer to first line chemotherapies is encouraging, but 20-30% of patients develop chemoresistance to these drugs, and consequently, have a cancer reoccurrence 7-10 months after their last treatment. Chemoresistance is believed to be due to drug efflux proteins responsible for the removal of many commonly used anti-neoplastic agents. One possible way to overcome these drug efflux pumps is to give higher doses of chemotherapy, but high doses of such agents commonly lead to chemocytotoxicity. Targeted PLGA-Lipid hybrid nanoparticle (NP) drug delivery systems have been developed that can deliver high doses of chemotherapy agents specifically to breast cancer cells. A practical cancer targeting drug delivery system will reduce the overall amount of chemotherapy agents given to patients for a given amount of targeted NPs endocytosed by cancer cells. Biodegradable NPs were synthesized using a novel nano-precipitation lipid-polymer hybrid platform which also allows for the encapsulation of hydrophobic chemotherapy drugs within the NPs. Using this method, drug free NPs have been shown to have an average diameter size of 81.78 nm (PDI: 0.25), while single loaded NPs, with Paclitaxel or Doxorubicin, show an average size between 72.33 to 89.64 nm (PDI: 0.242 to 0.339), signifying that the synthesis technique creates consistent sub 100nm particles. The majority of all NPs show a zeta-potential value of &gt; -30 mV consistent with the NPs having sufficient repulsive interaction to be mono-dispersed in solution under physiological conditions. Folate receptors are often over expressed on the surfaces of cancer cells; therefore, folic acid was incorporated to the surface of these NPs as a cancer targeting ligand. Previous studies have shown that HeLa cells, a cervical cancer cell line, over expresses folate receptors. Immunofluorescence studies show that folic acid coated PLGA-Lipid hybrid NPs are readily endocytosed by HeLa cells compared to non-targeted NPs. Cytoxicity studies will determine the increased effectiveness of drug delivery with targeted PLGA-Lipid hybrid NPs vs. untargeted PLGA-Lipid hybrid NP in cell lines and in animal models.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2308. doi:10.1158/1538-7445.AM2011-2308
Abstract 2310: Down-regulating BCL-2 gene expression in a resistant GIST cell line by a RNA G-quadruplex interacting small molecule ligand
Authors: Parkinson Gary N. , Gunaratnam Mekala , Li Xiong Wei , Collie Gavin , Reszka Anthony P. , Todd Alan R. , Fletcher Jonathan A. , Neidle Stephen 
Published: June 2012

Abstract
We have previously shown that KIT protein expression in the gastrointestinal tumour (GIST) cell line GIST882 can be down-regulated using a small molecule approach that targets expression at the transcriptional level. The small-molecule naphthalene diimide derivative ND1 developed as a G-quadruplex telomere targeting agent can inhibit telomerase activity and can also reduce c-kit mRNA levels, consistent with a dual G-quadruplex mechanism of action in this cell line. An Imatinib (Gleevec) resistant patient-derived cell line GIST48 expresses high levels of the anti-apoptotic protein bcl-2. The compound ND1 down-regulates the expression of bcl-2 in this resistant cell line, while having no discernable effect on c-kit protein expression levels or telomerase activity, both associated with DNA quadruplex stabilization. Instead we observe that translation of the apoptosis-related protein is impeded, while mRNA levels remain unaffected. The identification of a G-rich quadruplex-forming sequence in the 5’-UTR region of the bcl-2 gene, upstream of the translation start site, lead us to the development of a dual luciferase reporter assay. Utilizing a psiCHECK-2 vector we inserted the G-rich 67 base pair bcl-2 5’-UTR gene sequence upstream of the Renilla luciferase start codon. In vitro experiments have shown that the G-rich sequence can form a stable RNA G-quadruplex and interfere with translation. Our in vivo transfection experiments with ND1 in a GIST cell line shows concentration-dependent inhibition of bcl-2 protein expression. RNA G-quadruplex formation and ligand stabilization may thus be a novel anti-cancer route for the down-regulation of the anti-apoptotic protein bcl-2 in chemo-resistant cancers.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2310. doi:10.1158/1538-7445.AM2011-2310
Abstract 2321: Pyrrolobenzodiazepine (PBD) antitumour agents as chemical probes to determine the number of base pairs required for DNA minor groove structure
Authors: Rahman Khondaker M. , Hijon Isabel G. , James Colin H. , Thurston David E. 
Published: June 2012

