bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2850: A systems genetics approach reveals Rnaseh2c-immune response axis that affects metastasis severity in breast cancer
Authors: Deasy Sarah , Hunter Kent 
Published: July 2017

Abstract
Metastatic breast cancer is a devastating disease with a 5-year survival rate of only 26%. This is due to a lack of effective therapies against established metastases and an inability to identify high risk patients who would benefit from specific adjuvant therapies to prevent metastatic progression. We have shown in mouse models that spontaneously arising tumors metastasize with different severity based on the mouse genetic background. Using systems genetics approaches we have identified genes correlated with metastasis and survival in both mice and humans. Rnaseh2c was identified as a novel candidate metastasis susceptibility gene. This gene encodes a scaffolding subunit of the Ribonuclease H2 enzyme which removes ribonucleotides misincorporated into the DNA. Experimentally modulating Rnaseh2c expression in a murine mammary cancer cell line resulted in significant changes in pulmonary metastasis, confirming this gene as a metastasis modifier. Mutations in Rnaseh2c are known to cause Aicardi-Goutieres Syndrome, a neurological autoinflammatory disorder that overlaps clinically with congenital viral infections and the autoimmune disease Systemic Lupus Erythematosus. Given this, we hypothesized that altered expression of Rnaseh2c in breast cancer cells affects metastasis by engaging the immune system. To investigate immune system involvement, we analyzed metastasis in immunocompromised mice. T cell deficiency ablated the effect of reduced Rnaseh2c expression on metastasis, revealing for the first time an Rnaseh2c-immune response axis in metastasis. Gene ontology pathway analysis following mRNA-sequencing of Rnaseh2c knockdown and overexpression tumors revealed that 20% of the genes with altered expression are involved in immune system-related pathways, including T cell signaling and antigen presentation. Furthermore, genes with significant changes included Type I interferons, T cell markers, and immune regulators. These results confirm that Rnaseh2c is a novel metastasis modifier gene and validate our hypothesis that the immune system is mediating the effect of Rnaseh2c on metastasis. This mechanism highlights a potential new target for combination with immune modulatory therapies to combat this devastating disease and adds to a panel of genes we identified that together could determine patients with high risk for metastasis.
Citation Format: Sarah Deasy, Kent Hunter. A systems genetics approach reveals Rnaseh2c-immune response axis that affects metastasis severity in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2850. doi:10.1158/1538-7445.AM2017-2850
Abstract 286: Forecast of the incidence and etiology of liver cancer in Taiwan, Japan, United States, and United Kingdom: toward harmonization of East and West
Authors: Hsiue Emily Han-Chung H. , Lo Wei-Cheng , Lin Hsien-Ho , Hsu Chih-Hung , Cheng Ann-Lii 
Published: July 2017

Abstract
Background The global epidemiology of primary liver cancer (PLC), primarily hepatocellular carcinoma (HCC), has evolved significantly in the past decades because of improved control of viral hepatitis and the growing prevalence of metabolic factors. We conducted a quantitative forecast of the incidence and etiology of PLC. Methods Incidence rates of PLC were projected in two endemic Asian countries (Taiwan and Japan) and two Western countries (the United States and United Kingdom) with rigorous cancer registry. The annual incidence of PLC (ICD-10 C22.0) between 1980 and 2013 were obtained from the Taiwan Cancer Registry Database, the Japan National Cancer Center, the US SEER 9 database, Cancer Research UK, and the European Network of Cancer Registry. Incidence rates were projected to year 2035 by an age-period-cohort model with a power link function. The population attributable fractions (PAF) of chronic hepatitis B (HBV), chronic hepatitis C (HCV), alcohol consumption, obesity, and diabetes mellitus (DM) for HCC in Taiwan were projected to 2045. The prevalence of each risk factor was obtained from national surveys and projected inferentially by using a log-linear model or simple linear assumption. The relative risk of each factor was derived from pooled literature data. Results From 2013 to 2035, incidence rates of PLC in Taiwan are estimated to decrease by more than 50% in both men (49.3 to 24.2/100,000) and women (19.7 to 9.2/100,000). In Japan, incidence rates have plateaued in the 1990s, and are expected to continue to decline to 17.0/100,000 for men and 6.3/100,000 for women. Conversely, rates in the UK are projected to increase by more than 30% in both men (13.5 to 18.2/100,000) and women (6.0 to 8.1/100,000). A more modest increase is expected in the US, from 10.2 to 12.5/100,000 for men and 3.3 to 3.5/100,000 for women. In Taiwan, the PAF of HBV, the predominant risk factor of HCC, is predicted to decrease from 54.3% in 2015 to 34.4% in 2045. By 2045, the PAFs of obesity and DM are estimated to reach 11.9% and 15.4%, respectively, the latter similar to that of HCV (15.0%). Conclusion PLC incidence rates are forecast to follow a trend of convergence in four representative countries. Metabolic factors are expected to play increasingly important etiologic role in HCC even in regions currently endemic for viral hepatitis.
Citation Format: Emily Han-Chung H. Hsiue, Wei-Cheng Lo, Hsien-Ho Lin, Chih-Hung Hsu, Ann-Lii Cheng. Forecast of the incidence and etiology of liver cancer in Taiwan, Japan, United States, and United Kingdom: toward harmonization of East and West [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 286. doi:10.1158/1538-7445.AM2017-286
Abstract 2860: 89Zr-trastuzumab immunoPET imaging to monitor src status after treatment in HER2 breast cancer
Authors: McKnight Brooke N. , Viola-Villegas Nerissa T. 
Published: July 2017

