bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 2474: Synthesis and antiproliferative activity of novel 17β-acetyl-testosterone-7α-platinum(II) hybrids designed for the treatment of human prostate cancer.
Authors: Fortin Sébastien , Brasseur Kevin , Morin Nathalie , Asselin Éric , Bérubé Gervais
Published: August 2014

Prostate cancer is a major public health problem worldwide. In the United-States, prostate cancer is ranked first of all new cancer cases diagnosed in men and it is the second most lethal cancer. Antiandrogens are normally used in clinic to slow down the progression of androgen-sensitive (AR+) prostate cancer inducing prolonged remission without definite cure. In general, 10 years after the initial treatment of early prostate cancers, 19% of patients will experience local tumor progression, 15% distant metastases and 10% will die. Furthermore, advanced prostate cancers quickly (18 to 24 months) become androgen-insensitive (AR-) and antihormone therapy becomes ineffective. At this point, the median survival of approved drug combination treatments is then under 20 months. Consequently, the search for new, more selective and efficient treatments is still a subject of intense research.

To that end, we used the natural tropism of testosterone for prostate tissues to target platinum(II) complexes to prostate cancer cells. The platinum complexes were linked to the 7α position on testosterone as it is located between the 3-carbonyl and 17-hydroxyl groups involved in key hydrogen bonds essential for androgen receptor interactions. L- and D-2-pyridylalanine, L-histidine and L-4-thiazolylalanine derivatives were linked to 17β-acetyl-testosterone selected to chelate platinum(II). Four new amino acid platinum(II) complexes were prepared (compounds 1a-1d), characterized and evaluated for their antiproliferative activity on LNCaP (AR+), PC3 (AR-) and DU145 (AR-) human prostate adenocarcinoma cancer cell lines.

The new testosterone-platinum(II) complexes exhibited antiproliferative activities at the micromolar level on all prostate cancer cell lines tested. Structure-activity relationships show that the stereochemistry of amino acids (compounds 1a, b) does not affect the antiproliferative activity. Moreover, the replacement of a pyridinyl moiety by an imidazolyl group (compound 1c) decreased the activity by up to 10 fold whereas the replacement by a thiazolyl group (compound 1d) showed an antiproliferative activity between 2.5 to 8.0 times higher than that of cisplatin.

The innovative design and the significant activity of our testosterone-platinum(II) complexes toward AR+ and AR- prostate cancer cells suggest that they might be useful for treatment of advanced prostate cancers.

Citation Format: Sébastien Fortin, Kevin Brasseur, Nathalie Morin, Éric Asselin, Gervais Bérubé. Synthesis and antiproliferative activity of novel 17β-acetyl-testosterone-7α-platinum(II) hybrids designed for the treatment of human prostate cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2474. doi:10.1158/1538-7445.AM2013-2474
Abstract 2476: Synthesis of novel aza-podophyllotoxins derivatives substituted at ring-A and their activities on NCI-60 human tumor cell line.
Authors: Kumar Ajay , Kumar Vineet , Malhotra Sanjay V. , Antonio Alegria E.
Published: August 2014

Podophyllotoxin is a major cytotoxic constituent of several members of Podophyllum peltatum species. The semisynthetic derivatives namely etoposide, etopophos and teniposide have been developed from podophyllotoxin and are currently used in clinic for the treatment of several human tumors since five decades. Synthesis of podophyllotoxin is not feasible so far and due to this reason structural modification of podophyllotoxin could not be explored very well. The structural complexity of podophyllotoxin, arising from the presence of four stereogenic carbons in ring C has restricted most of the structural activity relationship (SAR) studied by derivatization of the parent natural product rather than by de novo multi-step chemical synthesis. In past we have developed various heterocyclic analogues of podophyllotoxin derivatives. Owing to their promising activity against 60 cell lines at NCI, we are actively engaged in developing new library of N-hydroxyethyl-4-aza-didehyropodophyllotoxin derivatives. A new library of aza-podophyllotoxin derivatives substituted at ring-A has been developed and followed by a screen of in vivo activity using a panel of tumor hollow-grafts implanted in mice consisting of breast (MDA-MB-231), non-small lung (NCI-H23 and NCI-H522), colon (SW-620 and COLO 205), melanoma (UACC-62, MDA-MB-435 and LOXIMVI), ovarian (OVCAR-5 and OVCAR-3) and CNS (U251 and SF-295) cell lines. These new compounds found to have comparatively good activity against colon and cancer lines.

Citation Format: Ajay Kumar, Vineet Kumar, Sanjay V. Malhotra, Alegria E. Antonio. Synthesis of novel aza-podophyllotoxins derivatives substituted at ring-A and their activities on NCI-60 human tumor cell line. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2476. doi:10.1158/1538-7445.AM2013-2476

Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.
Abstract 2478: Novel tyrosine derivatives of temozolomide active against breast cancer cell lines.
Authors: O'Sullivan Jordan Kiefer , Helphrey Taylor R. , Laim Johnny , Louie Maggie C. , Carranza Maria Graciela
Published: August 2014

