bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2246: Progesterone generates cancer stem cells through membrane progesterone receptor-triggered signaling in basal-like human mammary cells
Authors: Vares Guillaume , Sai Sei , Wang Bing , Fujimori Akira , Nenoi Mitsuru , Nakajima Tetsuo 
Published: August 2015

Abstract
Among the four main subtypes of breast cancer, basal-like breast cancer (the predominant subtype of triple-negative breast cancer) is of particular concern, due to its high frequency, relative lack of effective therapies and poor prognosis. Ionizing radiation (for example as treatment for other cancers) and cumulative exposure to steroid hormones (as seen in postmenopausal women under hormone replacement therapy) are known risk factors for breast cancer. Because of their tumor-initiating properties, cancer stem cells (CSCs) were proposed to be responsible for relapse and metastasis. In MCF10A non-cancerous basal-like PR-negative cells, progesterone treatment and 1 Gy X-rays generated ALDH+ and CD44+/CD24- CSCs. Here, we report that progesterone activated the Pi3k/Akt pathway via membrane progesterone receptor (mPR). Inhibition of the Pi3k/Akt pathway counteracted the generation of CSCs by progesterone and irradiation. The stimulation of Pi3K/Akt by progesterone resulted in the inactivation of FOXO3 and a downregulation of miR-29 expression. Stabilization of miR-29 expression impeded the generation of CSCs, while its inhibition alone was sufficient to generate CSCs. This study provides a new mechanistic basis for progesterone and radiation-induced breast cancer risk. In addition, the elucidation of new pathways and miRNA regulations involved in CSC generation and maintenance may open the door to potential new strategies for basal cancer primary or adjuvant therapy, by blocking non-CSCs from replenishing the pool of CSCs and by targeting mechanisms responsible for CSC maintenance. Such CSC-focused therapies may be effective at preventing metastasis and relapse.
Citation Format: Guillaume Vares, Sei Sai, Bing Wang, Akira Fujimori, Mitsuru Nenoi, Tetsuo Nakajima. Progesterone generates cancer stem cells through membrane progesterone receptor-triggered signaling in basal-like human mammary cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2246. doi:10.1158/1538-7445.AM2015-2246
Abstract 2253: Cadherin 17 plays an important role in breast cancer metastasis to bone marrow
Authors: Okada Tomoko , Furihata Mutsuo , Kurabayashi Atsushi , Imamura Toru 
Published: August 2015

Abstract
To understand the mechanism underlying bone marrow metastasis in breast cancer, we have established a highly bone marrow metastatic mouse breast cancer cell line, 4T1E/M3. While metastatic potential of 4T1E/M3 to bone was quite high (about 80%) when injected intravenously to mice, it was rather low (about 20%) when injected subcutaneously. Then using 4T1E/M3 cells, we carried out the in vitro and in vivo selection and established higher bone marrow metastatic cells, FP10SC2, which have a very high potential of metastases to lungs (100%) and spines (85%) when subcutaneously injected to mice. DNA microarray analysis revealed that the gene expression of cadherin17 was upregulated in FP10SC2 compared to the parental 4T1E/M3. When the expression of cadherin17 was suppressed by RNAi, the anchorage independent growth and migration activity was dramatically decreased. Moreover, metastatic activity of cadherin17(-)/FP10SC2 to spines was significantly reduced compared to control/FP10SC2. When cadherin 17 was overexpressed in 4T1E/M3 parental cells, the colony formation and migration activity was clearly augmented. Taken together, it was suggested that cadherin 17 plays an important role on breast cancer metastasis to bone marrow.
Citation Format: Tomoko Okada, Mutsuo Furihata, Atsushi Kurabayashi, Toru Imamura. Cadherin 17 plays an important role in breast cancer metastasis to bone marrow. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2253. doi:10.1158/1538-7445.AM2015-2253
Abstract 2259: Requirement for BUB1B in tumor progression of lung adenocarcinoma
Authors: Chen Honglin , Lee James , Kljavin Noelyn M. , Haley Benjamin , Daemen Anneleen , Liang Yuxin , Johnson Leisa 
Published: August 2015