Abstract
Around 30% of patients with early stage breast cancer have recurrent disease due to resistance. One of the putative causes of acquired resistance can be attributed to the hyperactivation of Src kinases, which are particularly stabilized by aberrant HER2 signaling, which itself is overexpressed in nearly 30% of early stage breast cancers. HER2 downstream effectors include Src, thus, we aim to investigate the use of a HER2-specific monoclonal antibody positron emission tomography (PET) probe, 89Zr-trastuzumab, to monitor Src therapy via surrogate HER2 expression. We hypothesize that 89Zr-trastuzumab can be a surrogate imaging tool for monitoring Src treatment.
89Zr-trastuzumab was previously developed and has demonstrated excellent specificity for breast cancer. Dasatinib-treated HER2+ BT474 (IC50 ~ 1.3 μM), SK-BR-3 (IC50 ~ 5.5 µM), and JIMT-1 (IC50 ~ 8 μM) breast cancer cells lines have shown a negative correlation between treatment and HER2. We next conducted tumorigenic studies using athymic nu/nu mice bearing JIMT-1 or BT474 xenografts, which were treated for 7 or 14 days with dasatinib (75 mg/kg/day). At the end of each treatment, the tumors were subsequently imaged with 18F-FDG, and then followed by 89Zr-trastuzumab, 24 h later. Images were analyzed using AsiPro (show version here and decay-corrected to the time of injection. Tumor uptake values were measured by drawing volumes-of-interest, expressed as % injected dose per gram (%ID/g) of tissue on regions showing the most binding. 18F-FDG did not demonstrate a predictive response in both treated and placebo tumors, whereas, HER2 PET was able to show differential response in treated vs. control cohorts. In JIMT-1 mice imaged with 89Zr-trastuzumab, a two-fold difference (p &lt; 0.01) was observed between untreated and both treated groups (8.0 ± 1.5 %ID/g, n= 7 vs. 7-day treated: 3.8 ± 1.5 %ID/g, n=4, and 14-day-treated: 4.5 ± 1.3 %ID/g, n= 4) mice imaged with 89Zr-trastuzumab. Confirmatory ex vivo western blots of JIMT-1 tumors have shown a decrease in HER2 as treatment time increases, with a decrease in p-Src (Y-416). In vivo studies with BT-474 xenografts are currently underway. Immunohistochemistry on excised tumors, as well as treatment on a metastatic patient-derived xenograft model is currently in progress.
We have shown that HER2 PET can potentially be a surrogate marker of Src treatment. The findings from this study potentially afford a powerful tool to non-invasively detect and monitor changes in Src-targeted therapy in man at the early phases of treatment.
Citation Format: Brooke N. McKnight, Nerissa T. Viola-Villegas. 89Zr-trastuzumab immunoPET imaging to monitor src status after treatment in HER2 breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2860. doi:10.1158/1538-7445.AM2017-2860
Abstract 2872: Quantitative mass spectrometry imaging of erlotinib in skin rashes of cancer patients receiving erlotinib
Authors: Nishimura Meiko , Aikawa Hiroaki , Hayashi Mitsuhiro , Mizutani Yu , Takenaka Kei , Imamura Yoshinori , Chayahara Naoko , Toyoda Masanori , Kiyota Naomi , Mukohara Toru , Hamada Akinobu , Minami Hironobu 
Published: July 2017