A series of L- and D-tyrosine derivatives of temozolomide (TMZ) was synthesized and evaluated as potentially improved anticancer agents against breast cancer cell lines. TMZ is a well tolerated, broad spectrum oral alkylating agent that crosses the blood–brain barrier. It has demonstrated activity against glioma and melanoma, as well as preclinical activity against breast cancer. Recent studies have shown the effectiveness of combining alkylating agents with the amino acid tyrosine, yielding analogs with significantly improved in vitro anticancer activity when compared with the parent compound. Following from this, we seek to improve the efficacy of TMZ by chemically modifying the C-8 position of the imidazotetrazine to include L- and D-tyrosine adducts attached either directly or via a linker of varying size. The novel TMZ derivatives were synthesized in good yields through efficient peptide synthesis methods. The anticancer efficacy of the derivatives was evaluated over several hormone-dependent and hormone-independent (ER+ and ER-) breast cancer cell lines. Preliminary results show that at a concentration of 2 x 10−5 M the novel derivatives display at least a 20% greater in vitro growth inhibitory activity when compared to TMZ, particularly in hormone-dependent MCF-7 breast cancer cell line. Structure–activity relationship (SAR) analysis suggests the influence of both the length of the linker and the stereochemistry of the tyrosine adduct on the anticancer activity of the derivatives. Further investigation will reveal if interaction with hormone-related receptors is involved in the mechanism of action of the newly synthesized derivatives.

Citation Format: Jordan Kiefer O'Sullivan, Taylor R. Helphrey, Johnny Laim, Maggie C. Louie, Maria Graciela Carranza. Novel tyrosine derivatives of temozolomide active against breast cancer cell lines. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2478. doi:10.1158/1538-7445.AM2013-2478
Abstract 2480: Discovery and mechanistic characterization of AV220, a novel small molecule targeting cancer cell metabolism.
Authors: Millard Melissa , Neamati Nouri
Published: August 2014

Metabolic plasticity is an adaptive mechanism tumors rely upon for growth advantage. Without sufficient energy and biomass, cell replication cannot proceed. Therefore, interrupting cancer-specific metabolic processes presents a novel means to inhibit tumor growth. The clinical benefit of this approach has not yet been fully realized due to a lack of suitable agents targeting cancer cell metabolism. To address this unmet need we screened our in-house compound library for chemical scaffolds with potential metabolic activity. In the course of our studies we identified the small molecule AV220 as a potent metabolic antagonist suitable for preclinical development. In a panel of cancer cell lines, AV220 showed anti-proliferative activity in the low micromolar range. Mechanistic studies indicate a mode of action that involves energy sensing and regulatory pathways. AV220 treatment produced a rapid and sustained phosphorylation of AMPK and its substrate acetyl-CoA carboxylase. Prolonged treatment with AV220 resulted in profound intracellular vacuolation and increased autophagic flux followed by accumulation of Grp78, CHOP and ATF4. Additional early intracellular signaling events associated with AV220 treatment included phosphorylation of p38 and Erk 1/2 and Src and Akt inhibition. A structure-based search of our small molecule library led to the identification of additional analogs, many of which displayed similar cytotoxicities and a shared mechanism of action.

Citation Format: Melissa Millard, Nouri Neamati. Discovery and mechanistic characterization of AV220, a novel small molecule targeting cancer cell metabolism. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2480. doi:10.1158/1538-7445.AM2013-2480
Abstract 2482: Development of novel small-molecule inhibitors of androgen receptor variants lacking the ligand-binding domain.
Authors: Tian Xiaohong , Liu Weiguo , Geng Guoyan , Wu Jian Hui
Published: August 2014

Over 30,000 men die from prostate cancer in Canada and USA each year. Current therapeutic strategy for advanced prostate cancer is to suppress androgen receptor (AR) signaling by reducing level of androgens (via castration) and by antiandrogens to compete with endogenous androgens for binding in the AR ligand-binding domain (LBD). Despite of initial response, lethal ‘castration-resistant’ prostate cancer (CRPC) arises as a result of oncogenic reactivation of the AR. Current treatments for CRPC provide only a modest improvement in overall survival (a few months). It is now firmly established that reactivation of the AR signaling in CRPC is due to multiple mechanisms, including point mutations in the AR LBD and expression of AR variants lacking the LBD. Recently, a series of AR splice variants lacking the LBD, such as AR-v7, were identified from tissue specimen of CRPC patients. Significantly, AR-v7 is constitutively active even in the absence of androgens and it is thus no longer possible to be inhibited by conventional LBD-targeting antiandrogens (such as bicalutamide) or by androgen-depleting agents (such as Abirateron). This potentially provides a novel mechanism for the development of CRPC. Our recent work has identified a novel chemical compound that inhibits AR-v7 in reporter assays. We found this compound is also active against full-length ARs, including the wild type and multiple clinically-relevant mutant ARs, such as the T877A, H874Y and W741C mutants. Our study indicated this compound targets the N-terminal domain of the AR. We have obtained structure-activity relationship (SAR) of this compound.

