bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3248: PSMA specific imaging of prostate cancer
Authors: Reddy Joseph A. , Xu Le-Cun , Dorton Ryan , Bloomfield Alicia , Nelson Melissa , Klein Patrick , Kularatne Sumith , Low Philip , Leamon Christopher 
Published: February 2011

Abstract
A peptide derivative of a prostate specific membrane antigen (PSMA) targeting ligand [Glu-C(O)-Glu] was designed to efficiently coordinate 99mTc. This chelate, referred to as EC0652, was found to bind cultured PSMA-positive LNCaP tumor cells in a concentration-dependent manner with very high affinity (Kd ∼ 20 nM). Its binding was reduced &gt; 10 fold in the presence of the ligand competitor PMPA (a high affinity PSMA binder). In addition, this molecule did not bind to panel of PSMA negative cells (4T1, A549, IGR-OV1, J6456, KB, L1210 and M109), thereby demonstrating the agent's PSMA-specific binding property. Following intravenous injection into nu/nu mice, 99mTc-EC0652 was rapidly cleared from circulation (and non-targeted tissues), and only 1.3% of the injected dose remained in the blood after 1 hour. Data from quantitative biodistribution studies confirmed that 99mTc-EC0652 predominantly accumulates in PSMA-positive subcutaneous LNCaP tumor and kidney (PSMA/glutamate carboxypeptidase positive) tissues. Net uptake in the tumor and kidney remained steady throughout the 8 h experiment resulting in a continued increase in tumor to background tissue radioactivity with time. Radioactive uptake in both of these tissues was reduced &gt; 10 fold when this radiodiagnostic imaging agent was co-dosed with PMPA. The safety of decayed 99mTc-EC0652 was evaluated as a single intravenous dose in an acute toxicology study in male mice. All doses tested were well tolerated with no demonstrated toxicity. The study established a no observed adverse effect level (NOAEL) of 14.0 mg/kg, a dose which provides an appropriate safety margin relative to the FDA designated Phase 0 dose. Equipped with these encouraging results, preparations have begun for a Phase 0 clinical trial to evaluate 99mTc-EC0652 distribution in patients with metastatic prostate cancers.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3248.
Abstract 3255: Relevance of mutated PIK3CA to normal mammary gland development and malignancy
Authors: Merino Vanessa F. , Park Sunju , Liang Xiaohui , Chun Yong Soon , Sukumar Saraswati 
Published: February 2011

Abstract
In the current study we generated transgenic mice with mammary gland specific- overexpression of PIK3CA wild type and mutant protein with the aim to characterize the effects of activation of PI3K signaling on normal mammary gland and tumor development. PIK3CA encodes p110α, the predominant isoform of the catalytic subunit of class 1A phosphatidylinositol 3-kinase (PI3K), a lipid phosphokinase. The family of PI3Ks provides signaling for diverse cellular functions, including proliferation, metabolism, migration, translation, apoptosis avoidance, and angiogenesis. Disruption of this tightly regulated pathway by gene loss (PTEN), mutation (PIK3CA, AKT1, or less commonly PIK3R1), or amplification (PIK3CA), is one of the most common alterations in human cancers. PIK3CA mutations result in constitutive activation of p110α, increasing lipid kinase activity and resulting in an increase in activated AKT. The majority of mutations in breast cancer occur at three hotspots: E542K and E545K at exon 9, which encode the helical domain, and H1047R at exon 20, which encodes the kinase domain. Previously, it was described that human mammary epithelial cells expressing these alleles grew efficiently in soft agar and as orthotopic tumors in nude mice. In a mouse model in which PI3K is activated by forced recruitment of p110α to the membrane, increased ductal branching, alveolar hyperplasia, intraductal neoplasia and a low frequency of mammary tumors were observed. To date, no in vivo studies have been reported to determine if PIK3CA mutations play a causative role in breast tumorigenesis. By performing whole mount analysis of mammary gland at 8 weeks of age, we have shown that mice harboring E545K mutation showed increased ductal branching, while expression of H1047R (high copy numbers) results in duct enlargement and defects in duct elongation. Two mice harboring low and high copy numbers of H1047R mutation developed mammary tumors at 14 and 16 months of age respectively. Histological analysis revealed that both were carcinomas with tubular, papillary and comedo features. In conclusion, transgenic mice with mammary gland specific- overexpression of PIK3CA wild type and hot spot mutations were generated. In transgenic mouse studies, we show that PI3K signaling activation appears to alter normal mammary gland development and initiate mammary tumor formation.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3255.
Abstract 3259: HIV protease inhibitors induce apoptotic and non-apoptotic cell death in ovarian cancer cells in vitro and in vivo
Authors: Vandeven Natalie A. , McLean Karen , Sorenson Dorothy R. , Liu J. Rebecca 
Published: February 2011

