bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4544: The induction of KLF5 transcription factor by progesterone contributes to progesterone-induced breast cancer cell proliferation and de-differentiation
Authors: Liu Rong , Zhao Dong , Zhou Zhongmei , Chen Ceshi 
Published: June 2012

Abstract
Progesterone (Pg) promotes normal breast development during pregnancy and lactation and increases the risk of developing basal-type invasive breast cancer. However, the mechanism of action of Pg has not been fully understood. In this study, we demonstrate that the mRNA and protein expression of Klf5, a pro-proliferation and pro-survival transcription factor in breast cancer, was dramatically up-regulated in mouse pregnant and lactating mammary glands. Pg, but not estrogen and prolactin, induced the expression of KLF5 in multiple Pg receptor (PR)-positive breast cancer cell lines. Pg induced the KLF5 transcription is through PR in the PR-positive T47D breast cancer cells. Importantly, Pg failed to promote T47D cell proliferation when the KLF5 induction was blocked by siRNA. In addition, KLF5 overexpression was sufficient to induce the cytokeratin 5 (CK5) expression and the induction of CK5 by Pg was partially abrogated by KLF5 siRNA. Consistently, the expression of KLF5 was positively correlated with that of CK5 in a panel of breast cancer cell lines. Taken together, we conclude that KLF5 is a Pg-induced gene that contributes to Pg-mediated breast epithelial cell proliferation and de-differentiation. This work was supported by a grant from the American Cancer Society (RSG-08-199-01) and a grant from the Department of Defense (W81XWH-07-1-0191).
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 4544. doi:10.1158/1538-7445.AM2011-4544
Abstract 4548: The role of GPR30/G-protein coupled estrogen receptor (GPER) in lung cancer development
Authors: Jala Venkatakrishna R. , Bodduluri Haribabu , Radde Brandie , Klinge Carolyn M. 
Published: June 2012

Abstract
Lung cancer is currently the leading cause of cancer deaths both in men and women. Estrogens, including 17β-estradiol (E2), are known to promote various cancers including breast, endometrial, and ovarian cancers. Women are at higher risk for lung adenocarcinoma than men, implying a potential role for estrogens in lung cancer. E2 mediates its genomic effects through two well-characterized nuclear receptors, estrogen receptor α (ERα) and estrogen receptor β (ERβ), both of which are expressed in normal lung and lung adenocarcinomas. In addition to genomic estrogen action, i.e., transcriptional regulation of gene expression, estrogens activate rapid, non-genomic responses such as intracellular calcium release, cAMP production, MAPK and PI3K/AKT phosphorylation, and up regulation of c-fos transcription. These observations prompted a search for new estrogen receptors and culminated in the discovery of GPR30 (GPER) as a bona fide estrogen receptor that mediates some of the membrane actions of E2. GPR30 is a seven transmembrane G-protein coupled receptor (GPCR) unrelated to nuclear ERα and ERβ. Although GPR30 is expressed in healthy lung, its expression in lung tumors/lung cancer cell lines as well as its functional activities has not been investigated. In the current study, we investigated the expression of GPR30 in human and murine lung cancer cell lines and tumor tissues both at the transcript and protein levels. Our analyses demonstrated for the first time that GPR30 expression is significantly increased (2 to140 fold) in lung cancer cells lines (A549, H1435, H1395, H1944, H1792, H1793, H2073, H23, H1299, LLC) compared to immortalized normal human bronchioepithelial cells (HBEC3-ET, HBEC2-E, HBEC2-KT). The expression of GPR30 in lung tissue microarrays (LC242, LC1005 from USBiomax) containing 87 cases of lung cancer tissues along with normal and cancer adjacent tissues were analyzed by immunohistochemnistry (IHC). IHC scores confirm that GPR30 is significantly overexpressed in more than 80% of lung adenocarcinomas (p&lt;0.0001), 75% of large cell carcinoma (p&lt;0.0001) and 60% in squamous cell carcinoma (SCC) (p&lt;0.0001). These observations suggest that E2, as well as other GPER ligands, signaling through GPR30 might play a critical role in lung carcinogenesis independent of the classical ERα and ERβ. Given the cross-talk between GPR30, ERα and epidermal growth factor receptor (EGFR) reported in other cell types, we suggest that blocking the signaling activities of GPR30, ERα, and EGFR may synergize to provide a better therapeutic option for treating lung 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 4548. doi:10.1158/1538-7445.AM2011-4548
Abstract 4549: Expression and localization of progesterone receptor membrane component 1 and 2 in normal and malignant endometrial cells
Authors: Kavandi Leyla , Ivanova Vessela S. , Nguyen Huyen , Syed Viqar 
Published: June 2012

