bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 534: Oncogenes alter mammary epithelial cell lineage identity prior to tumor formation
Authors: Breindel Jerrica , Nampanya Felix , Datye Aditya , Miller Daniel H. , Gupta Piyush , Kuperwasser Charlotte 
Published: August 2018

Abstract
Background: Breast cancer is a heterogeneous disease encompassing multiple subtypes that differ in their molecular profiles, clinical course of progression, and response to therapeutics. Interestingly, breast cancers fall broadly into luminal and basal subtypes, which resemble the normal luminal and basal epithelial cells of the breast. This correlation suggests that the molecular mechanisms controlling epithelial cell lineage identity during normal mammary development may also influence tumor subtype during cancer formation. Since many breast cancers are driven by oncogenes that are important for normal mammary development, we hypothesize that dysregulated oncogene signaling may alter mammary epithelial cell lineage identity at an early step of cancer initiation, priming the breast tumor subtype that will be formed upon full tumorigenesis.
Methods: Human breast cell lines, MCF10a and MCF10f, and primary human breast tissues were infected with virus expressing single breast cancer oncogenes. Flow cytometry and quantitative RT-PCR were performed on breast cell lines to determine changes in the balance of luminal to basal cells and expression of luminal or basal gene sets. Primary tissues were grown in hydrogels and stained for luminal and basal markers to determine the effect of oncogene expression on the growth of mammary ductal structures. Mouse tumor models, MMTV-Myc and MMTV-Wnt1, were investigated for changes in their mammary epithelial architecture by histology and flow cytometry at ages prior to tumor formation.
Results: Oncogene overexpression in human breast cell lines causes shifts in basal and luminal cell balance that correlate with changes seen in mammary ductal growth in hydrogel cultures of primary human breast epithelial cells. In mouse models, individual oncogenes alter mammary epithelial architecture and cell balance at early stages prior to tumor formation. In both models, individual oncogenes are able to regulate mammary epithelial cell lineage identity in the absence of other tumor-initiating signals, indicating that oncogenes may influence breast cancer subtype through mammary epithelial cell lineage regulation at early stages of cancer progression.
Citation Format: Jerrica Breindel, Felix Nampanya, Aditya Datye, Daniel H. Miller, Piyush Gupta, Charlotte Kuperwasser. Oncogenes alter mammary epithelial cell lineage identity prior to tumor formation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 534.
Abstract 5376: Whole-exome sequencing of acquired nevi identifies novel mechanisms for development and maintenance of benign neoplasms
Authors: Stark Mitchell S. , Tan Jean-Marie , Tom Lisa , Jagirdar Kasturee , Lambie Duncan , Schaider Helmut , Soyer H. Peter , Sturm Richard A. 
Published: August 2018

Abstract
Background: Acquired melanocytic nevi (AMN) are often mimicking melanoma and ~30% of all melanomas arise within a pre-existing nevus. However, the melanoma transformation rate of each nevus is rare despite the detection of oncogenic mutations BRAF or NRAS mutations in 100% of nevi.Objective: To identify the underlying genetic mechanisms for nevus development.Methods: Nevi, adjacent normal skin, and saliva were sampled from a cross-sectional study. All nevi were clinically, dermoscopically, and histopathologically documented. Using whole-exome sequencing (WES) we assessed the somatic mutational landscape, mutation signatures and copy-number aberrations (CNA) in 30 acquired melanocytic nevi and matching normal skin.Results: In addition to identifying somatic mutations, we confirm the presence of mutational signatures relating to age and ultra-violet radiation (UVR) which mirrors those observed in melanomas of the skin. In matching normal skin of all nevi, we rarely observed the presence of a UVR mutation signature (10% vs. 97% in nevi) despite being exposed to the same amount of UVR as the associated naevus. Instead, we have identified the predominance of defective DNA repair mutation signatures (93%) which we postulate creates the environment for melanocyte transformation sufficient for nevi and perhaps de novo melanoma growth. In copy number aberration (CNA) analysis, in nevi with copy number loss of tumour suppressor genes (TSG), these were balanced by loss of potent oncogenes. Moreover, reticular and non-specific patterned nevi revealed an increased (p&lt;0.0001) number of CNA as compared with globular patterned nevi. Conclusion: The mutation signature data generated in this study confirms that UVR and defective DNA repair mechanism strongly contributes to nevogenesis. The observed copy number changes reflect at a genomic level, the dermoscopic differences of AMN. Lastly, we propose that the balanced loss of TSGs and oncogenes is a protective mechanism of AMN.
Citation Format: Mitchell S. Stark, Jean-Marie Tan, Lisa Tom, Kasturee Jagirdar, Duncan Lambie, Helmut Schaider, H. Peter Soyer, Richard A. Sturm. Whole-exome sequencing of acquired nevi identifies novel mechanisms for development and maintenance of benign neoplasms [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5376.
Abstract 5407: MicroRNA expression analysis of advanced colorectal cancer reveals a microRNA signature with prognostic and predictive value
Authors: Zeng Zhaolei , Lu Jiahua , Zuo Zhixiang , Zhao Qi , Xu Ruihua 
Published: August 2018