Abstract
Lung adenocarcinoma is often discovered as metastatic disease with very poor prognosis. However, much remains unknown about the mechanisms of lung adenocarcinoma tumor progression. In this study we showed that knockdown of BUB1B, a critical mitotic checkpoint protein, significantly inhibited anchorage-independent growth of lung adenocarcinoma cell lines. In allograft and tail vein mouse model studies, BUB1B suppression inhibited primary tumor growth and reduced metastasis to the lung and lymph nodes, resulting in prolonged survival in both tumor prevention and tumor intervention settings. Mechanistic studies revealed that BUB1B knockdown sensitized cells to anoikis. The N-terminal region of BUB1B was required for its functions in both anchorage-independent growth and anoikis resistance, whereas the kinase domain was less critical. Overexpression of BUB1B is associated with disease progression and poor survival in human lung adenocarcinoma patients. Collectively, these data reveal a novel function for BUB1B in mediating anchorage-independent survival and growth, thereby facilitating lung adenocarcinoma dissemination during metastasis. Thus, targeting BUB1B could provide potential therapeutic benefit in suppressing metastasis and prolonging survival in lung adenocarcinoma patients.
Citation Format: Honglin Chen, James Lee, Noelyn M. Kljavin, Benjamin Haley, Anneleen Daemen, Yuxin Liang, Leisa Johnson. Requirement for BUB1B in tumor progression of lung adenocarcinoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2259. doi:10.1158/1538-7445.AM2015-2259
Abstract 2264: Dual effects of podoplanin on the regulation of cancer cell gene expression and platelet CLEC-2 signaling during cancer metastasis
Authors: Tseng Ching-Ping , Chang Yao-Wen , Hsieh Pei-Wen , Cheng Ju-Chien 
Published: August 2015

Abstract
Podoplanin (PDPN) is frequently up-regulated in squamous cell carcinoma and is a marker for poor prognosis. PDPN facilitates cancer metastasis and tumor cell-induced platelet aggregation (TCIPA) by modulating cancer cell cytoskeleton reorganization and platelet C-type lectin-like receptor 2 (CLEC-2) activation. In this study, the effects of PDPN on the regulation of cancer cell gene expression and platelet CLEC-2 signaling are investigated. Using xenograft injection of the C6 glioma cells into nude mice as a metastatic model, the cells that colonized at lung tissue were isolated to establish a subline C6-Lung that was found to express high levels of PDPN. Knockdown of PDPN expression in C6-Lung resulted in the abrogation of TCIPA, indicating that PDPN plays a key role in platelet activation and TCIPA. Microarray analyses revealed differential gene expression signatures between low and high PDPN-expressed cells. Several genes were up-regulated (Sncg, Timp1, Mmp3 and Pla1a) and down-regulated (Calcb, Filip1, Agrn and Itga4) significantly in high PDPN-expressed C6-Lung cells. On the other hand, distinct platelet protein tyrosine phosphorylation profiles were revealed when platelets were treated with different CLEC-2 agonists including PDPN, aggretin and fucoidan. In addition to the activation of common CLEC-2 signaling proteins such as Src family kinase, Syk, and phospholipase Cγ2, Akt1/PDK1 and PKCμ were identified as the two novel signaling pathways activated by PDPN, indicating the presence of SFK-independent pathway downstream of CLEC-2. Our data together provide a definitive evidence for the presence of a unique network for PDPN-regulated cancer cell gene expression and platelet CLEC-2 signaling that shed a new insight for the functional roles of PDPN in cancer metastasis.
Citation Format: Ching-Ping Tseng, Yao-Wen Chang, Pei-Wen Hsieh, Ju-Chien Cheng. Dual effects of podoplanin on the regulation of cancer cell gene expression and platelet CLEC-2 signaling during cancer metastasis. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2264. doi:10.1158/1538-7445.AM2015-2264
Abstract 2269: A novel molecular subset of metastatic lung adenocarcinoma is defined by the function of the proteoglycan receptor HMMR
Authors: Stevens Laura E. , Zhao Minghui , Liu Zongzhi , Nguyen Don 
Published: August 2015