Citation Format: Xiaohong Tian, Weiguo Liu, Guoyan Geng, Jian Hui Wu. Development of novel small-molecule inhibitors of androgen receptor variants lacking the ligand-binding domain. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2482. doi:10.1158/1538-7445.AM2013-2482
Abstract 2484: Proteomic identification of ubiquitin conjugating enzyme E2N and proteasome activator complex subunit 3 as potential biomarkers in colorectal cancer tissues.
Authors: Kang Kee R. , Kang Jung H. , Ju Young-Tae
Published: August 2014

Colorectal cancer (CRC) is the third most prevalent cancer worldwide and has poor prognosis. Recent improvement in methods for proteome analysis has offered the possibility of identifying disease-associated protein markers to assist in diagnosis or prognosis, and for selecting potential targets for specific drug therapy. In current study, the proteome of colorectal adenocarcinoma and the corresponding normal tissues was visualized and analyzed a number of proteins to isolate and identify tumor-specific proteins for CRC. Ten proteins were dominantly expressed and five proteins were largely repressed in CRC by the analysis of 2-DE and MALDI-TOF/mass spectrometry. Ubiquitin conjugating enzyme E2N, one of enzyme necessary for ubiquitination, and proteasome activator complex subunit 3 were focused to be increased in CRC tissues compared with normal colorectal tissues. The elevated expression of E2N and proteasome activator complex subunit 3 in CRC was confirmed by Western blot analysis and real time PCR. Immunohistochemistry also verified largely up-regulation of E2N and proteasome activator complex subunit 3 in 85 CRC patients. These findings suggest that ubiquitin conjugating enzyme E2N and proteasome activator complex subunit 3, which are involved in the ubiquitin-proteasome system, could be possible tumor biomarker candidates in CRC tissues. [Funding source: NRF grant (R13-2005-012-01003-0)].

Citation Format: Kee R. Kang, Jung H. Kang, Young-Tae Ju. Proteomic identification of ubiquitin conjugating enzyme E2N and proteasome activator complex subunit 3 as potential biomarkers in colorectal cancer tissues. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2484. doi:10.1158/1538-7445.AM2013-2484
Abstract 2486: Plasma proteomic changes induced by effective chemopreventive ratios of N-3:N-6 fatty acids against MNU-induced mammary carcinogenesis of the rat.
Authors: Skibinski Christine G. , Thompson Henry J. , Das Arunangshu , Manni Andrea , El-Bayoumy Karam
Published: August 2014

The development of sensitive, specific, and reliable biomarkers for early detection of breast cancer and the discovery of novel chemopreventive agents are two strategies with promising clinical applications. It has been postulated that the risk of breast cancer can be influenced by certain dietary compounds such as the type and amount of dietary fats ingested. We have shown that a diet high in an n-3:n-6 ratio (10:1 and 25:1), that provided 30% calories from fat (10% monounsaturated, 10% polyunsaturated, and 10% saturated fatty acids), significantly reduced rat mammary cancer induced by 1-methyl-1-nitrosourea(MNU). In the present study we used a proteomic approach to gain insights into the mechanisms of protection by a high n-3:n-6 ratio with the goal of identifying biomarkers that can be employed to monitor efficacy of chemopreventive agents. The plasma from six rats from each of three groups, a control group(n-3:n-6=1:1) and two groups fed a high n-3 diet(n-3:n-6=10:1 and 25:1) was pooled and submitted to the isobaric Tags for Relative and Absolute Quantitation(iTRAQ) method, which includes matrix-assisted laser desorption/ionization tandem mass spectroscopy(MALDITOF/TOF) to identify and quantify proteins that were regulated as a result of n-3 fatty acid supplementation. There were 148 proteins identified in our study with 95% confidence(unused score 1.3 or greater) by ProteinPilot 4.0. In plasma of rats fed 10:1 n-3:n-6, and 25:1 n-3:n-6 the number of proteins that met our criteria(p<0.05, error factor≤2) were 10 and 14 proteins, respectively. Our results illustrated that many proteins were modified in a manner consistent with chemoprevention. Validation of the iTRAQ by Western Blotting showed up-regulation of vitamin D binding protein and gelsolin postulated to have a tumor suppressive effect through modulation of inflammation and actin depolarization, respectively. We also observed that 14-3-3 sigma, a well known tumor suppressor in breast tissue, was increased in a ratio dependent fashion. In contrast, we observed down-regulation of alpha-1b-glycoprotein which has been reported to be elevated in the serum of breast cancer patients. These proteins may serve in future studies as candidate biomarkers in early detection and clinical chemoprevention trials with well-defined ratios of n-3:n-6 fatty acids. Support: Susan G. Komen Foundation(KG081632)

Citation Format: Christine G. Skibinski, Henry J. Thompson, Arunangshu Das, Andrea Manni, Karam El-Bayoumy. Plasma proteomic changes induced by effective chemopreventive ratios of N-3:N-6 fatty acids against MNU-induced mammary carcinogenesis of the rat. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2486. doi:10.1158/1538-7445.AM2013-2486
Abstract 2488: Novel candidate protein biomarkers for cisplatin response prediction in non-small cell lung cancer.
Authors: Schaaij-Visser Tieneke B M , Nagel Remco , de Reus Inge , Piersma Sander R. , Pham Thang V. , Smit Egbert F. , Thunnissen Frederik B. , Brakenhoff Ruud H. , Berns Anton , Jimenez Connie R.
Published: August 2014

The five-year survival rate for non-small cell lung cancer (NSCLC) is still less than twenty percent in part due to treatment failure and lack of biomarkers for personalized therapy. Most NSCLC patients are treated by chemotherapy and cisplatin is still the major component of most chemotherapy regimens. However, resistance to cisplatin is a common phenomenon. Aim of this study was to identify protein biomarkers that can be used for cisplatin response prediction.