Abstract
Background
Prognostic and predictive markers are needed to predict the clinical outcomes of patients with advanced colorectal cancer (CRC) who receive standard first-line treatments. We performed a prospective cohort study in patients with advanced CRC to identify a miRNA signature that could predict the benefit of receiving first-line chemotherapy for these patients.
Methods
Twenty-one paired tumours and adjacent normal tissues were collected from patients with advanced CRC and analysed by miRNA microarrays. Between tumour and normal tissues, 33 miRNAs were differentially expressed. The differential expression of these miRNAs was confirmed by qRT-PCR using paraffin-embedded specimens from another group of 76 patients from a prospective cohort study. A two-miRNA-based signature was obtained using the least absolute shrinkage and selection operator (LASSO) Cox regression model based on the association between the expression of each miRNA and the progression-free survival (PFS) time of individual patients. Internal and external validation cohorts, including 45 and 50 patients with advanced CRC, respectively, were performed to validate the prognostic and predictive accuracy of this signature.
Results
A signature based on two miRNAs, miR-125b-2-3p and miR-933, was built by the LASSO model. CRC patients were classified into high- and low-risk groups for disease progression based on this tool. The patients with high risk scores generally had worse PFS than those with lower risk scores. In the training set, the average PFS was 23.906 months for the low-risk group and 9.010 months for the high-risk group (hazard ratio [HR] 2.535, 95% CI 1.478-4.348, p=0.001). In the internal validation set, the average PFS was 14.029 months for the low-risk group and 6.334 months for the high-risk group (HR 3.173, 95% CI 1.415-7.116, p=0.005). In the external validation set, the average PFS was 16.815 months for the low-risk group and 7.657 months for the high-risk group (HR 2.498, 95% CI 1.281-4.871, p=0.007). Furthermore, we detected miR-125b-2-3p associated with CRC cell sensitivity to first-line chemotherapy. The two-miRNA-based signature was an independent prognostic factor for predicting the outcome of patients with metastatic CRC receiving first-line chemotherapy.
Citation Format: Zhaolei Zeng, Jiahua Lu, Zhixiang Zuo, Qi Zhao, Ruihua Xu. MicroRNA expression analysis of advanced colorectal cancer reveals a microRNA signature with prognostic and predictive value [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5407.
Abstract 5414: The correlation between the expression of microRNA hsa-miR-101 and the prognosis of the patient with hepatocellular carcinoma
Authors: Nakajima Go , Hayashi Kazuhiko 
Published: August 2018