Abstract
Lung adenocarcinoma (LUAD) is a heterogeneous and deadly subtype of non-small cell lung cancer that metastasizes rapidly to distant organs. Recent transcriptional profiling of primary LUADs by TCGA identified three molecular subgroups with unique clinical and biological features. Amongst the most aggressive LUADs are tumors classified in the proximal inflammatory (PI) subtype. However, the molecular mechanisms that dictate metastatic competence of this tumor type remain undefined. Using a bioinformatic approach, we found that PI tumors are significantly enriched for the expression of extracellular matrix genes and their corresponding cell surface receptors compared to tumors of other subtypes. Among these receptors, hyaluronan mediated motility receptor (HMMR) was found to be significantly upregulated. Knockdown of HMMR in LUAD cells decreased their potential to invade, migrate, and form colonies in vitro. In an experimental mouse model of metastasis, suppression of HMMR decreased metastatic incidence and burden. Interestingly, using an orthotopic model of LUAD, suppression of HMMR attenuated tumor initiating capacity of LUAD cells within an inflammatory microenvironment without affecting tumor progression. In distant organs, HMMR is similarly essential for tumor re-initiation and expansion of micrometastases to macrometastases. Our findings suggest that the aggressive behavior of PI LUADs requires the interaction between HMMR and the tumor microenvironment.
Citation Format: Laura E. Stevens, Minghui Zhao, Zongzhi Liu, Don Nguyen. A novel molecular subset of metastatic lung adenocarcinoma is defined by the function of the proteoglycan receptor HMMR. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2269. doi:10.1158/1538-7445.AM2015-2269
Abstract 2295: AMP-activated protein kinase (AMPK) signaling in the context of gain-of-function mutant p53 in vivo
Authors: Jo Se-Young , Moon Hye-Min , Lee ChuHee , Jang Se Jin , Suh Young-Ah 
Published: August 2015

Abstract
There is growing evidence that tumor cells depend on unique metabolism for their continued growth and survival, and that cancer cells are peculiarly addicted to the rapacious uptake of glucose and glutamine. AMP-activated protein kinase (AMPK) is one of the central regulators of cellular and organismal metabolism in eukaryotes, playing critical roles in regulating cell growth and reprogramming metabolism. Several of the downstream effects of AMPK on metabolic adaptation can be attributed to the AMPK-dependent activation of the p53 tumor suppressor, resulting in its transcriptional activation and initiating a metabolic cell cycle checkpoint. However, in the absence of p53, treatment with the blood glucose-lowering drug metformin delays tumor progression, suggesting that the AMPK-p53 signaling axis responds in diverse manner depending on genetic alteration. Due to the gain-of-function, mutant p53 protein contributes to tumor metastasis and shortening the latency of tumor progression. Thereby activated K-ras/mutant p53 mouse is preferentially used as lung adenocarcinoma preclinical model. Here, we have established mouse tumor cells derived from activated K-ras/mutant p53 mouse to generate syngeneic lung cancer mouse model, allowing in vivo imaging. We asked whether the gain-of-function metastatic phenotype observed in the mouse is responsible for unique metabolic conditions resulting in the formation of lung tumors. We have evaluated tumor metabolic environment of this model and examined AMPK signaling pathways.
Citation Format: Se-Young Jo, Hye-Min Moon, ChuHee Lee, Se Jin Jang, Young-Ah Suh. AMP-activated protein kinase (AMPK) signaling in the context of gain-of-function mutant p53 in vivo. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2295. doi:10.1158/1538-7445.AM2015-2295
Abstract 23: Nuclear receptor PPARα activation triggers hepatic cell death in Ikkβ-deficient mice
Authors: Kim Jung-Hwan , Kim Taehyeong , Qu Aijuan , Gonzalez Frank J. 
Published: August 2015

Abstract
Peroxisome proliferator-activated receptor α (PPARα) plays a critical role in lipid metabolism, inflammation, carcinogenesis, and cell survival. Recent study showed that PPARα agonist dramatically induced the cell cycle arrest genes, such as p21 and Gadd45b, in the liver of mice. However, the inductions of these genes were not lead to hepatic cell death. Thus, here, we investigated the Ikkb gene whether this can affect the hepatic cell death or survival after induction of p21 and Gadd45b. To exam the function of Ikkb after PPARα activation, the Wild-type (IkkbF/F) and liver-specific Ikkb-null (IkkbF/F-AlbCre) mice were treated with the PPARα agonist Wy-14,643 for two weeks. As results, Hepatic cell death was undergone to apoptosis by increases of cleaved-caspase-3 and cleaved poly (ADP-ribose) polymerase only in the liver of IkkbF/F-AlbCre mice by Wy-14,643 and this was also supported by TUNEL staining. Moreover, Wy-14,643 treatment elevated phosphorylation of c-Jun N-terminal kinase only in the liver of IkkbF/F-AlbCre mice. Liver histology showed notable feature of hepatitis only in the IkkbF/F-AlbCre mice treated with Wy-14,643. And marked increase Tnfa mRNA was followed in Wy-14,643-treated IkkbF/F-AlbCre mice. However, expression of the gene related to lipid metabolism such as Ppara and Acox1 were not significantly changed by Wy-14,163 in both IkkbF/F and IkkbF/F-AlbCre mice. These studies suggest that Ikkb gene may play a critical role in hepatic cell survival against PPARα activation.
Citation Format: Jung-Hwan Kim, Taehyeong Kim, Aijuan Qu, Frank J. Gonzalez. Nuclear receptor PPARα activation triggers hepatic cell death in Ikkβ-deficient mice. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 23. doi:10.1158/1538-7445.AM2015-23
Abstract 2304: The role of methyltransferase, enhancer of zeste homolog 2 (EZH2) in mouse hepatocyte and human hepatocellular carcinoma
Authors: Bae Woo Kyun , Shim Hyun Jeong , Cho Sang Hee , Chung Ik-Joo , Park In-Kyu , Hennighausen Lothar 
Published: August 2015