The proteomes and secretomes1 of a series of human NSCLC cell lines with a range of IC50-values for cisplatin (1.5 - 15 μM) were analyzed by label-free proteomics based on GeLC-MS/MS and quantified by spectral counting. Significant differential expression of proteins was determined by the in-house developed beta-binomial statistical test2. Network and gene ontology analysis was performed, with STRING and DAVID respectively, to reveal cellular and molecular functions associated with the differential proteins.

In total, 2885 and 2342 proteins were detected in the cell lysates and secretomes, respectively. The proteins with significantly higher expression in the resistant cell lines were associated RNA processing and vesicle transport, while the proteins with higher expression in the sensitive cell lines were known to be involved in RNA splicing, DNA damage repair and extracellular matrix organization. The most promising candidates are being validated in tissues and sputum of patients with known response to cisplatin.

1 Piersma SR et al. J Proteome Res. 2010 Apr 5;9(4):1913-22.

2 Pham TV et al. Bioinformatics. 2010 Feb 1;26(3):363-9.

Citation Format: Tieneke B M Schaaij-Visser, Remco Nagel, Inge de Reus, Sander R. Piersma, Thang V. Pham, Egbert F. Smit, Frederik B. Thunnissen, Ruud H. Brakenhoff, Anton Berns, Connie R. Jimenez. Novel candidate protein biomarkers for cisplatin response prediction in non-small cell lung cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2488. doi:10.1158/1538-7445.AM2013-2488
Abstract 2491: Dynamics changes in antigen-autoantibody profiles involving glycolysis and spliceosome proteins precede a diagnosis of ER+ and triple negative breast cancer among post-menopausal women.
Authors: Ladd Jon , Johnson Melissa , Chao Timothy , Chin Alice , Pitteri Sharon , Mao Jianning , Amon Lynn M. , McIntosh Martin , Lampe Paul , Li Christopher , Prentice Ross , Disis Nora , Hanash Samir
Published: August 2014

We assessed the circulating autoantibody repertoire in breast cancer using genetically engineered mouse models and human plasmas collected at a pre-clinical time point and at the time of clinical diagnosis of breast cancer. We aimed to identify common pathways, networks and protein families associated with the humoral response to tumors and to elucidate the dynamic nature of tumor antigens and autoantibody interactions in ER+ and triple negative breast cancer. Lysate proteins from immortalized mouse cell lines from MMTV-neu and C3(1)-T mouse models and from the MCF7 and MDA-MB-231 human breast cancer cell lines were spotted onto nitrocellulose microarrays and hybridized with mouse and human plasma samples, respectively. Ig-based plasma immunoreactivity against glycolysis and spliceosome proteins was a predominant feature observed both in MMTV-neu tumor bearing mice and in pre-diagnostic ER+ human samples. A cytoskeletal signature was uniquely observed in C3(1)-T mice and in human patients with triple negative breast cancer. We provide evidence for dynamic changes in autoantibody reactivity and in antigen-antibody interactions with tumor development and progression.

Citation Format: Jon Ladd, Melissa Johnson, Timothy Chao, Alice Chin, Sharon Pitteri, Jianning Mao, Lynn M. Amon, Martin McIntosh, Paul Lampe, Christopher Li, Ross Prentice, Nora Disis, Samir Hanash. Dynamics changes in antigen-autoantibody profiles involving glycolysis and spliceosome proteins precede a diagnosis of ER+ and triple negative breast cancer among post-menopausal women. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2491. doi:10.1158/1538-7445.AM2013-2491
Abstract 2496: Identification and functional characterization of a novel oxidatively modified protein in the cardiac tissue after doxorubicin-induced cardiotoxicity.
Authors: Aryal Baikuntha P. , Jeong Jinsook , Rao V. Ashutosh
Published: August 2014

Doxorubicin (Dox) is an anthracycline drug that is effectively used as a chemotherapeutic agent for the treatment of a variety of cancers. Its dose-dependent cardiotoxicity, however, has limited its chemoprotective properties in clinical practice. One of the primary mechanisms of Dox-induced cardiotoxicity is the generation of intracellular reactive oxygen species (ROS) by an iron-catalyzed reaction. We hypothesized that the consequent protein oxidation under oxidative stress can be monitored and correlated with cellular outcome of survival or death. First, to understand how Dox-induced oxidative stress is related to the cardiotoxicity, we identified specific cardiac proteins that are oxidatively modified under Dox-induced oxidative stress in a spontaneously hypertensive rat model of acute toxicity. Next we characterized the type(s) of modifications and the amino acid residues within the protein that undergo modification under oxidative stress. Finally, we investigated the functional consequences of such oxidative modifications. Based on our findings, we focused on protein carbonylation as an indicator of severe oxidative damage. We detected a highly carbonylated protein in the cardiac tissue after Dox-treatment. The Dox-induced carbonylated protein was identified as a cardiac myosin binding protein C (MyBPC) using mass spectrometry. To determine the carbonylated sites and effect of such modification in the protein structure and function, we expressed MyBPC in E. coli and purified recombinant MyBPC. Consistent with the in vivo results, recombinant MyBPC showed an increase in carbonylation under excessive oxidative conditions. The degree of carbonylation was time- and concentration-dependent. Excessive carbonylation was associated with the degradation of MyBPC. Identification of carbonylated sites and the effect of such carbonylation in the protein functions will help to better understand the Dox-induced cardiac toxicity. Our findings also indicate the potential for an oxidative biomarker for monitoring the Dox-induced cardiotoxicity.