Abstract
Aim: MicroRNAs (miRNA) are small RNAs that regulate gene expression at the post-transcriptional level, and they play a various role in cancer cell such as proliferation, migration and metastasis. Our previous study identified forty-nine miRNAs that are differentially expressed by comparing 26 pair samples of hepatocellular carcinoma (HCC) tumor and adjacent liver tissue using next-generation sequencer system. One of them, hsa-miR-101 is chosen in this validation study. The hsa-miR-101 expression in HCC tumor samples and its adjacent liver tissues were measured by real-time PCR, and were examined the correlation between the miRNA expression and clinical data.
Patients and Methods: Forty-three patients diagnosed as HCC had undergone surgical removal from 1991 to 1997 at the Department of Surgery, Institute of Gastroenterology, Tokyo Women's Medical University, Japan. The formalin-fixed paraffin embedded samples were prepared using the standard protocol. The paraffin blocks were cut into 10 micrometer sections, and the tumor and its adjacent non-tumor liver tissue were collected using laser-captured microdissection and total RNA including miRNA fraction were isolated. After synthesized cDNA using miRNA specific primer, real-time PCR was performed using miRNA specific primer/probe.
Results: The expression of hsa-miR-101 in tumor tissue was downregulated compared to adjacent liver tissue (P=0.003). No significant differences were obtained in survival time between higher or lower intratumoral expression level (P=0.8039). The patients were divided into two groups, higher/lower hsa-miR-101 expression in the tumor or in the adjacent liver tissue, the group of the higher expression in adjacent liver tissue and the lower in tumor was longer survival time compared to the other groups (P=0.0184).
Conclusion: The hsa-miR-101 expression may be related to tumorigenesis, and both the expression in the tumor and in the adjacent liver tissue may be potential prognostic factor for HCC patients.
Citation Format: Go Nakajima, Kazuhiko Hayashi. The correlation between the expression of microRNA hsa-miR-101 and the prognosis of the patient with hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5414.
Abstract 5420: Nuclear PTEN directly regulates androgen receptor activity in prostate cancer
Authors: Nguyen Yen T. , Rodriguez-Nieves Jose A. , Yang Qi , VanderWeele David 
Published: August 2018

Abstract
The deletion of PTEN, a negative regulator of the PI3K pathway, is among the most frequent genomic alterations in prostate cancer. Attempts to target this alteration using PI3K pathway inhibitors, however, have yielded little clinical benefit for patients, and the function of PTEN loss in prostate cancer progression is not fully understood. Prostate cancers lacking PTEN are less responsive to therapy targeting the Androgen Receptor (AR), a dominant driver of prostate cancer growth, but how PTEN function interacts with AR activity is not clear. We used immunoblotting, immunoprecipitation, proximity ligation assay, chromatin immunoprecipitation, and transcriptome sequencing in cells with endogenous PTEN or PTEN knocked down to evaluate the interactions between these major factors in prostate cancer progression. We demonstrate that PTEN interacts with the Androgen Receptor in the nucleus, and PTEN can bind chromatin at known Androgen Response Elements. Stimulation of cells with androgen and other media components leads to accumulation of phosphorylated (inactive) PTEN, loss of nuclear PTEN, and decreased PTEN-AR interaction. Transcriptome analysis of cells with PTEN knocked down demonstrates increased expression of AR pathway genes, even in the absence of androgen stimulation. These results suggest nuclear PTEN may play a direct role in negative regulation of the Androgen Receptor, with implications for management of PTEN-negative prostate cancers.
Citation Format: Yen T. Nguyen, Jose A. Rodriguez-Nieves, Qi Yang, David VanderWeele. Nuclear PTEN directly regulates androgen receptor activity in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5420.
Abstract 5423: Lysine-52 stabilizes the MYC oncoprotein through a SCFFBXW7-independent mechanism
Authors: Melo Jason De , Kim Sam S. , Lourenco Corey , Resetca Diana , Sunnerhagen Maria , Raught Brian , Penn Linda Z. 
Published: August 2018

