bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB-254: XBP1-NFkappaB signaling promotes antiestrogen resistance in breast cancer animal model.
Authors: Hu Rong , Zwart Alan , Warri Anni , Clarke Robert 
Published: August 2014

Abstract
There are nearly 3 million breast cancer survivors in the United States, with more than 230,000 women being newly diagnosed with invasive breast cancer each year. Of total breast cancer patients, around 70 percent are estrogen receptor (ER) positive and often receive endocrine therapy. Endocrine resistance, either de novo or acquired, is a major hurdle for treating ER positive breast cancer patients. Unfolded protein response (UPR) is known to be activated and promote endocrine resistance in breast cancer cells. As an essential component of URP signaling, X-box binding protein 1 (XBP1) was shown up-regulated in endocrine resistant breast cancer. XBP1 was demonstrated as an important mediator for endocrine resistance in vitro cell culture model in our previous findings. In this study, the effect of XBP1 in endocrine resistance in animal model was examined. XBP1 contains two alternative splice variants: XBP1(S) and XBP1(U). In order to differentiate the role of each variant, we generated XBP1 mutant constructs that overexpress specifically only either the XBP1(S) or XBP1(U).
The XBP1 over-expressing human breast cancer cells have been injected into the mammary fat pad of female nude mice. The preliminary data shows that the over-expression of both XBP1 splice variants promotes tumor growth in vivo. More importantly, tumors with over-expressed XBP1 show less sensitivity to tamoxifen treatment. Our previous finding revealed that NFkappaB signaling is regulated by XBP1 and required for antiestrogen resistance in cultured cells. In the current study, we have treated XBP1-overexpressed breast tumor bearing animals with NFkappaB inhibitor Parthenolide, and find that it enhances tamoxifen sensitivity. In conclusion, our data demonstrate that XBP1-NFkappaB signaling plays an important role in antiestrogen resistance in vivo.
Citation Format: Rong Hu, Alan Zwart, Anni Warri, Robert Clarke. XBP1-NFkappaB signaling promotes antiestrogen resistance in breast cancer animal model. [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 LB-254. doi:10.1158/1538-7445.AM2013-LB-254
Abstract LB-262: Excessive Wnt activity is insufficient for intestinal tumor growth or regeneration without gp130/Jak2/Stat3 signaling.
Authors: Phesse Toby , Buchert Michael , Ernst Matthias 
Published: August 2014

Abstract
The majority of sporadic and familial colorectal cancers (CRC) arise from unregulated, excessive activation of the WNT signaling pathway as a result of impairment mutations in the tumor suppressor gene APC. Meanwhile, controlled activation of WNT signaling is required for intestinal regeneration in response to injury and ensures intestinal homeostasis. Thus far, however, therapeutic targeting of the WNT pathway has proven difficult in human disease. Here, we show genetically that activation of the cytokine-dependent gp130/Jak/Stat3 pathway augments intestinal regeneration in wild-type mice and promotes intestinal tumorigenesis in Apc mutant mice. Conversely, genetic restriction of gp130/Jak/Stat3 signaling suppresses regeneration and inhibits tumor burden despite persistent, excessive WNT activity. Moreover, therapeutic administration of the Jak2-kinase specific inhibitor AZD1480 in mouse models of either sporadic or inherited CRC effectively blocked de novo tumor initiation and progression. Likewise, AZD1480 suppressed the growth of human APC mutant, but not of isogenic APC wild-type, CRC cell lines in vitro and as tumor xenografts. We identify Stat3-dependent Bmi1 induction and the resulting repression of p16 and p21 as the mechanism by which the gp130/Jak/Stat3 pathway modulates the cellular response to excessive WNT signaling. We therefore propose that the gp130/Jak2/Stat3 pathway is rate-limiting selectively for the growth of APC mutant tumors, and that it provides a readily exploitable target for the therapeutic treatment of CRC.
Citation Format: Toby Phesse, Michael Buchert, Matthias Ernst. Excessive Wnt activity is insufficient for intestinal tumor growth or regeneration without gp130/Jak2/Stat3 signaling. [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 LB-262. doi:10.1158/1538-7445.AM2013-LB-262
Abstract LB-275: Epithelial-mesenchymal transition rewires mechanisms upstream of PI3K-dependent growth.
Authors: Salt Megan B. , McCormick Frank 
Published: August 2014