Abstract
Background
The development of rashes is the most common adverse event observed in cancer patients treated with epidermal growth factor receptor-targeted tyrosine kinase inhibitors (EGFR-TKI) such as erlotinib. A significant relationship exists between the severity of a rash and survival in various cancers. However, whether erlotinib becomes distributed to the skin and whether its concentration is higher in a rash than in normal skin of treated cancer patients remains unknown. Here, using quantitative mass spectrometry imaging (qMSI), we successfully visualized the distribution of erlotinib in rashes and normal skin of patients with advanced pancreatic cancer receiving this drug.
Methods
We studied five patients with advanced pancreatic cancer who developed rashes after treatment with gemcitabine (1000 mg/m² by intravenous infusion for 30 minutes on days 1, 8, and 15 every 4 weeks) and erlotinib (given orally at 100 mg/day). We biopsied both rashes and normal skin, and compared the distribution of erlotinib using matrix-assisted laser desorption ionization mass spectrometry imaging (MALDI-MSI). The plasma concentration of erlotinib was measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS).
Results
Erlotinib concentrations in five patients were 2.55 ± 1.46 ng/mm3 in normal skin and 3.18 ± 1.53 ng/mm3 (mean ± SD) in rashes (p=0.123). In four out of five patients, the erlotinib concentration in rashes was higher than that in normal skin. The epidermis showed the strongest expression of EGFR in skin as judged by immunohistological staining. Erlotinib showed a greater tendency for distribution to the epidermis than subcutaneous
tissue. There was no correlation between erlotinib plasma concentrations vs. concentrations in rashes or normal skin.
Conclusions
Using qMSI, we, for the first time, visualized the distribution of erlotinib in skin tissue of pancreatic cancer patients receiving erlotinib. We found a tendency for a higher concentration of erlotinib in rashes than in normal skin. A greater distribution of erlotinib to the epidermis than subcutaneous tissue suggests erlotinib may directly bind EGFR expressed in the epidermis.
Citation Format: Meiko Nishimura, Hiroaki Aikawa, Mitsuhiro Hayashi, Yu Mizutani, Kei Takenaka, Yoshinori Imamura, Naoko Chayahara, Masanori Toyoda, Naomi Kiyota, Toru Mukohara, Akinobu Hamada, Hironobu Minami. Quantitative mass spectrometry imaging of erlotinib in skin rashes of cancer patients receiving erlotinib [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2872. doi:10.1158/1538-7445.AM2017-2872
Abstract 2876: Loss of the stem cell and basal lineage regulator LBH delays onset of basal-like triple negative breast cancer
Authors: Ashad-Bishop Kilan C. , Briegel Karoline 
Published: July 2017

Abstract
There is increasing evidence that basal-like triple negative breast cancer (TNBC) originates from luminal mammary epithelial cells. Specific gene signatures have already been experimentally proven to serve as genetic lineage switches that, when overexpressed, transform pre-malignant luminal cells to oncogenic cells with basal, stem-like characteristics. Conversely, depletion of these genes in oncogenic cells with basal, stem-like characteristics leads to luminal differentiation. These studies suggest that during the earliest steps of neoplastic transformation, specific gene sets can alter cell fate decisions and differentiation status in mammary epithelial cells, which ultimately contributes to the heterogeneity of breast tumors.
Our lab has identified a novel Wnt/β-Catenin target gene, Limb bud and heart (LBH) that is majorly overexpressed in TNBC. LBH is a regulator of the basal mammary stem cell lineage and repressor of luminal differentiation via induction of ΔNp63 and repression of estrogen receptor alpha. LBH is required for the self-renewal and maintenance of adult basal mammary stem cells, which tend to be enriched in TNBC. Knockout studies in mice have shown that genetic ablation of LBH does not impair embryogenesis or normal adult organ function, making it a possible therapeutic target.
Using crosses between MMTV-Wnt-1 transgenic mice and K14Cre LBHloxP knockout mice, we are studying the effect of LBH ablation in the basal cells of the mammary epithelium downstream of ectopic Wnt expression in the mammary gland. We postulated that LBH may be an effector of Wnt-driven TNBC, therefore its inhibition would lead to decreased Wnt-induced mammary gland hyperplasia and tumor formation. In our model, LBH ablation in the basal mammary epithelium of female Wnt transgenic mice reduces mammary gland hyperplasia and delays tumor onset. MMTV-Wnt-1 driven, LBH-null tumors also exhibit histopathological differences indicative of a luminal to basal conversion.
There is an urgent need to elucidate mechanisms underlying TNBC development and progression and find reliable avenues for treatment. Our data indicates a role for Lbh as a novel effector for Wnt-driven TNBC and further studies may prove antagonism of Lbh to be a novel method to control TNBC progression.
Citation Format: Kilan C. Ashad-Bishop, Karoline Briegel. Loss of the stem cell and basal lineage regulator LBH delays onset of basal-like triple negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2876. doi:10.1158/1538-7445.AM2017-2876
Abstract 288: Loss of a branched actin checkpoint in cancer cells
Authors: Molinie Nicolas , Rubtsova Svetlana , Gautreau Alexis 
Published: July 2017