Abstract
The oncogenic transcription factor c-MYC (MYC) is deregulated, and often overexpressed, in more than 50% of cancers. MYC deregulation is associated with poor prognosis and aggressive disease, suggesting that the development of therapeutic inhibitors targeting MYC would dramatically impact patient care and outcome. MYC is a highly regulated transcription factor, with a protein and mRNA half-life of approximately 30 min. The most extensively studied pathway regulating MYC protein stability involves ubiquitylation and proteasomal degradation mediated by the E3-ligase, SCFFBXW7. Here we provide evidence for a SCFFBXW7-independent regulatory mechanism centered on Lysine 52 (K52) within MYC Box I (MBI) of the MYC protein. This residue has been shown to be post-translationally modified by both ubiquitylation and SUMOylation, hinting at the interplay of post-translational modifications at this site, and the importance of this residue. We demonstrate that mutation of K52 to arginine (R) renders the MYC protein more labile. Mechanistically, we show that the degradation pathway regulated by K52 is independent of the Cullin-Ring-Ligase (CRL) family of E3-ligases, which includes not only the canonical SCFFBXW7, but also a number of other known MYC-targeting E3-ligases, such as SCFSKP2, SCFβTCRP, SCFFBXO28 and DCXTRUSS. To characterize this degradation pathway further we will utilize unbiased and targeted experiments to elucidate the proteins involved. Taken together, our data identifies a novel regulatory pathway centred on K52 that may be exploited for the development of anti-MYC therapeutics.
Citation Format: Jason De Melo, Sam S. Kim, Corey Lourenco, Diana Resetca, Maria Sunnerhagen, Brian Raught, Linda Z. Penn. Lysine-52 stabilizes the MYC oncoprotein through a SCFFBXW7-independent mechanism [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5423.
Abstract 545: NOTCH1 co-expression analysis reveals novel insights underlying its opposing effects as an oncogenic and tumor suppressor in lung cancer
Authors: Sinicropi-Yao Sara L. , Carbone David P. , Coombes Kevin R. , Amann Joseph M. , Lopez David Lopez 
Published: August 2018

Abstract
Background: Aberrations in the family of Notch receptors (1, 2, 3, and 4) have been implicated in a range of solid tumors, including lung cancer. NOTCH1 biology is complex where Notch plays an oncogenic and tumor suppressor role in lung adenocarcinoma and lung squamous cell carcinoma, respectively. Although the role of Notch in cancer development and progression has received increased appreciation in recent years, there is still a lack of understanding of the mechanisms underlying these opposing activities in lung cancer.
Methods: The Cancer Genome Atlas datasets were used to examine gene co-expression patterns of Notch1 in lung adenocarcinoma and lung squamous cell carcinoma. Biological pathways implicated by gene families were assessed using functional annotation tools (DAVID, ToppGene, and IPA). In vitro and in vivo knockdown studies assessed the functional role of Notch1.
Results: This novel co-expression analysis supports the hypothesis that NOTCH1 is co-expressed with different genes in lung adenocarcinoma and squamous cell carcinoma. Knockdown of Notch1 in vitro and in vivo support our in silico finding of opposing effects of NOTCH1. Our analysis implicates genes associated with metabolic pathways, immune pathways, angiogenesis and cell cycle that may underlie the differential role of NOTCH1 in lung adenocarcinoma and squamous cell carcinoma. In vitro and in vivo studies support our bioinformatics analysis.
Conclusion: These results demonstrate different NOTCH1 gene co-expression patterns in lung adenocarcinoma and squamous cell carcinoma. These findings provide novel insights underlying the context-dependent role of Notch as an oncogene and tumor suppressor in subtypes of lung cancer. Understanding the similarities and differences in co-expression patterns reveal novel insights, suggesting that tumor intrinsic and extrinsic pathways may underlie the dual role of NOTCH1 in lung cancer. Recognition of the mechanisms underlying NOTCH1 opposing roles in cancer may help direct development of Notch-targeted therapies as a monotherapy or in combination with approaches focusing on the tumor microenvironment.
Citation Format: Sara L. Sinicropi-Yao, David P. Carbone, Kevin R. Coombes, Joseph M. Amann, David Lopez Lopez. NOTCH1 co-expression analysis reveals novel insights underlying its opposing effects as an oncogenic and tumor suppressor in lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 545.
Abstract 5460: Discovery and evaluation of WX047, a potent and oral active phosphoinositide 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) dual inhibitor
Authors: Li Ning , Guan Amy , Huang Lei , Hao Dongling , Gao Bo , Sun Jikui , Shih Nengyang , Kong Lingwei , Jiang Peipei , Li Yi , Yao Dan , Qin Yuxin , Yu Tao , Wu Chengde , Chen Shuhui , Yuan Hongyu , Lu Xiulian 
Published: August 2018