Citation Format: Baikuntha P. Aryal, Jinsook Jeong, V. Ashutosh Rao. Identification and functional characterization of a novel oxidatively modified protein in the cardiac tissue after doxorubicin-induced cardiotoxicity. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2496. doi:10.1158/1538-7445.AM2013-2496
Abstract 2497: Upregulation of annexin A8 is a common molecular phenotype of aberrant breast acinar morphogenesis induced by different genetic factors.
Authors: Rossetti Stefano , Corlazzoli Francesca , Sacchi Nicoletta
Published: August 2014

It is estimated that up to 90% of women have benign breast lesions, some of which are pre-malignant. In situ lesions, particularly the ones that involve the ducts (ductal carcinoma in situ, DCIS), have the potential to progress into invasive malignant lesions and become life threatening. These breast premalignant states are identified because of specific morphological tissue abnormalities. Three-dimensional (3D) cultures of human mammary epithelial cells closely recapitulate breast acinar morphogenesis. While untransformed mammary epithelial cells form hollow acini, lined by polarized, non-proliferating cells, breast cancer cells form acini filled with non-polarized, actively proliferating cells, similar to DCIS. By using a proteomic approach in a panel of morphologically aberrant acini derived from human breast epithelial cells, we found that the disruption of acinar morphogenesis by different genetic factors generates a common proteomic signature. Among the proteins that we found consistently upregulated, we identified Annexin A8 (ANXA8), a member of the annexin family of calcium and membrane-binding proteins with a wide range of cellular functions, including cell division, apoptosis, and cell growth regulation. We tested ANXA8 expression in tissue samples from patients with atypical ductal hyperplasia (ADH), and tissue microarrays of DCIS, with or without, history of invasive breast cancer. Interestingly, this analysis detected ANXA8 increased expression in atypical proliferating ducts relative to non-proliferative ducts, making ANXA8 a potential marker of breast pre-malignancies.

Acknowledgments: this study was funded by grants of the Susan Komen Foundation, the Breast Cancer Coalition of Rochester, the Friends for an Earlier Test of Breast Cancer Foundation.

Citation Format: Stefano Rossetti, Francesca Corlazzoli, Nicoletta Sacchi. Upregulation of annexin A8 is a common molecular phenotype of aberrant breast acinar morphogenesis induced by different genetic factors. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2497. doi:10.1158/1538-7445.AM2013-2497

Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.
Abstract 250: Growth characteristics of breast cancer stem cells in vitro and in vivo.
Authors: Lee Carnella M. , Sawant Anandi , Cha Ha-Ram , Ponnazhagan Selvarangan
Published: August 2014

Breast cancer (BCa) is the most common malignancy in United States women, accounting for greater than 40,000 deaths each year. Studies have attributed the presence of cancer stem cells (CSC) with resistance to chemotherapy as a key component of refractories of treatments in BCa. Breast cancer stem cells (BCa-SC) are characterized by CD24lo and CD44hi phenotype with mesenchymal properties, which differ from the epithelial CD24hi and CD44hi phenotype expressed in the majority of BCa cells. Thus, further understanding properties of BCa-SC may lead to the development of novel treatment options towards treating refractory cancer cells. Fundamental to this, further characterization of BCa-SC will be needed to identify therapeutic targets based CSC biology. To this end, we sought to characterize the plasticity of BCa-SC based on cell cycle in vitro and growth kinetics in vivo. A murine BCa cell line, 4T1, was cultured in CSC medium and analyzed every 6 hrs for CD24 and CD44 expression by flow cytometry. Results of this analysis indicated that specific BCa-SC markers peaked every 24 hours. This data supports a possible reprogramming of BCa-SC based on cell cycle regulation, suggesting the use of cell cycle inhibitors to block cells in particular stages of the cell cycle, which may improve therapeutic approaches to induce cell death. The stemness of these cells was further confirmed by real-time PCR. BCa-SC showed increased expression of ALDH1, TWIST, and TGF-β3 with decreased E-Cadherin and CD24 levels correlating to the phenotypic changes observed with CD24 and CD44 expression. To further examine the role of BCa-SC in tumor growth in vivo, BALB/c mice were subcutaneously implanted with populations of 4T1 cells that constituted CSC and non- cancer stem cells (NCSC) in different combinations and tumor growth was analyzed. Results showed that the growth kinetics CSC and NCSC when used alone was significantly lower in vivo compared to mixed populations containing both CSC and NCSC, suggesting CSC may attribute for the repopulation of the disease but an aggressive growth requires differentiated non-stem cells in the tumor microenvironment.