Abstract
Tumors that show evidence of epithelial to mesenchymal transition (EMT) have been associated with metastasis, drug resistance, and poor prognosis. EMT may alter the molecular requirements for growth and survival in different contexts, but the underlying mechanisms remain incomplete. Given the heterogeneity along the EMT spectrum between and within tumors it is important to define the requirements for growth and survival in cells with an epithelial or mesenchymal phenotype to maximize therapeutic efficacy. We have established an inducible cell line model in which a tamoxifen regulatable Twist-ER fusion protein is stably expressed in the H358 non-small cell lung cancer cell line. Upon tamoxifen addition, cells undergo EMT and provide a system in which we can compare the growth and survival requirements directly related to EMT, removing confounding factors present when comparing different cell lines. Using this system we have found that while cells require PI3K for growth before and after the transition, the mechanisms through which they can activate the signal are altered. Specifically, before EMT basal PI3K is maintained by autocrine activation of ErbB3 signaling, despite the presence of an activating Ras mutation. Loss of ErbB3 ablates proliferation in pre-EMT cells suggesting that oncogenic KRas is not sufficient to drive growth in this context. After induction of EMT ErbB3 expression is downregulated along with downstream PI3K signal, leading to a loss of cell autonomous proliferation. Restoration of PI3K signaling by either re-expression of ErbB3, activated p110, or through stimulation with various growth factors is able to restore growth in post-EMT cells. These data have implications for therapeutic targeting of different RTKs, suggesting that within a heterogeneous tumor environment, only a subset of cells may respond to such treatments. Furthering the understanding of how EMT alters signaling through specific pathways will facilitate the design of more efficacious treatment strategies to target all cells along this phenotypic spectrum.
Citation Format: Megan B. Salt, Frank McCormick. Epithelial-mesenchymal transition rewires mechanisms upstream of PI3K-dependent growth. [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 LB-275. doi:10.1158/1538-7445.AM2013-LB-275
Abstract LB-280: Inhibition of SHP2 in basal-like and triple-negative breast cancer cells induces basal-to-luminal transition, suppresses tumorigenesis, and blocks metastasis.
Authors: Matalka Fatimah , Zhao Hua , Agazie Yehenew M. 
Published: August 2014

Abstract
One of the factors that contribute to the disproportionately high mortalities in basal-like and triple-negative breast cancer (BTBC) is the lack of targeted therapies. Identifying and characterizing potential targets is therefore critical for future development of such therapies. In the current report, we show that silencing the expression of the Src homology phosphotyrosyl phosphatase 2 (SHP2) in BTBC cell lines (MDA-MB231 and MDA-MB468) suppresses cell proliferation, reverses transformation, and blocks invasiveness. Unexpectedly, we have discovered that inhibition of SHP2 induces basal-to-luminal transition (BLT) in BTBC cells as evidenced by a decrease in the expression of mesenchymal markers and/or drivers (vimentin, ZEB1, Snail, and alpha smooth muscle actin) and an increase in the expression of the luminal marker cytokeratin 18. Furthermore, we have discovered that inhibition of SHP2 induces the expression of the estrogen receptor alpha in otherwise triple-negative breast cancer cells. Intramammary transplantation studies in the NOD/SCID mice demonstrated that inhibition of SHP2 suppresses tumorigenesis and blocks metastasis. Analyses of total cell lysates prepared from cells grown in 3D matrigel cultures demonstrated that SHP2 mediates the activation of the Ras-ERK, the PI3K, and the β-catenin signaling pathways to promote the tumorigenic, invasive, and metastatic potential of BTBC cells. By and large, the results presented in this report suggest that SHP2 plays an essential role in the biology of BTBC.
Citation Format: Fatimah Matalka, Hua Zhao, Yehenew M. Agazie. Inhibition of SHP2 in basal-like and triple-negative breast cancer cells induces basal-to-luminal transition, suppresses tumorigenesis, and blocks metastasis. [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 LB-280. doi:10.1158/1538-7445.AM2013-LB-280
Abstract LB-285: Pro-tumor N2 neutrophils contribute to the pre-metastatic niche.
Authors: Meyers Jered Cope , Pittman H. Keith , Story Hunter , Imes Dare M. , Howard George A. , Verbanac Kathryn M. 
Published: August 2014