Abstract
Cell proliferation depends on multiple signals, such as growth factors, adhesion to the substratum and to neighboring cells. Cancer cells proliferate independently of these signals. The same stimuli also induce actin polymerization. Here we investigate whether the actin cytoskeleton plays a role in transmitting the proliferation signal. We found that inactivation of the Arp2/3 complex by either a chemical inhibitor or by siRNAs blocks S phase entry in untransformed human breast cell lines and in primary breast epithelial cells. In contrast, breast cancer cell lines did not respond to Arp2/3 inhibition. Inactivating the tumor suppressor p21WAF1/CIP1, or Rb, converts sensitive cells into unresponsive cells further highlighting that this response to Arp2/3 inactivation is at the heart of the transformation process. The depletion of the WAVE complex, the Arp2/3 activator that generates branched actin in lamellipodia, but not of other Arp2/3 activators, blocks cell cycle progression. Conversely, activation of WAVE by active Rac, or depletion of Arpin, which antagonizes WAVE, potentiates cell cycle progression. Together, these results show that branched actin networks generated in lamellipodia are sensed and convey an essential signal for S Phase entry. The signal that branched actin delivers integrates stimulation from soluble growth factor with mechanotransduction from cell adhesions to the substratum and to neighboring cells. This signaling pathway qualifies as a checkpoint, which is required in normal cells, but lost in transformed cells, that monitors the integrity of branched actin networks and instructs the cell as a response that the required conditions to proliferate are fulfilled.
Citation Format: Nicolas Molinie, Svetlana Rubtsova, Alexis Gautreau. Loss of a branched actin checkpoint in cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 288. doi:10.1158/1538-7445.AM2017-288
Abstract 2882: The miR-200b-ZEB1 circuit regulates diverse stemness of human hepatocellular carcinoma
Authors: Hsieh Sen-Yung , Tsai Su-Chun 
Published: July 2017

Abstract
Background & aims: Hepatocellular carcinoma (HCC) can be derived from cancer stem cells (CSCs), which contribute to tumor initiation, metastasis, chemoresistance, and post-treatment recurrence. A great variety of HCC CSCs resulting in diverse clinical manifestations have been reported. We aimed to elucidate how CSC diversity is regulated.
Methods: MicroRNAs deregulated in HCC were identified by using array-based microRNA profiling. Diversity of HCC CSCs was assayed by flow-cytometry, in vitro and in vivo assays for tumorigenicity.
Results: MiR-200b downregulation occurred in early HCC and associated with shorter disease-free and overall survival. Ectopic expression of miR-200b or silencing of ZEB1 led to a decrease in CD13+ and CD24+ HCC CSCs and an increase in EpCAM+ HCC CSCs. MiR-200b directly suppressed BMI1 and ZEB1 expressions. ZEB1 transcriptionally upregulated CD13 and CD24 expression and downregulated EpCAM expression via directly targeting their promoters. Neither miR-200b nor ZEB1 had obvious effects on CD133 or CD90 expression. Silencing CD13 or CD24 expression suppressed tumorigenicity of HCC cells. Ectopic expression of CD24 reversed the suppression of tumorigenicity when these HCC cells had been ectopically expressing miR-200b. Clinically, miR-200b downregulation was coupled with ZEB1 upregulation in approximately two-thirds of HCC patients. ZEB1 expression was positively correlated with CD13 and CD24 expressions, while EpCAM expression was positively correlated with miR-200b expression in HCCs.
Conclusions: The miR-200b-ZEB1 circuit is a master regulator of diverse stemness of HCC, which distincts HCCs into those containing CD13+/CD24+ CSCs from those containing EpCAM+ CSCs, and a thus potential target for anti-HCC therapy.
Citation Format: Sen-Yung Hsieh, Su-Chun Tsai. The miR-200b-ZEB1 circuit regulates diverse stemness of human hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2882. doi:10.1158/1538-7445.AM2017-2882
Abstract 2885: Activation of IL1α signaling by HER2 overexpression promotes breast cancer stem cells
Authors: Liu Shou , Lee Ji shin , Chen Hexin 
Published: July 2017