Citation Format: Carnella M. Lee, Anandi Sawant, Ha-Ram Cha, Selvarangan Ponnazhagan. Growth characteristics of breast cancer stem cells in vitro and in vivo. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 250. doi:10.1158/1538-7445.AM2013-250
Abstract 2502: Proteomic identification of carboplatin resistance in ovarian cancer cells.
Authors: Wrzeszczynski Kazimierz O. , Fan Gaofeng , Fu Cexiong , Pappin Darryl J. , Lucito Robert , Tonks Nicholas K.
Published: August 2014

The analysis of quantitative protein expression is necessary for the determination of actual biochemical protein concentrations that can lead to a more accurate description of cellular function. A knowledgebase of cancer function based on cellular protein levels can more directly implicate potential gene candidates for the detection and treatment of disease. Therefore, we analyzed iTRAQ (isobaric tag for relative and absolute quantification) data from 11 serous ovarian cancer cell lines and 2 normal ovarian surface epithelial cell lines. We profiled cellular protein abundance in over 3000 proteins with 749 proteins common to all 13 cell lines. Of the 749, 52 proteins exhibited elevated expression and 46 proteins had diminished expression in the cancerous cells when compared to the normal cell lines. We identified the 300 most variable iTRAQ expressed proteins based on median absolute deviation within 8 carboplatin sensitive and resistant cell lines. Using iTRAQ protein expression profiles from these 300 we successfully segregated the cell lines based on carboplatin sensitivity and resistance measurements. We further examined correlations among iTRAQ protein expression, individual gene RNA expression and DNA methylation data. There was no substantial correlation between protein abundance and RNA expression or epigenetic data. Furthermore RNA expression and DNA methylation data alone did not show any significant discrimination for chemosensitivity or resistance. We therefore present the potential of proteomics based discovery for carboplatin response in ovarian cancer and also identify putative gene candidates that may be functionally responsible for chemotherapy response which otherwise would not have been predicted using other singular whole genome data sources.

Citation Format: Kazimierz O. Wrzeszczynski, Gaofeng Fan, Cexiong Fu, Darryl J. Pappin, Robert Lucito, Nicholas K. Tonks. Proteomic identification of carboplatin resistance in ovarian cancer cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2502. doi:10.1158/1538-7445.AM2013-2502
Abstract 2511: Comprehensive metabolic profiling of hepatocellular carcinoma and pancreatic tumors by capillary electrophoresis-mass spectrometry.
Authors: Tada Motohisa , Hirayama Akiyoshi , Kanai Fumihiko , Yoshitomi Hideyuki , Ohtsuka Masayuki , Miyazaki Masaru , Soga Tomoyoshi , Yokosuka Osamu
Published: August 2014

(Background) Most cancer types have been widely known to generate energy primarily by glycolysis rather than oxidative phosphorylation even under normoxia (Warburg effect). However, inadequate blood supply resulting from defective angiogenesis is often observed in different kinds of cancer tissues, and their microenvironment is considered nutritionally unfavorable. How these cancer cells generate ATP is therefore still unclear. We previously reported enhanced glycolysis and significant accumulation of all amino acids except glutamine in both colon and stomach cancer tissues (Hirayama A, et al Cancer Res 2009). (Methods) Here, we investigated the metabolic microenvironment of hepatocelluar carcinoma (HCC)(n=28, HBV-positive (B) 7, HCV-positive (C) 6, NonBnonC (NBNC) 15), and pancreatic tumors (n=40, Invasive ductal adenocarcinoma (PDAC) 21, Intraductal papillary mucinous adenoma (IPMA) 5, Intraductal papillary mucinous carcinoma (IPMC) 14), using capillary electrophoresis-mass spectrometry (CE-MS). (Results) The amount of glucose were more than ten times higher in liver tissues, which indicates that liver tissue exist in nutritionally favorable microenvironment even in tumor tissue compared with pancreas tissue. Significant lactate accumulation was found in all cancer tissues (HCC, IPMC, and PDAC), which imply enhanced glycolysis. However, significant organ-specific differences were found in the levels of amino acids. Organ and etiology-specific difference were found in intermediates of TCA cycle. For example, citrate was increased in B-HCC, malate was decreased in NBNC-HCC, fumarate was decreased in B-HCC, NBNC-HCC, and PDAC, citrate was decreased in IPMC, iso-citrate was decreased in PDAC, compared to normal tissue, significantly. The concentration of most amino acids were not changed between normal and tumor tissues in HCC and pancreatic tumors, which suggests that these type of cancers do not depend on autophagy for their amino acid source. (Conclusions)Overall, these results provide metabolic phenotypes of different cancer tissues that reflect the tumor microenvironment.

Citation Format: Motohisa Tada, Akiyoshi Hirayama, Fumihiko Kanai, Hideyuki Yoshitomi, Masayuki Ohtsuka, Masaru Miyazaki, Tomoyoshi Soga, Osamu Yokosuka. Comprehensive metabolic profiling of hepatocellular carcinoma and pancreatic tumors by capillary electrophoresis-mass spectrometry. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2511. doi:10.1158/1538-7445.AM2013-2511
Abstract 2512: Extreme value distributions describe cancer age-specific incidence data.
Authors: Soto-Ortiz Luis , Brody James P.
Published: August 2014

The incidence of cancers varies with age, if normalized this is called the age-specific incidence. A mathematical model that describes this variation should provide a better understanding of how cancers develop. We suggest that the age-specific incidence should follow an extreme value distribution, based on three widely accepted assumptions: (1) a tumor develops from a single cell, (2) many potential tumor progenitor cells exist in a tissue, and (3) cancer is diagnosed when the first of these many potential tumor cells develops into a tumor. We tested this hypothesis by comparing the predicted distribution to the age-specific incidence data for colon and prostate carcinomas collected by the Surveillance, Epidemiology and End Results network of 17 cancer registries. We found that colon carcinoma age-specific incidence data is consistent with an extreme value distribution, while prostate carcinomas age-specific incidence data generally follows the distribution. This model indicates that both colon and prostate carcinomas only occur in a subset of the population (22% for prostate and 13.5% for colon.) Because of their very general nature, extreme value distributions might be applicable to understanding other chronic human diseases.