Abstract
Metastasis is the primary cause of cancer-related mortalities and the tissue microenvironment that supports tumor cell attachment and growth at metastatic sites has become an active area of investigation. Here we present evidence that pro-tumor N2 neutrophils are one of the bone marrow-derived cell types that establish this pre-metastatic niche. In the murine Lewis Lung adenocarcinoma (LLC) in vivo metastasis model, tumor cells metastasize to the lungs with increasing primary tumor growth over time. In these studies, immunocompetent mice injected subcutaneously with syngeneic LLC cells are sacrificed sequentially 10-32 days later, before and after established lung metastases. Neutrophil chemoattractants KC/CXCL1 and MIP-2/CXCL2 are significantly elevated in pre-metastatic tissue compared to normal lungs of healthy contemporary controls. MCP-1/CCL2, a marker of pro-tumor N2 neutrophils, increases steadily over time in pre-metastatic lung tissue of study mice and is significantly elevated in pre-metastatic tissue and in metastases compared to normal lung tissue. Isolated lung-infiltrating neutrophils also express N2 markers. In contrast, TNF-alpha, a marker for anti-tumor N1 cells, remains low or undetectable in lung tissue throughout metastatic tumor development. Neither active nor total TGF-beta, the putative control switch for a pro-tumor phenotype, is elevated in pre-metastatic tissue. Notably, levels of all cytokines are low or undetectable in normal lungs from naïve mice and in other organs of tumor-bearing mice (non-metastatic sites). Ly6G+ neutrophils were detected at a higher density in the lungs of pre-metastatic and metastatic mice compared to normal lungs, although the density of myeloperoxidase (MPO)-stained cells was similar in all groups. These data are consistent with recent reports that MPO activity is low or absent from tumor-associated neutrophils, although high in MDSC and naïve neutrophils. Neutrophil distribution in metastatic lung tissue is most concentrated around the tumor foci and tumor vasculature. Finally, studies of lung tissue from mice bearing LLC variants with different metastatic capacities are also consistent with our premise that neutrophils help establish the pre-metastatic niche. Understanding the factors that regulate the development and growth of malignant cells at metastatic sites is critical for improved clinical strategies in the prevention, diagnosis and treatment of metastases.
Citation Format: Jered Cope Meyers, H. Keith Pittman, Hunter Story, Dare M. Imes, George A. Howard, Kathryn M. Verbanac. Pro-tumor N2 neutrophils contribute to the pre-metastatic niche. [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 LB-285. doi:10.1158/1538-7445.AM2013-LB-285
Abstract LB-3: Fully synthetic self-assembling tumor-targeted virus-like nanoparticles .
Authors: Tarasova Nadya , Chen Yuhong , Dyba Marzena , Tarasov Sergey G. 
Published: August 2014