Abstract
Introduction: HIV patients taking antiretroviral protease inhibitors have a lower incidence of HIV associated malignancies, leading to the hypothesis that these drugs have antineoplastic activity. Given the need for novel treatment approaches in ovarian cancer, we investigated the antineoplastic effects of the HIV protease inhibitors saquinavir and nelfinavir in vitro and in vivo. Methods: A panel of ovarian cancer cell lines was treated with saquinavir and nelfinavir. The effect of protease inhibitors on cell growth, viability, apoptotic and non-apoptotic cell death was determined. Stimulation of endoplasmic reticulum stress (ERS) response was assessed by immunoblotting for ERS regulators GRP78 and ATF6. Induction of autophagy was assessed using transmission electron microscopy (TEM), and confocal microscopy was performed to demonstrate changes in green fluorescent protein-labeled LC3 expression patterns. A xenograph model of ovarian cancer was used to assess the antineoplastic effect of nelfinavir in vivo. Results: HIV protease inhibitors induced cell death in chemosensitive and chemoresistant ovarian cancer cells in a time- and dose-dependent manner. Treatment with protease inhibitors resulted in caspase-dependent apoptosis and caspase-independent cell death characterized by induction of ERS and autophagy. Cellular morphology assessed by TEM revealed apoptotic, autophagic, and necrotic cell death. Preliminary results indicate that nelfinavir administer intraperitoneally inhibits tumor growth in vivo without inducing weight loss. In contrast, the dose of intraperitoneal cisplatin required to attain a similar antineoplastic effect resulted in significant weight loss and morbidity. Conclusions: Because protease inhibitors can induce both apoptotic and non-apoptotic cell death, these drugs may circumvent chemoresistance due to alterations in apoptotic response. Saquinavir and Nelfinavir are FDA-approved agents for the treatment of HIV, and our data suggest that these drugs may also have clinical application in the treatment of ovarian cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3259.
Abstract 327: Genomic profiling of sentinel lymph node breast cancer metastasis
Authors: Torresan Clarissa , Santos Savana C. , Camps Jordi , Pereira Silma F. , Ribeiro Enilze M. , Cavalli Iglenir J. , Haddad Bassem R. , Cavalli Luciane R. 
Published: February 2011