Abstract
To investigate the role of EZH1 and EZH2 in liver homeostasis, mice were generated that carried Ezh1-/- and EZH2fl/fl alleles and an Alb-Cre transgene. Only combined loss of EZH1 and EZH2 in mouse hepatocytes caused a depletion of global H3K27me3 marks and the specific loss over ∼1900 genes at 3 months of age. Ezh1-/-,Ezh2fl/flAlb-Cre mice exhibited progressive liver abnormalities manifested by development of regenerative nodules and concomitant periportal fibrosis, inflammatory infiltration and activation of A6-positive hepatic progenitor cells at 8 months of age. In response to chronic treatment with CCl4, all experimental mice but none of the controls (n = 27 each) showed increased hepatic degeneration associated with liver dysfunction and reduced ability to proliferate. After 2/3ds partial hepatectomy, mutant mice (n = 5) displayed increased liver injury and a blunted regenerative response. Genome-wide analyses at 3-months of age identified 51 genes that had lost H3K27me3 marks and their expression was significantly increased. These genes were involved in regulation of cell survival, fibrosis, and proliferation. H3K27me3 levels and liver physiology were unaffected in mice lacking either EZH1 globally or EZH2 specifically in hepatocytes. This work demonstrates a critical redundancy of EZH1 and EZH2 in maintaining hepatic homeostasis and regeneration. Next, we checked the expression EZH2 and H3K27me3 status in 67 human hepatocellular carcinoma (HCC) samples. We also checked the gene expression by the next-generation sequencing based on EZH2 expression. This work demonstrates candidate EZH2 target genes in human HCC.
Citation Format: Woo Kyun Bae, Hyun Jeong Shim, Sang Hee Cho, Ik-Joo Chung, In-Kyu Park, Lothar Hennighausen. The role of methyltransferase, enhancer of zeste homolog 2 (EZH2) in mouse hepatocyte and human hepatocellular carcinoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2304. doi:10.1158/1538-7445.AM2015-2304
Abstract 2309: Murine model of dual mTORC kinase inhibition identifies CDK6 as a synergistic target in T-ALL
Authors: Gary Joy M. , Xu Jinfei , Simmons John , Zhang Shuling , Gamache Benjamin , Zhang Ke , Kovalchuk Alexander , Michalowski Aleksandra , Chen Jin-Qiu , Herrmann Michelle , Dubois Wendy , Testa Joseph , Mock Beverly A. 
Published: August 2015