Abstract
Recently, two progesterone receptor membrane components (PGRMC) have been identified. PGRMC-1 protein has been shown to be overexpressed in breast, colon, and thyroid cancers, whereas far less is known about PGRMC2. The purpose of this study was to assess the expression, localization and hormonal regulation of PGRMC-1 and PGRMC-2 in normal and malignant endometrial tissues and cell lines. Immunohistochemical analysis showed a high expression of PGRMC-1 in normal tissues and a stage dependent decrease was observed in endometrial cancer tissues. A progressive decrease of PGRMC-2 expression was evident in endometrial cancer tissues but was not as marked as in PGRMC-1. Dual immunofluorescent confocal microscopy demonstrated colocalization of PGRMC-1 and PGRMC-2 in the cytoplasm and nucleus of endometrial cancer (Ishikawa and ACI-126) cells. Of significance, in normal epithelial endometrial (NEE) cells PGRMC-2 was predominantly localized in the membrane, whereas PGRMC-1 showed cytoplasmic and nuclear expression. Treatment of cancer cells with progesterone (P4) translocated both PGRMCs to the nucleus, while in normal cells PGRMC-1, but not PGRMC2 was translocated to the nucleus of cells. The results suggest that expression of PGRMCs is regulated by P4 and the dynamic pattern of PGRMC1 and PGRMC2 expression in normal and malignant cells implicate their role in tumorigenesis.
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 4549. doi:10.1158/1538-7445.AM2011-4549
Abstract 4556: AR intragenic rearrangement and altered androgen receptor mRNA splicing in castration-resistant prostate cancer
Authors: Li Yingming , Alsagabi Majid , Tewfik Ahmed , Dehm Scott M. 
Published: June 2012

Abstract
Androgen depletion for advanced prostate cancer (PCa) targets activity of the androgen receptor (AR), a steroid receptor transcription factor required for PCa growth. The emergence of lethal castration-resistant PCa (CRPCa) is marked by aberrant re-activation of the AR despite ongoing androgen depletion. Recently, alternative splicing has been described as a mechanism giving rise to COOH-terminally truncated, constitutively active AR isoforms that can support the CRPCa phenotype. However, the pathologic origin of these truncated AR isoforms has not been described. The goal of this study was to investigate alterations in AR expression arising in a cell-based model of PCa progression driven by truncated AR isoform activity. We demonstrate that stable, high-level expression of truncated AR isoforms in 22Rv1 CRPCa cells coincides with intragenic rearrangement of a ∼35kb AR genomic segment, which contains several alternative AR exons. Analysis of metastatic CRPCa tissues indicated that related AR copy number alterations are frequent and often occur in conjunction with high-level AR amplification. Nucleotide-level resolution of the break fusion junction in 22Rv1 cells revealed a DNA repair signature consistent with a microhomology-mediated, replication-based mechanism of origin. Together, these data provide the first report of AR intragenic rearrangements in CRPCa and a link with pathologic expression of truncated AR isoforms in a cell-based model of PCa progression.
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 4556. doi:10.1158/1538-7445.AM2011-4556
Abstract 4558: Synergistic effect of alcohol and estradiol in breast cancer
Authors: Singh Ajeet , Shanmugam Arulkumaran , Rajoria Shilpi , George Andrea , Suriano Robert 
Published: June 2012