Abstract
Virus particles have evolved as highly effective delivery systems. They are able to deliver whole proteins and large nucleic acid molecules to certain types of cells. Genetically engineered virus-like particles (VLPs) have been explored as drug delivery and imaging agents. However, generation of fully synthetic VLPs has not been achieved. We have found that properly derivatized synthetic analogs of transmembrane domains not only inhibit the function of the corresponding receptor, but can self-assemble into virus-like particles with high precision (Proc. Natl. Acad. Sci. U. S. A 108: 9798 (2011). The described particles have intrinsic biological activity of the peptide they are composed of and fuse with cell spontaneously. Particles composed of CXCR4 antagonist fuse spontaneously with cell membrane, inhibit CXCR4 function in vitro and CXCR4-mediated metastasis in vivo. However, the fusion is non-selective. We have now developed the first fully synthetic VLPs that fuse with cells like real viruses, in receptor-mediated manner. Prevention of non-selective fusion was achieved by derivatization of self-assembling peptides with polyethylene glycol. Addition of ligands recognizing receptors over expressed on prostate tumor cells allowed for the particles that fuse selectively with receptor-positive cells. Particles targeting gastrin-releasing peptide receptor (GRPR), luteinizing hormone-releasing hormone (LHRH) receptor and prostate-specific membrane antigen (PSMA) are remarkably stable, more than 99 % homogeneous in size and undergo receptor-mediated fusion with tumor cells expressing corresponding receptor. Whole- animal fluorescence tomography of nude mice injected with fluorescent nanoparticles targeted to PSMA and GRPR revealed that particles rapidly accumulate in tumors and allow for tumor detection as early as two hours after the injection. Development of fully synthetic VLPs establishes a foundation for generation of delivery systems with investigator-defined biophysical properties and targeting ability for a wide range of biomedical applications. Tumor-targeted self-assembling particles represent a new class of agents with dual and triple biological activity for the therapy and detection of tumors.
Citation Format: Nadya Tarasova, Yuhong Chen, Marzena Dyba, Sergey G. Tarasov. Fully synthetic self-assembling tumor-targeted virus-like nanoparticles . [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 LB-3. doi:10.1158/1538-7445.AM2013-LB-3
Abstract LB-300: Development of an orally-administrative MELK (maternal embryonic leucine zipper kinase)-targeting small molecule inhibitor that suppresses the growth of various types of human cancer.
Authors: Chung Suyoun , Suzuki Hanae , Miyamoto Takashi , Takamatsu Naofumi , Tatsuguchi Ayako , Ueda Koji , Kijima Kyoko , Matsuo Yo , Nakamura Yusuke 
Published: August 2014

Abstract
Breast cancer is the most common malignancy among women worldwide. Treatment for breast cancer acting on molecular targets in critical signaling pathways in cancer cells have successfully reduced the motility rate in a subset of breast cancer patients, but a significant portion of patients expect to have little benefit from these treatments. Therefore, development of new therapeutics for those patients is urgently required. We previously reported MELK (maternal embryonic leucine zipper kinase) as a novel therapeutic target for breast cancer. MELK was highly upregulated in multiple types of human cancer including breast, prostate and lung cancers, and plays indispensable roles in cancer cell survival, particularly in the maintenance of tumor-initiating cells. Although several substrates of MELK were reported, we still do not understood fully how MELK contributes to breast cancer development and/or progression. To elucidate the MELK signaling pathway in breast cancer cells, we screened and identified two novel MELK substrates, DBNL and PSMA1, which were also found to play critical roles in human carcinogenesis and mammary tumor-initiating cells. Furthermore, we conducted a high-throughput screening of a compound library followed by structure-activity relationship studies, and successfully obtained a highly potent MELK inhibitor OTSSP167 with IC50 of 0.41 nM. OTSSP167 inhibited the phosphorylation of these two substrates by MELK as well as mammosphere formation of breast cancer cells, and exhibited significant tumor growth suppression in xenograft studies using breast, lung, prostate, and pancreas cancer cell lines in mice by both intravenous and oral administration. Here, we report the biological function of novel substrates of MELK and the first MELK inhibitor OTSSP167 that is a promising compound to treat various types of human cancer.
Citation Format: Suyoun Chung, Hanae Suzuki, Takashi Miyamoto, Naofumi Takamatsu, Ayako Tatsuguchi, Koji Ueda, Kyoko Kijima, Yo Matsuo, Yusuke Nakamura. Development of an orally-administrative MELK (maternal embryonic leucine zipper kinase)-targeting small molecule inhibitor that suppresses the growth of various types of human 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 LB-300. doi:10.1158/1538-7445.AM2013-LB-300
Abstract LB-301: Copper chelation therapy suppresses tumor growth by inhibiting mitochondrial ATP production in tumors.
Authors: Ishida Seiko , Andreux Pénélope , Auwerx Johan , Hanahan Douglas 
Published: August 2014