Citation Format: Luis Soto-Ortiz, James P. Brody. Extreme value distributions describe cancer age-specific incidence data. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2512. doi:10.1158/1538-7445.AM2013-2512
Abstract 2516: Are alcohol drinking and cigarette smoking related to risk of glioma? A large prospective U.S. cohort study.
Authors: Braganza Melissa Z. , Rajaraman Preetha , Park Yikyung , Inskip Peter D. , Freedman Neal D. , Berrington de González Amy , Kitahara Cari M.
Published: August 2014

Background: Glioma is a relatively uncommon and highly fatal malignancy with few known risk factors. Alcohol consumption and cigarette smoking are associated with an increased risk of several types of cancer, but whether these exposures are related to the risk of glioma remains unclear.

Methods: We prospectively examined the relationship between cigarette smoking, alcohol intake, and risk of glioma in the National Institutes of Health-AARP Diet and Health Study, a large prospective cohort of 477,095 U.S. men and women between the ages of 50-71 years. Hazard ratios (HRs) and 95% confidence intervals (CIs) for glioma risk according to alcohol intake (total alcohol, beer, wine, and liquor) and smoking status, intensity, and, among former smokers, time since quitting were calculated using models adjusted for sex, education, marital status, and race/ethnicity.

Results: During a median 10.5 person-years of follow-up, 492 men and 212 women were diagnosed with glioma. Among men, current, heavier (>20 cigarettes per day) smoking was associated with a reduced risk of glioma compared to never smoking (HR=0.40, 95% CI: 0.21-0.79). Men who quit smoking <5 years before baseline had a non-significant reduced risk of glioma (HR=0.73, 95% CI: 0.46-1.14) relative to male never smokers. Smoking behaviors were not associated with glioma risk in women. Greater alcohol consumption was associated with a decreasing risk of glioma in men (>2 drinks per day versus <1 drink per week: HR=0.65, 95% CI: 0.47-0.90; P-trend=0.02) but not women. An inverse association with greater beer intake was apparent both in men (>2 drinks per day versus <1 drink per week: HR=0.56, 95% CI: 0.33-0.93; P-trend=0.03) and women (≥1 drink per week versus <1 drink per week: HR=0.66, 95% CI: 0.33-1.34; P-trend=0.27). Results were similar by education level, after mutual adjustment for smoking and alcohol, and after restricting to glioblastoma, the most common and lethal histological subtype of glioma.

Conclusions: Among men, current, heavy cigarette smoking and greater alcohol, particularly beer, consumption were inversely associated with the risk of glioma. Pooled analyses of prospective studies are needed to investigate more precisely the potential influence of these exposures on glioma risk.

Citation Format: Melissa Z. Braganza, Preetha Rajaraman, Yikyung Park, Peter D. Inskip, Neal D. Freedman, Amy Berrington de González, Cari M. Kitahara. Are alcohol drinking and cigarette smoking related to risk of glioma? A large prospective U.S. cohort study. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2516. doi:10.1158/1538-7445.AM2013-2516
Abstract 2517: Deaths due to smoking in a population where women started to smoke as teenagers: Nationally representative prospective cohort study.
Authors: Gram Inger T. , Sandin Sven , Braaten Tonje , Lund Eiliv , Weiderpass Elisabete
Published: August 2014

Background: Recent studies suggest that the population attributable fraction (PAF) of mortality due to smoking is larger than previously reported. We wanted to examine the effect of smoking on all-cause and cause-specific mortality and calculate the corresponding PAF in the Norwegian Women and Cancer Study, a nationally representative prospective cohort study.

Methods: We followed 85,320 women, aged 31-70 years, who completed a questionnaire in 1991-1997, through linkages to national registries through December 2008. Questionnaire data included information on lifestyle factors, including lifetime history of smoking. Poisson regression models were fitted to estimate relative risk s (RR) with 95% confidence intervals (CIs) adjusting for age, birth cohort, education, alcohol consumption and body mass index, all at enrollment. During a mean follow-up time of 14 years 2,842 deaths occurred. Compared with that of never smokers, current smokers had a mortality rate that was double (RR=2.38; 95% CI 2.17-2.62) from deaths overall, triple (RR=3.32; 95% CI 2.27-4.85) from cerebrovascular diseases, almost four fold (RR=3.71; 95% CI 2.21-6.21) from myocardial infarction (MI), twelve times (RR=12.26; 95% CI 7.89-19.07) from lung cancer and seventeen times (RR=17.08; 95% CI 5.98-48.81) from chronic obstructive pulmonary diseases . The attributable fraction and the PAF of mortality due to smoking was 47% and 30%, respectively Conclusions: We find that one in two deaths among ever smokers, and one in three deaths among middle aged women in Norway can be attributed to smoking. Our results may be generalizable to populations where women start to smoke as teenagers.