Abstract
The sentinel lymph node (SLN) is the first node in the axilla to harbor malignant cells in breast tumors with metastasis, and its positivity is an indication for axillary lymph node dissection. Despite significant improvement in the methods for detection of tumor cells at this site, there are a still significant number of false negative cases and the inability to detect malignant cells in lower abundance, such as in the case of micrometastasis. We propose to use methods based on the genomic alterations, which present higher sensitivity and accuracy, and can be used to augment the current methods to identify the epithelial malignant cells at the SLN. In this study, we performed CGH and array-CGH analysis in microdissected tumors cells from the SLN metastatic lesions to identify DNA copy number changes. We compared the changes observed in the SLN lesion to the ones present in the corresponding primary tumors (PT) from the same patients. Here we present the results from the initial analysis of 10 FFPE (formalin-fixed paraffin-embedded) breast cancer samples (5 pairs of SLN and PT). DNA copy number changes were detected by both methods in all the cases analyzed. A remarkable similarity in the DNA profiles between the SLN metastatic lesions and the corresponding PT were observed, despite the high level of heterogeneity observed among the cases. CGH analysis revealed most frequently gains of chromosomal regions (at both lesions) involving 1p, 1q, 6q, 9q, 11p, 11q, 13q, 16p, 17q, 19p, 19q and Xq. Array-CGH analysis detected both amplifications and deletions, affecting mostly the chromosome regions 1p (genes affected KLHL17, NOC2L, PPIAL4), 9q (ANKRD20A, COL5A), 11p (PSMD13, SIRT3), 15q (MAN2C1), 19p (MUC16, AZU1) and 20q regions (PSMA7). In addition, several genes of the HIST, FLJ, SLC and TRIM family as well as the homeobox families HOX and NK were involved in the alterations. FISH analysis is being conducted to confirm the array-CGH findings as well as the analysis of additional matching samples. The assessment of copy number changes in the SLN metastasis (and in its correspondent PT) using genomic profiling is a very sensitive method and will lead to the identification of genomic alterations that can reliably characterize breast tumor cells at the SLN lesions. Once these alterations are validated in larger series of patients, they can be used as molecular markers that can improve the predictive value of the current established methods of SLN evaluation in the identification of patients at higher risk of developing axillary lymph node metastasis.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 327.
Abstract 3277: The Fps/Fes protein-tyrosine kinase serves a stromal tissue-specific supporting role in an orthotopic mouse model of breast cancer
Authors: Zhang Shengnan , Elliott Bruce B. , Greer Peter A. 
Published: February 2011

Abstract
Fes (also known as Fps) is a cytoplasmic protein tyrosine kinase that is highly expressed in breast epithelial cells during lactation, as well as in vascular endothelial and myeloid cells. Retrovirally encoded oncogenic alleles of Fps/Fes are associated with tumors in chickens and cats and cause tumors in transgenic mice; however, a role for Fes in human cancer has not been established.
We hypothesized that Fes promotes breast tumorigenesis through tumor cell intrinsic functions as well as through functions in stromal tissues including vascular endothelial cells and macrophages. To test the potential tumor cell intrinsic role, AC2M2 cells, a highly metastatic mouse mammary carcinoma cell line, were transduced with expression plasmids encoding wild-type, kinase-inactivated or activated Fes. These cells were then engrafted into the mammary fat pads of nude mice and tumorigenesis was assessed by ultrasound (longitudinal tumor volume measurement), Doppler (tumor-associated vascular flow) and biophotonic imaging of GFP-expressing tumor cells (lung metastasis). There was no obvious difference in tumor growth and angiogenesis at the orthotopic site between each cell line and no apparent difference in lung metastasis. To test the potential stromal role of Fes in breast tumorigenesis, parental AC2M2 cells were injected into the mammary fat pads of wild type and Fes-null nude mice, and tumorigenesis and metastasis were assessed as described above. Wild type mice developed tumors significantly faster than Fes-null mice and there was earlier tumor neovascularization and more recruitment of macrophages. There was also a significantly higher degree of lung metastasis in wild type vs Fes-null mice.
These observations are consistent with a tumor promoting role for Fes acting at the level of the vascular endothelium and macrophages. This might include promoting early tumor neovasularization through direct roles in vascular endothelial cells as well as indirect roles associated with macrophages. The increased metastatic potential also suggests roles in both these cell lineages. This provides genetic evidence that the Fes protein-tyrosine kinase represents a potential novel therapeutic target in breast cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3277.
Abstract 3278: Mitochondria derived from breast cancer MDA-MB-231 cells confer oncogenic properties in the normal breast epithelial nuclear background
Authors: Ma Yewei , Wong Lee-Jun C. 
Published: February 2011