Abstract
Breast cancer is the most common malignancy and the second leading cause of death among women in the United States. In addition to the various risks associated with breast cancer development, an interesting epidemiological observation exists, which is an increase in breast cancer incidence with increased alcohol consumption. Post-menopausal women on estrogen replacement therapy are at an even greater risk suggesting a synergistic interplay between estrogen and alcohol. Since the risk of alcohol for breast cancer can be partly attributed to circulating estrogens, the alcohol-estrogen axis, currently understudied at the biological level, is a viable breast cancer etiological agent. The precise cellular and biochemical mechanism for the role of the estrogen- alcohol axis in breast cancer progression is poorly understood. To investigate this, an in-vitro study was performed using 4T1 breast cancer cell line. The breast cancer cells were treated with alcohol (0.5%), estradiol (E2, 10-8 M) and with combination of alcohol and E2. Alcohol and E2 treatment modulates activation of cell surface receptors, specifically the epidermal growth factor receptor 2 (Erb2), which subsequently affects signaling through downstream pathways, such as Akt and mTOR. Akt/mTOR pathways are related to tumor development, and are target for any therapeutic agent. Alcohol, E2 and the combination treatments elicited a significant stimulation of estrogen receptor (ERα), Erb2, Akt and mTOR in 4T1 breast cancer cells. Accordingly, our data suggest that ERα, Erb2, Akt and mTOR may serve as key regulators that are involved in alcohol induced breast cancer progression. Thus the present study reveals the key pathways for alcohol-mediated promotion of cancer that could be targeted for therapy or prevention of alcohol-related 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 4558. doi:10.1158/1538-7445.AM2011-4558
Abstract 4574: Towards a new targeted therapy for ovarian cancer : Development of an anti-human müllerian inhibiting substance type II receptor humanized antibody
Authors: Jacquet Alexandra , Kersual Nathalie , Garambois Véronique , Colombo Pierre-Emmanuel , Goncalvez Rui-Bras , Theillet Charles , Gaucher Christine , Fournier Nathalie , De Romeuf Christophe , Prost Jean-François , Urbain Rémi , Pèlegrin André , Teulon-Navarro Isabelle 
Published: June 2012

Abstract
Asymptomatic in early stages, ovarian cancer is a “silent killer” corresponding to the 5th cause of female deaths in US. In 2010 it is estimated that 21,880 women in US will be diagnosed with ovarian cancer. Due to the limitations of the current therapeutic approaches, there is a strong need for novel, more efficient, therapies. We describe here a humanized monoclonal antibody 3C23K targeting the human Müllerian Inhibiting Substance type II Receptor (MISRII), expressed on most ovarian cancer subtypes, including epithelial ovarian cancer (EOC) representing more than 90% of ovarian cancers.
Starting from murine monoclonal antibody 12G4, 3C23K was obtained following chimerization, humanization by CDR grafting and affinity maturation. Moreover, 3C23K displays a particular glycosylation profile known to favor effector recruitment in vitro and in vivo (EMABling®). Assessed on MISRII transfected cells (cov434-MISRII), 3C23K was characterized by an affinity constant to the antigen increased by 3 fold as compared to murine 12G4. In order to evaluate 3C23K efficacy in vitro and in vivo, we have established several MISRII expressing cell lines derived from patient primary EOC tumors. Functional characterization of 3C23K has been carried out in vitro, including antibody-dependent cell-mediated cytotoxicity (ADCC), complement dependent cytotoxicity, apoptosis and intracellular signaling. In particular, 3C23K was found to display a higher ADCC activity on MISRII expressing cell lines as compared to the same sequence expressed in CHO cells. In vivo, 3C23K exhibited a significant effect on tumor growth against several ovarian tumor xenografted models derived from patient primary EOC tumors.
Altogether these data strongly suggest that humanized monoclonal antibody 3C23K may represent a promising candidate for ovarian cancer immunotherapy.
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 4574. doi:10.1158/1538-7445.AM2011-4574
Abstract 4584: Pre-clinical studies of a novel antibody to treat pancreatic and colorectal cancers
Authors: Bristol Andrew , Kantor Judith , Luka Janos , Stafford Joe , Gupta Rishab , Arlen Philip 
Published: June 2012