Abstract
The pyrrolo[2,1-c][1,4]benzodiazepines (PBDs) are sequence-selective covalent-binding DNA-interactive agents that fit perfectly in the minor groove of double-stranded DNA due to their isohelical 3-dimensional shape. They possess an electrophilic N10-C11 imine (or the equivalent) that can form a covalent aminal bond between their C11-position and the C2-NH2 group of a guanine. One synthetic PBD dimer, SJG-136, has just entered Phase II clinical trials. Previous studies using HPLC/MS, CD spectroscopy, high-field NMR, X-ray crystallography and gel-based assays such as DNA footprinting and in vitro transcription stop are all consistent with the requirement for duplex DNA for covalent binding. Conversely, it is well-documented that PBDs will not interact with single stranded DNA which lacks minor groove structure. In this study, these observations served as a basis to use PBDs as chemical probes to determine the minimum number of bases required to create a minor groove environment within a DNA duplex. Thus we studied reaction of the naturally-occurring anthramycin (3 base pair span) and the synthetic C8-linked PBD bis-pyrrole conjugate GWL-78 (6 base pair span) with a range of designed duplex oligonucleotides of increasing length (3 to 11 base pairs), each containing an AGA binding triplet. Reaction was monitored by HPLC/MS which provided data on both the rate and extent of reaction, and the structure of DNA adducts formed. For both anthramycin and GWL-78, we found that a minimum of 7 DNA base pairs were required for reaction to occur, suggesting that this may represent the minimum necessary to provide a suitable minor groove environment. Furthermore, we found that the rate of reaction for both PBDs increased with the length of the oligonucleotide between 7 to 10 base pairs. It is noteworthy that GWL-78 is approximately twice the length of anthramycin but both require at least 7 base pairs in order to covalently bind. This suggests that both may be responding to the formation of a minor groove environment in an oligonucleotide that reaches 7 base pairs in length, rather than a direct relationship between the length of the PBD and the number of base pairs in the oligonucleotide. These observations were supported by molecular modeling which confirmed that 7 base pairs are required to provide minor groove structure. This is the first study to use a chemical probe of this type to monitor formation of a minor groove. This information should be useful in the design of future generations of PBDs and similar DNA-interacting anticancer agents.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2321. doi:10.1158/1538-7445.AM2011-2321
Abstract 2326: The first crystal structure of a telomeric quadruplex DNA with a metal-containing ligand
Authors: Campbell Nancy H. , Abd Karim Nurul H. , Parkinson Gary N. , Vilar Ramon , Neidle Stephen 
Published: June 2012

Abstract
The inhibition of telomerase function in cancer cells via induction of a higher-order four-stranded quadruplex arrangement in the telomeric DNA substrate, requires the participation of a quadruplex-stabilizing ligand. We showed several years ago that certain metal complexes could fulfil this role and not only have selectivity for a quadruplex arrangement but had significant biological activity.
We now report on the crystal structures of square-planar nickel (II) and copper (II) complexes containing salphen ligands with a human telomeric quadruplex. The structures show that the metal complexes are bound on an external G-quartet face of the quadruplex, and that the metal itself is positioned above the potassium-containing ion channel of the quadruplex, providing important stabilization.
The planar groups of the ligand are stacked onto guanine bases, and the charged amino side-chains are positioned in the grooves of the quadruplex. These features are enabling the available structure-activity data to be rationalized and will be discussed in terms of the design of future complexes with enhanced activity.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2326. doi:10.1158/1538-7445.AM2011-2326
Abstract 2349: Integrin α6β4 contributes to HGF-stimulated migration and invasion by promoting autocrine EGFR signaling in pancreatic cancer
Authors: Chen Min , Cruz-Monserrate Zobeida , Knifley Teresa , Davis Kelley A. , O'Connor Kathleen L. 
Published: June 2012