Abstract
Previous reports showing somatic mitochondrial DNA alterations, the reduction of respiratory chain function, and the essential roles of mitochondria in apoptosis and autophagy, have implicated that mitochondria are vital in cancer development. To study the contribution of cancer mitochondria to tumor properties, the major effects from the nucleus must be removed. We developed an in vitro transmitochondrial cybrid system, in which, mitochondria derived from normal breast epithelial cells (MCF-10A) or breast cancer cells (MDA-MB-231) were fused with ρ0 nuclear donor cells derived from immortalized normal breast epithelial A1N4 cells. Studies of these cybrids showed reduced respiratory chain activities, ATP synthesis rates, and oxygen consumption, in 231/A1N4 cybrids compared to 10A/A1N4 cybrids. In addition, higher production of ROS and lactate were also noted. These results suggested that cancer mitochondria had reduced oxidative energy production function. With the same normal breast epithelial nuclear background, cybrids containing cancer mitochondria exhibited higher expression of oncogenes and growth factors than cybrids containing mitochondria derived from non-cancer epithelial cells (MCF-10A). The 231/A1N4 cybrid cells lost growth contact inhibition, had higher ability to form colonies, and were more resistant to serum starvation compared to 10A/A1N4 cybrids, supporting the hypothesis that mitochondria derived from cancer cells contribute to tumor properties even in the normal nuclear background. These studies provide useful insights to the cross-talk between the mitochondrial and nuclear genomes of altered mitochondria to normal cells.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3278.
Abstract 3280: Generation of orthotopic mouse models of breast cancer
Authors: Palafox Marta , Pellegrini Pasquale , Barbera Laura , Urruticoechea Ander , Climent Josefina , Soler Maria Teresa , Gonzalez-Suarez Eva 
Published: February 2011

Abstract
The current systemic treatments for breast cancer include chemotherapy, and targeted approaches such as anti-hormonal and anti-Her2 treatments. These treatments are effective only in a percentage of cases and even those initially responsive tumors eventually acquire resistance. It is critical to define the mechanisms of resistance and to identify the population of resistant cells to target them efficiently. We have generated mouse models for the study of breast cancer tumors based on the orthotopic implantation of fresh primary human tumor pieces and cancer cells isolated from pleural effusions in immunodeficient mice. A total of 55 fresh tumor pieces and tumor cells isolated from 5 pleural effusions have been implanted into the cleared fat pad of nude, NOD/SCID and SCID/beige mice. Slow release estrogen pellets have been implanted in the intercapsular region at the same time as tumors. Nine out of the 60 samples implanted gave rise to palpable lesions, 5 derived from fresh tumor pieces and 4 from tumor cells isolated from pleural effusions and are being maintained by serial passages in mice. Currently we have five well-established tumors, 2 TNBC (triple negative breast cancer), 2 luminal tumors and one Her2 positive tumor. Morphologically tumors growing in mice resemble human tumors. Latency to tumor development and growth rates are being evaluated in different serial passages and host mice. Tumors at different passages are being characterized at the histological level and for the expression of ER, PR, Her2, EGFR, cytokeratins and p53, and compared with the primary human tumor. Once tumors are established and characterized we will test their sensitivity to drugs currently used in the clinic. Orthotopic tumor xenografts will allow gaining insight into the molecular mechanisms involved in the resistance. Genetic and epigenetic analysis will allow to identify the chromosomal regions related with resistance. Similarly, differential gene expression profiling will be determined by microarray analysis.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3280.
Abstract 3283: Developmental and metabolic deregulation in 14-3-3zeta knockout mouse
Authors: Yang Jun , Li Ping , Yu Dihua 
Published: February 2011