Abstract
The PI3K/AKT/mTOR pathway is frequently hyperactivated in T- cell acute lymphoblastic leukemia (T-ALL). To model inhibition of this pathway in lymphoma, mice with constitutively-active AKT specific to T-lymphocytes (Lck-MyrAkt2) were crossed with mice that have genetically-reduced mTOR expression (mTOR knock-down, KD). Lck-MyrAkt2 mice with mTOR KD had altered thymic T-lymphocyte development; these mice also had delayed thymic pre-T cell lymphoblastic leukemia/lymphoma (pre-T LBL) progression and increased survival relative to wild type (WT) mTOR/ Lck-MyrAkt2 mice (average survival of 24 versus 14 weeks, respectively). Delayed pre-T LBL formation was also observed when WT mTOR/Lck-MyrAkt2 mice were treated for 8 weeks with the rapamycin analog, everolimus, an inhibitor of the mTOR TORC1 complex. Transcriptional profiling of thymic lymphomas from the WT vs KD mTOR/ Lck-MyrAkt2 mice revealed that mTOR KD was associated with decreased expression of Cdk6, a critical proliferative control node in T- cell development and oncogenic transformation. Pharmacologic inhibition of mTOR in tumor cells also decreased CDK6. Tumor cells from WT mTOR/Lck-MyrAkt2 mice were more sensitive to CDK4/6 inhibitors than tumor cells from KD mTOR/Lck-MyrAkt2 mice. Combining an mTOR inhibitor (rapamycin) with a CDK4/6 inhibitor (PD-0332991) synergistically inhibited the viability and decreased downstream signaling in both mouse lymphoma cells and human T-cell acute lymphoblastic leukemia (T-ALL) cell lines. Combining a dual mTORC inhibitor (PP242) with a CDK4/6 inhibitor decreased downstream signaling to an even greater extent in human T-ALL cell lines. Our results suggest that an mTORi/CDKi combination may be beneficial in the treatment of human T-ALL.
Citation Format: Joy M. Gary, Jinfei Xu, John Simmons, Shuling Zhang, Benjamin Gamache, Ke Zhang, Alexander Kovalchuk, Aleksandra Michalowski, Jin-Qiu Chen, Michelle Herrmann, Wendy Dubois, Joseph Testa, Beverly A. Mock. Murine model of dual mTORC kinase inhibition identifies CDK6 as a synergistic target in T-ALL. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2309. doi:10.1158/1538-7445.AM2015-2309
Abstract 2314: d16HER2 splice variant regulates the activity of HER2-positive breast cancer-initiating cells
Authors: Castagnoli Lorenzo , Koschorke Ada , Ghedini Gaia C. , Galvani Lorenzo , Ciravolo Valentina , Ghirelli Cristina , Palladini Arianna , Lamolinara Alessia , Iezzi Manuela , Lollini Pier Luigi , Triulzi Tiziana , Nanni Patrizia , Tagliabue Elda , Pupa Serenella M. 
Published: August 2015

Abstract
The transmembrane tyrosine kinase receptor HER2, overexpressed in ∼20% of human breast cancers (BCs), identifies an aggressive tumor subtype and is reportedly an important regulator of breast cancer-initiating cell activity (BCIC). We found that ∼90% of HER2+ BC patients constitutively express a splice isoform of wild-type HER2 (WTHER2) gene characterized by the lack of exon 16 (d16HER2), a deletion that promotes the generation of a particularly aggressive HER2 isoform and that forms stable and constitutively activated d16HER2 homodimers. Our comparison of the tumorigenic potential of the human d16HER2 and WTHER2 genes in the corresponding transgenic mouse models revealed a significantly shorter tumor latency period (p&lt; 0.001) and a higher tumor incidence in the d16HER2 mice (p&lt;0.001), suggesting a role for this variant in HER2-driven activation of BCICs. In this context, our preliminary analyses of HER2-positive primary mammary tumor cell lines MI6 and MI7 derived from spontaneous transgenic d16HER2 mice showed a significantly higher mammosphere-forming efficiency and higher levels of stem cell marker transcripts, including CD44, Wnt, Notch and Bmi1, compared to transgenic mouse WTHER2 tumor cells (WTHER2_1 and WTHER2_2). Mammospheres generated from human HER2-overexpressing breast cancer cell lines BT474 and MDA-MB-361, which also express the d16HER2 variant, exhibited an increase in the relative abundance of d16HER2 mRNA compared with that in the same parental cells cultured in adhesion conditions, as indicated by qPCR analyses. Experiments in mice injected into the mammary fat pad with the d16HER2- and WTHER2-positive cell lines at different serial dilutions indicate a consistently higher “stemness potential” of MI6 and MI7 cells compared to WTHER2_1 and WTHER2_2 cells, strongly suggesting that the d16HER2 variant plays a greater role than WTHER2 in regulating BCICs of HER2-driven mammary tumors.
Supported by Minister of Health and AIRC
Citation Format: Lorenzo Castagnoli, Ada Koschorke, Gaia C. Ghedini, Lorenzo Galvani, Valentina Ciravolo, Cristina Ghirelli, Arianna Palladini, Alessia Lamolinara, Manuela Iezzi, Pier Luigi Lollini, Tiziana Triulzi, Patrizia Nanni, Elda Tagliabue, Serenella M. Pupa. d16HER2 splice variant regulates the activity of HER2-positive breast cancer-initiating cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2314. doi:10.1158/1538-7445.AM2015-2314