Abstract
Through our yeast genetic screen, we have previously identified the copper transporter Ctr1 as a major mediator of cisplatin uptake in mammals (1), and have subsequently shown in a transgenic mouse model of human cervical cancer that reducing systemic copper levels with a copper chelator, which is clinically used to treat patients with copper disorders, results in enhanced uptake of cisplatin selectively in tumors but not in normal, non-cancerous tissues (2), suggesting that tumors are particularly sensitive to changes in copper levels. In fact, environmental copper exposure has been associated with cancer risk in humans, although the nature of its effects on tumourigenesis remains unclear. Using a transgenic mouse model of pancreatic islet carcinoma, here we demonstrate that chronic exposure to elevated levels of copper in drinking water, corresponding to the maximum level allowed in our drinking water, accelerate tumor growth by stimulating proliferation of cancer cells. Conversely, reducing systemic copper with a chelating drug resulted in inhibition of tumor growth and cancer cell proliferation. Under copper limitation, tumors displayed decreased activity of the copper-binding mitochondrial enzyme cytochrome c oxidase and reduced ATP levels, despite enhanced glycolysis. The anti-proliferative effect of copper chelation was not observed in cells deficient in cytochrome c oxidase activity, but was enhanced when combined with inhibitors of glycolysis. Interestingly, larger tumors contained less copper than smaller tumors, and exhibited lower activity of cytochrome c oxidase and higher glucose uptake, suggesting that a shift towards glycolytic metabolism observed in tumors even in the presence of ample oxygen (Warburg effect) may in part reflect insufficient copper bioavailability in the tumour microenvironment. Our work identifies copper as a rate-limiting element for tumor growth and mitochondrial ATP production, and provides experimental evidence that explains the association between copper intake levels and cancer implicated in previous epidemiological and clinical studies. These findings offer a novel concept of limiting intake levels of this environmental factor as a strategy for cancer prevention and treatment.
Citation Format: Seiko Ishida, Pénélope Andreux, Johan Auwerx, Douglas Hanahan. Copper chelation therapy suppresses tumor growth by inhibiting mitochondrial ATP production in tumors. [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 LB-301. doi:10.1158/1538-7445.AM2013-LB-301
Abstract LB-310: Small molecule inhibitors of IKBKE with antitumor activity in cancer cells overexpressing IKBKE .
Authors: Xin Yu , Guo Jianping , Cheng Jin Q. 
Published: August 2014

Abstract
The serine/threonine kinase IKBKE is frequently overexpressed/activated in human cancer. Ectopic expression of IKBKE induces malignant transformation, cell migration, invasion and chemoresistance. Thus, IKBKE is a new attractive target for anti-cancer drug discovery. By screening of NCI Diversity Set and Clinical Collection I and II compound libraries using cell-based assay, we identified several IKBKE inhibitors, 3 of which directly inhibited IKBKE kinase activity in vitro and in vivo and the others only reduced phospho-IKBKE in vivo. One of the inhibitors, MCCK1, was further characterized and was found to directly bind to IKBKE. It inhibits IKBKE kinase as well as its downstream targets such as IkappaB, p65 and IRF3. MCCK1 is selective for IKBKE with moderate effect on TBK1 but does not inhibit the activation of IKKalpha/beta, STAT3, Erk-1/2, p38 or JNK. The inhibition of IKBKE by MCCK1 results in induction of cell growth arrest and apoptosis selectively in human cancer cells that harbor aberrant expression IKBKE. Further, MCCK1 inhibits tumor growth in nude mice of human cancer cells in which IKBKE is elevated but not of those cancer cells in which it is not. These data indicate that MCCK1 is an IKBKE inhibitor with anti-tumor activity in vitro and in vivo and could be a potential anti-cancer agent for patients whose tumors express elevated IKBKE.
Citation Format: Yu Xin, Jianping Guo, Jin Q. Small molecule inhibitors of IKBKE with antitumor activity in cancer cells overexpressing IKBKE . [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 LB-310. doi:10.1158/1538-7445.AM2013-LB-310