Abstract
14-3-3s are a family of proteins conserved throughout eukaryotics. By binding to specific phosphorylated serine/threonine containing motifs in the target proteins, 14-3-3s modulates their molecular structure, stability, subcellular localization and/or enzymatic activity. Our lab recently found that 14-3-3ζ (zeta) is overexpressed in ∼45% breast cancers and 14-3-3ζ overexpression predicts poor patient survival. Additionally, 14-3-3ζ prevents anoikis by suppressing p53 and promotes epithelial mesenchymal transition by activating TGB-β signaling pathway, which plays important roles during tumor formation and progression. These led us to we hypothesizing that 14-3-3ζ plays important role in breast cancer.
In our initial attempt to systematically study the role of 14-3-3ζ in breast cancer in vivo, we have recently generated 14-3-3ζ conventional knockout mouse by Gene Trap. We obtained the ES cell line RRR334 (which has no functional 14-3-3ζ based on the 5’ RACE data of the Baygenomics) from the Mutant Mouse Regional Resource Center. We confirmed silencing of 14-3-3ζ in the clone by RT-PCR. The integration site of the Gene Trap vector was located about 5kb downstream of exon 3 inside the intron 3 and PCR genotyping primers were designed accordingly. The ES cells were injected into C57Bl/6 albino mouse blastocysts. Chimera mice with high ES cell contributions based on their fur color were mated with C57Bl/6 albino mice to determine germ line transmission. When we mated the founder 14-3-3ζ heterozygous (+/−) male with 14-3-3ζ +/− female, only ∼ 5% of the offspring's were 14-3-3ζ homozygous (−/−) mice, indicating 14-3-3ζ −/− mice are embryonic lethal. This lethality hinders our study of the role of 14-3-3ζ in tumorigenesis and progression. To overcome this, we outbred to CD-1 mouse strain and the resulting mice are viable and fertile. Interestingly, the 14-3-3ζ knockout mice are smaller than their littermates. This growth retardation did not seem to be mediated by deregulated growth hormone level. The 14-3-3ζ null mice also had lower blood glucose level and their livers and brain had a reduced glucose uptake. Our preliminary studies indicated that HIF1-α, a well known oncogene and a master regulator of metabolism (e.g., glycolysis), is downregulated in 14-3-3ζ null mice. We are currently further characterizing the phenotypes of 14-3-3ζ knockout mouse and also studying the molecular mechanism of how loss of 14-3-3ζ leads to growth retardation and how 14-3-3ζ regulates glucose metabolism.
We are also studying whether loss of 14-3-3ζ has any impact on tumor formation and metastasis.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3283.
Abstract 3285: Phenotypic characterization of circulating tumor cells (CTCs) in triple negative breast cancer patients
Authors: Kallergi Galatea , Agelaki Sofia , Mathioudaki Argyri , Mavroudis Dimitris , Georgoulias Vassilis 
Published: February 2011

Abstract
Background: Molecular classification of breast cancer revealed that there are five different subtypes related to clinical outcome:. luminal A, luminal B, normal-like, ERBB2-positive and basal-like. Triple negative patients (ER-negative, PR-negative, HER2-negative) belong to the basal-like subtype. Their tumors commonly express EGFR and are associated with poor prognosis. Circulating Tumor Cells (CTCs) have been proposed as a “real time liquid biopsy” in breast cancer patients. CTCs are associated with disease relapse and could serve as a target for molecular cancer therapies. The aim of the present study was, for the first time, the phenotypic characterization of CTCs in triple negative breast cancer patients. Methods: We evaluated peripheral blood mononuclear cells (PBMC) cytospins from 40 triple negative patients and found CTCs in thirty one of them (15 early and 16 metastatic). The expression of Cytokeratins (CK), Estrogens Receptor (ER), Progesterone Receptor (PR), Epidermal Growth Factor Receptor (EGFR) and Human Epidermal Growth Factor Receptor (HER2) in CTCs was assessed using double immunofluorescent staining and confocal laser scanning microscopy and the Ariol system. PBMCs were stained with a monoclonal A45-B/B3 pancytokeratin antibody in combination with ER, PR, EGFR or HER2 antibodies, respectively. Results: Our results demonstrated that ER, PR, EGFR and HER2 were expressed in 58%, 45%, 55% and 58% of the examined CK-positive patients. The respective proportions for early versus (vs) metastatic patients were 67% vs 50% for ER, 53% vs 38% for PR, 60% vs 44% for EGFR and 60% vs 56% for HER2. In addition ER, PR, EGFR and HER2 were expressed in 5.6%, 79.7%, 80.7% and 13.4%, respectively, of the total examined CTCs. Triple staining experiments with the Ariol system revealed no co-expression of CK/EGFR/ER in CTCs; however, there was only one patient with CTCs co-expressing CK/HER2/ER. Conclusions: ER is expressed but in a minority of CTCs in triple negative breast cancer patients though the majority of CTCs revealed expression of PR and EGFR. However the clinical significance of these findings remain unknown and need further evaluation.
Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3285.