Abstract
Introduction:
NPC-1C is a chimeric monoclonal antibody being developed as a novel biological treatment for pancreatic and colorectal cancers. NPC-1C appears to recognize a variant form of MUC5AC expressed specifically by human pancreatic and colorectal tumor tissues and cell lines. Here we show pre-clinical studies in preparation for testing this therapeutic for a Phase I clinical trial.
Methods:
The NPC-1C antibody was selected from a panel of hybridomas generated from mice immunized with semi-purified membrane-associated proteins derived from biologically screened, pooled human allogeneic colon cancer tissues. In vitro assays and in vivo studies were performed to characterize the GMP-grade antibody.
Results:
Here we show that NPC-1C reacts with colorectal and pancreatic tumor tissues, but does not cross-react with normal human tissues, except for occasional, weak binding to certain GI tract tissues, which may indicate a pre-malignant state. The NPC-1C antibody exhibits cell-specific binding and ADCC activity against human colorectal and pancreatic tumor cells, but not against control tumor cell lines. In vivo, the anti-tumor efficacy of NPC-1C was tested using pre-established subcutaneous human tumor xenograft models. The data showed significant, and reproducible, anti-tumor action, including some complete tumor regressions. The pre-clinical toxicity profile of NPC-1C in normal BALB/c mice demonstrated little, if any, toxicity following single or multiple intravenous injections. The bio-distribution of radiolabeled NPC-1C in mice with pre-established human tumors revealed specific accumulation of NPC-1C at the tumor site, with little or no binding or accumulation in several major organ systems. Finally, the cytokine and antibody responses to NPC-1C were studied in the pre-clinical mouse model. Although anti-NPC-1C antibodies were detected (as expected) in a time-dependent fashion, there were no changes detect in Type I and Type II cytokines either 3 days or 14 days after intravenous administration.
Conclusions:
The pre-clinical development of NPC-1C indicates that it is safe and efficacious, and suggests that it may have clinical activity in patients whose tumor expresses the variant MUC5AC epitope. The potential clinical application for this antibody was bolstered by showing approximately 50-70% of human pancreatic and colon tumor tissues stained positively with NPC-1C. The therapeutic antibody is now being tested in a Phase I clinical trial in patients with advanced pancreatic and colorectal 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 4584. doi:10.1158/1538-7445.AM2011-4584
Abstract 4586: Essential role of fibroblast growth factor receptor 2 (FGFR2) in tumorigenesis of human cancers with activated FGFR2 signaling demonstrated by functional blocking antibodies
Authors: Bai Ailin , Meetze Kristan , Vo Nhi Y. , Kollipara Sriram , Mazsa Elizabeth K. , Winston William M. , Weiler Solly , Poling Laura L. , Chen Ting , Haserlat Sara , Abbott Sandra , Tissire Hamid , DiPrima Michael , Ismail Nesreen S. , Jiang Jinwei , Lerner Lorena , Gyuris Jeno , Weng Zhigang 
Published: June 2012

Abstract
Aberrant activation of fibroblast growth factor receptor 2 (FGFR2) signaling, through overexpression of FGFR2 and/or its ligands, mutations, and receptor amplification have been found in a variety of human tumors. We generated monoclonal antibodies against the extracellular ligand binding domain of FGFR2 to address the role of FGFR2 in tumorigenesis and to explore the potential of FGFR2 as a novel therapeutic target. We identified a broad panel of human cancer cell lines with dysregulated FGFR2 signaling and examined the sensitivity of these human cell lines to monoclonal antibodies specifically targeting FGFR2. These FGFR2 antibodies potently suppressed ligand-induced phosphorylation of FGFR2 and downstream signaling, as well as cell proliferation in vitro. The administration of FGFR2 monoclonal antibodies in mice significantly inhibited the growth of human cancer xenografts harboring activated FGFR2 signaling. Our findings support that dysregulated FGFR2 signaling is one of the critical oncogenic pathways involved in the initiation and/or maintenance of tumors. Cancer patients with aberrantly activated/amplified FGFR2 signaling could potentially benefit from therapeutic intervention with FGFR2-targeting antibodies.
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 4586. doi:10.1158/1538-7445.AM2011-4586
Abstract 4589: Gamma-tocopherol and mixed tocopherols inhibit AOM-induced colon carcinogenesis that was promoted by moderate but not severe colon inflammation caused by dextran sodium sulfate
Authors: Jiang Qing , Jiang Ziying , Moreland Michelle 
Published: June 2012