Abstract
Breast cancer is a heterogeneous disease and only a small proportion of cells known as cancer stem cells (CSCs) have ability to generate tumor. Recently, it has been reported that HER2 overexpression increase breast cancer stem cells (BCSCs). However, the underlying mechanism is not clearly known. In this study, we explored the molecular mechanism how HER2 increase BCSCs. Our data has demonstrated HER2 induces BCSCs by indirectly activating NF-kB and STAT3 signaling. To figure out the direct target of HER2, we did the microarray and found that HER2 upregulates the expressions of IL1a and IL6, two major cytokines which directly activates NFkB and STAT3, respectively. Interestingly, we found that IL1a also indirectly activates STAT3. IL1α induced STAT3 was blocked when IL6 was knock out from cells. We found that HER2 enhances IL1α transcription by activating PU.1 which is known transcription factor of IL1a. Finally, we studied effect of IL1a on tumorigenesis, and found that IL1α KO dramatically attenuates the tumor growth in NOD/SCID mice. Taken together, we found that HER2 induces BCSCs by upregulating IL1a and IL6 expression. We for first time demonstrating that IL1α plays a critical role in HER2-induced expansion of BCSC population and may be a potential therapeutic target for HER2 positive breast cancer.
Citation Format: Shou Liu, Ji shin Lee, Hexin Chen. Activation of IL1α signaling by HER2 overexpression promotes breast cancer stem cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2885. doi:10.1158/1538-7445.AM2017-2885
Abstract 2895: Octamer-4/microRNA-1246 signaling axis drives Wnt/β-catenin activation in liver cancer stem cells
Authors: Chai Stella , Ng Kai-Yu , Tong Man , Lau Eunice Y. , Lee Terence K. , Chan Kwok Wah , Yuan Yun Fei , Cheung Tan To , Cheung Siu Tim , Wang Xiao Qi , Wong Nathalie , Lo Chung Mau , Man Kwan , Guan Xin Yuan , Ma Stephanie K. 
Published: July 2017

Abstract
Hepatocellular carcinoma (HCC), the main type of liver cancer in human, is one of the most prevalent and deadly malignancies in the world. Despite advances in therapy, prognosis remains dismal, largely attributed by our limited understanding on information related to the progressive development of the disease, particularly in their cancer-initiating and stem cell-like properties. Wnt/β-catenin signaling is activated in CD133 liver cancer stem cells (CSC), a subset of cells known to be a root of tumor recurrence and therapy resistance in HCC. However, the regulatory mechanism of this pathway in CSCs remains unclear. Here, we show that human miRNA, miR-1246, promotes cancer stemness including self-renewal, drug resistance, tumorigencity and metastasis by activation of Wnt/β-catenin pathway via suppressing the expression of AXIN2 and GSK3β, two key members of the β-catenin destruction complex. This observation was validated by both in vitro and in vivo functional / cell biological studies on HCC cell lines with or without miR-1246 expression modulated by lentiviral based knockdown and overexpression strategies as well as in miR-1246 repressed HCC cells with concomitant expression of wild-type or constitutively active β-catenin. Clinically, high endogenous and circulating miR-1246 was identified in HCC clinical samples and correlated with a worse prognosis. Further functional analysis identified Oct4 to be the direct upstream regulator of miR-1246, which cooperatively drive β-catenin activation in liver CSCs. In conclusion, our findings not only uncover the non-canonical regulation of Wnt/β-catenin in liver CSCs by Oct4/miR-1246 signaling axis, but also provide a novel diagnostic marker as well as therapeutic intervention for HCC.
Citation Format: Stella Chai, Kai-Yu Ng, Man Tong, Eunice Y. Lau, Terence K. Lee, Kwok Wah Chan, Yun Fei Yuan, Tan To Cheung, Siu Tim Cheung, Xiao Qi Wang, Nathalie Wong, Chung Mau Lo, Kwan Man, Xin Yuan Guan, Stephanie K. Ma. Octamer-4/microRNA-1246 signaling axis drives Wnt/β-catenin activation in liver cancer stem cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2895. doi:10.1158/1538-7445.AM2017-2895