Abstract
The lethality of pancreatic cancer is due to elevated incidences of invasion and metastasis. Previous studies from our lab and others show that pro-invasive integrin α6β4 is upregulated in early stage pancreatic cancer, maintained during tumor progression and, in turn, promotes chemotactic migration and invasion toward HGF. To gain insight into the mechanisms governing how integrin α6β4 promotes these processes, we performed Affymetrix Gene Chip analysis on Panc-1 clones with differing levels of integrin α6β4 expression. After statistical processing, we found 582 genes altered by integrin α6β4 signaling. From these results, we found that high integrin α6β4-expressing Panc1 clones substantially enhanced expression of genes affecting epidermal growth factor receptor (EGFR) signaling. The genes upregulated by integrin α6β4 included EGFR, EGF-like ligands amphiregulin (AREG) and epiregulin (EREG), ectodomain cleavage proteases ADAMTS1, MMP1, and hyaluronan synthase 3. The upregulation of these genes was confirmed by real-time PCR, immunoblot analysis and/or ELISA. Stable overexpression of integrin β4 in low integrin β4 expressing cells increased the levels of AREG and EREG by real-time PCR. We further tested the role of autocrine EGFR signaling by pretreating cells with EGFR blocking antibodies (LA1) or EGFR-specific protein tyrosine kinase inhibitor (PD153035) and tested HGF-stimulated chemotaxis, chemo-invasion and invasive growth in three-dimensional culture. Interestingly, these inhibitors blocked integrin α6β4-dependent HGF-stimulated chemotaxis, invasion and invasive growth. In summary, our data suggest integrin α6β4 confers a motile and invasive phenotype to pancreatic carcinoma cells, in part, by coordinately regulating expression of key elements of autocrine EGFR signaling.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2349. doi:10.1158/1538-7445.AM2011-2349
Abstract 2352: GSK3b can phosphorylate Slug and modulate cancer metastasis
Authors: Kao Shih-Han , Wang Wen-Long , Hong Tse-Ming , Yang Pan-Chyr 
Published: June 2012

Abstract
Metastasis is a process complicated by multiple factors and genetic events. Slug, a Snail/Slug family transcription factor, promotes epithelial-mesenchymal transition (EMT), a process pivotal in development and tumor invasion and migration. Thus, how to regulate Slug may be useful in treating or preventing tumor metastasis in cancer. Glycogen synthase kinase-3β (GSK-3β) is a Serine/Threonine selective kinase and may regulate a broad range of cellular functions. It has been shown that GSK-3β is mostly inactivated in epithelial cancers and hence may enhance the stability of various oncogenic transcription factors. Recently, we have found that GSK-3β can interact with Slug protein, implying Slug as a possible phosphorylation substrate of GSK-3β. We confirm that GSK-3β can phosphorylate Slug by mutating the consensus motif of GSK-3β phosphorylation sites within the Slug protein (S/TxxxS/T) in the in vitro kinase assay. The cycloheximide-chase assay showed that the phosphorylation mutant (4SA) was more stable than the wild-type counterpart (wtSlug). Moreover, the wtSlug protein became more stable in the presence of kinase-dead GSK-3β or when GSK-3β was knocked down, suggesting that Slug may be more labile under GSK-3β phosphorylation. To further study whether the functions of Slug are affected by GSK-3β-induced phosphorylation, we carried out the luciferase assay and the preliminary data show that the 4SA mutant retains the transcription repression activity but is less sensitive to GSK-3β treatment. The downstream effector of EMT, E-cadherin, was repressed in HEK293/wtSlug and HEK293/4SA. More functional assays are needed to confirm that GSK-3β-induced Slug phosphorylation is involved in cancer progression. Overall, this study may provide the molecular mechanism by which the GSK-3β/Slug pathway regulates cancer cell migration, invasion and metastasis.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2352. doi:10.1158/1538-7445.AM2011-2352