Citation Format: Inger T. Gram, Sven Sandin, Tonje Braaten, Eiliv Lund, Elisabete Weiderpass. Deaths due to smoking in a population where women started to smoke as teenagers: Nationally representative prospective cohort study. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2517. doi:10.1158/1538-7445.AM2013-2517
Abstract 2522: Complementary and alternative medicine use among cancer survivors in the United States.
Authors: Laiyemo Maryam , Nunlee-Bland Gail , Lombardo Frederick , Adams R. George , Laiyemo Adeyinka
Published: August 2014

Background: Although there is little evidence of effectiveness of Complementary and Alternative Medicine (CAM), there has been an increase in the number of patients turning to these largely unproven medical therapies. In this study, we sought to determine if those with a personal history of cancer were more likely to have utilized CAM as compared to those without a history of cancer.

Methods: We analyzed the 2007 Health Information National Trends Survey (HINTS) and identified 976 respondents who were cancer survivors and 6,235 respondents without a personal history of cancer. We compared the demographic, lifestyle, and healthcare perceptions of these participants and used logistic regression models to evaluate the association of personal history of cancer, cancer treatment and the time since cancer treatment with CAM use. We used survey weights in all analysis and Taylor series linearization to perform variance estimations to account for the complex survey design.

Results: Overall, cancer survivors were as likely as those without history of cancer to use CAM in the previous 12 months (27.1% vs. 25.2%; OR = 1.09; 95%CI: 0.86-1.38). Cancer treatment and time since cancer treatment was not associated with CAM use (Table 1).

Conclusions: Cancer survivors were as likely as adults without a history of cancer to use complementary and alternative medicine irrespective of cancer treatment.

Table 1. The effect of cancer treatment and time since treatment on CAM use among cancer survivors By cancer treatment Cancer survivor characteristics Weighted% with CAM use CAM use versus no CAM use OR (95% CI) No history of cancer (n = 6,235) 25.2% Reference No cancer treatment (n = 117) 32.6% 1.69 (0.82–3.47) Had cancer treatment (n = 847) 26.3% 1.01 (0.78–1.29) By time since cancer treatment No history of cancer (n = 6,235) Reference Still undergoing cancer treatment (n = 94) 29.4% 1.15 (0.50–2.63) Completed cancer treatment less than 1 year ago (n = 143) 22.6% 0.96 (0.55–1.66) Completed cancer treatment 1 or more years ago (n = 537) 26.5% 1.00 (0.72–1.41)

Adjusted for respondent's age, sex, marital status, place of birth, race, income, education level, health insurance status, BMI, perception of health status, perception of health care quality received, and confidence in taking care of one's own health

Citation Format: Maryam Laiyemo, Gail Nunlee-Bland, Frederick Lombardo, R. George Adams, Adeyinka Laiyemo. Complementary and alternative medicine use among cancer survivors in the United States. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2522. doi:10.1158/1538-7445.AM2013-2522
Abstract 2533: Inverse association between circulating vitamin D and mortality - dependent on sex and cause of death.
Authors: Rohrmann Sabine , Braun Julia , Bopp Matthias , Faeh David
Published: August 2014

Background: Vitamin D has immune-modulation properties as well as effects on cell differentiation and proliferation, on angiogenesis, but also on blood pressure and glucose tolerance, and in various populations, vitamin D deficiency is associated with chronic diseases and mortality. We examined the association between concentration of circulating 25-hydroxyvitamin D [25(OH)D], a marker of vitamin D status, with all-cause and cause-specific mortality.

Methods: The study included 3191 participants of the general adult Swiss population, who were recruited between November 1988 and June 1989 and followed-up until the end of 2008. Serum 25(OH)D was measured by protein-bound assay. Cox proportional hazards regression was used to examine the association between 25(OH)D concentration and overall and cause-specific mortality adjusting for sex, age, season, diet, nationality, blood pressure, and smoking status.

Results: Mean serum 25(OH)D concentration was 19.8 ng/mL in men and 20.5 ng/mL in women. Participants with low 25(OH)D (≤13.4 ng/mL) were more likely to have participated during winter months, but less likely to have spent ≥30 minutes outdoors per day or been on vacation in the month prior to blood collection. Individuals with 25(OH)D concentrations ≥25 ng/mL tended to be less often of foreign nationality, current smokers and more frequently in the upper educational level. During the follow-up period, 459 study participants died (188 of cancer and 122 of cardiovascular diseases). Per 10 ng/mL increase in 25(OH)D concentration, all-cause mortality decreased by 20% (HR=0.83; 95% CI 0.74-0.92). Excluding the first five years of follow-up did not materially affect the observed associations. 25(OH)D concentration was inversely associated with cardiovascular mortality in women (0.68, 0.46-1.00), but not in men (0.97; 0.77-1.23). In contrast, 25(OH)D concentration was inversely associated with cancer mortality in men (0.72, 0.57-0.91), but not in women (1.14, 0.93-1.39). Multivariate adjustment only slightly modified the 25(OH)D-mortality association.

Conclusion: 25(OH)D was similarly inversely related to all-cause mortality in men and women. However, we observed opposite effects in women and men with respect to cardiovascular- and cancer-related mortality.

Citation Format: Sabine Rohrmann, Julia Braun, Matthias Bopp, David Faeh. Inverse association between circulating vitamin D and mortality - dependent on sex and cause of death. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2533. doi:10.1158/1538-7445.AM2013-2533