Abstract
Our previous studies indicate that specific forms of vitamin E such as gamma-tocopherol (gT), the predominant form of vitamin E in US diets, have anti-inflammatory activities by inhibition of proinflammatory eicosanoids including prostaglandin E2 and leucotriene B4. These eicosanoids are known to promote carcinogenesis of different types of cancer including colon cancer. We therefore hypothesize that gT may be an effective anticancer agent against colon cancer. In male BALC mice, we examined potential effect of gT and mixed tocopherols at 1000mg/kg diet on AOM induced colon carcinogenesis which was promoted by 3-cycle DSS (dextrane sodium sulfate, 1.5%, 2.5% and 2%). The results show that two months after carcinogenesis was induced, all the AOM-DSS mice developed tumors located in the distal colon with ∼12 tumors per mouse. Supplementation of gT or gT-rich mixed tocopherols had no significant effects on tumor incidence or tumor size. In a subsequent study, potential effect of gT and gT rich mixed tocopherols were examined in the AOM induced colon cancer that was promoted by moderate colon inflammation caused by one-cycle 1.5% DSS. GT supplementation, although had no effects on total tumor incidence, significantly (P &lt; 0.05) suppressed the incidence of large tumor (&gt;2 mm2) by 60%. Mixed tocopherols showed strong tendency in attenuation of tumor development (50%, P = 0.06). Interestingly, gT but not mixed tocopherols significantly attenuated DSS-induced colon inflammation. These results indicate that gT appears to have anticancer activities via anti-inflammatory mechanisms.
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 4589. doi:10.1158/1538-7445.AM2011-4589
Abstract 459: Activation of macrophages by IL-4 and other cytokines: priming for protumoral functions
Authors: Wang Hao-Wei , Gocheva Vasilena , Joyce Johanna A. 
Published: June 2012

Abstract
While macrophages are a fundamental constituent of the host immune system, tumor-associated macrophages (TAMs) have been shown to fuel tumorigenesis, although there remain many critical open questions regarding how TAMs acquire their tumor-promoting functions and how they actually facilitate tumor growth and progression. Previously, we have shown that TAM-supplied cysteine cathepsin proteases play critical roles in several steps of carcinogenesis including cell proliferation, angiogenesis and invasion. We have also identified interleukin-4 (IL-4) as a key tumor-derived factor which induces high cathepsin activity in TAMs. Here we set out to investigate the mechanisms underlying the induction of cathepsin activity in TAMs by IL-4, and to identify other factors that act in concert with IL-4 to trigger this activity switch.
Using a cell-based model, we have demonstrated that IL-4 upregulates the transcription of several cathepsins in bone marrow-derived macrophages (BMDMs) through a STAT6-dependent mechanism. In addition, by using an activity-based probe for cathepsin proteases, we have also shown that IL-4 can induce the secretion of active cathepsins from BMDMs. Moreover, several other cytokines that are expressed in the tumor microenvironment can act redundantly or synergistically with IL-4 to induce cathepsin expression and secretion. In sum, our data indicate that complex cytokine signaling pathways in the tumor microenvironment are capable of shaping the tumor-promoting phenotypes of TAMs in part through the induction of cathepsin 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 459. doi:10.1158/1538-7445.AM2011-459