Abstract
Background: The PI3K/AKT/mTOR signaling pathway is important in regulating cell cycle, which is directly related to cellular quiescence, proliferation and longevity. Dysfunctional signaling of the PI3K/AKT/mTOR pathway in cancer, and its crucial role in cell growth and survival have made it a much desired target for cancer therapeutics.
Methods: By using structure-based design, the 4H-pyrido[1,2-a]pyrimidin-4-one derivative as an early lead was discovered. Further SAR studies optimized the in vitro and PK properties and led to the identification of WX047 as a potent dual inhibitor of PI3K and mTOR. Antitumor efficacy of WX047 was evaluated in the PC-3M xenograft tumor model.
Results: A series of 7-(pyridin-3-yl)-4H-pyrido[1,2-a]pyrimidin-4-one derivatives were synthesized and evaluated for in vitro and in vivo activities. Among them, WX047 was identified as a potent dual PI3K and mTOR inhibitor with IC50 for mTOR of 19.17 nM and IC50 for PI3Kα of 3.13 nM. The cellular activity of WX047 was determined in PC-3M cells by western blot analysis of p-Akt and p-70S6K with p-Akt and p-70S6K inhibition IC50 of 16 nM and 65 nM respectively. WX047 had low clearance and high oral bioavailability relative to those of the reference compound GSK2126458. In addition, WX047 also demonstrated significant antitumor efficacy in the PC-3M xenograft tumor models (79% TGI@10mpk, PO, QD).
Conclusions: WX047 has been identified as an orally active PI3K and mTOR dual inhibitor. It displays significant antitumor efficacy in the PC-3M xenograft tumor model. These support moving the compound forward to clinical investigation.
Citation Format: Ning Li, Amy Guan, Lei Huang, Dongling Hao, Bo Gao, Jikui Sun, Nengyang Shih, Lingwei Kong, Peipei Jiang, Yi Li, Dan Yao, Yuxin Qin, Tao Yu, Chengde Wu, Shuhui Chen, Hongyu Yuan, Xiulian Lu. Discovery and evaluation of WX047, a potent and oral active phosphoinositide 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) dual inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5460.
Abstract 5470: IKK-epsilon supports anchorage independent growth via alternative NF-kB signaling in triple-negative breast cancer
Authors: House Carrie D. , Grajales Valentina , Ozaki Michelle , Jordan Elizabeth , Wubneh Helmae , Kimble Danielle , Kim Marianne , Annunziata Christina M. 
Published: August 2018

Abstract
Metastatic breast cancer carries a poor prognosis despite the success of newly targeted therapies and treatment options remain especially limited for the subtype of triple negative breast cancer (TNBC). Several signaling pathways, including NF-κB, are altered in TNBC. Given that ΙΚΚε behaves as an oncogene in breast cancer we hypothesized that IKKε regulates classical or alternative NF-κB signaling to control diverse oncogenic functions in TNBC. Vector expression and RNA interference were used to investigate the functional role of IKKε in triple-negative breast cancer cells. Viability, protein expression, NF-κB binding activity, invasion, anoikis, and spheroid formation were examined in cells expressing high or low levels of IKKε in conjunction with alternative NF-κB p52 RNA interference or MEK inhibition. Our data show that p52 protein levels and binding activity are inversely proportional to ΙΚΚε. Moreover, knockdown of IKKε leads to increased expression of p52 and the p52-regulated gene CXCL1. This interaction was confirmed by CHiP-PCR experiments showing increased binding of p52 in the CXCL1 promoter of cells with IKKε knockdown relative to control. We further found that IKKε and MEK were required for growth in anchorage supportive conditions whereas p52 was required in anchorage resistant conditions. Western blots confirm diminished IKKε expression and enhanced p52 processing in anchorage resistant conditions relative to anchorage supportive conditions. In this model, IKKε and MEK cooperate to support growth of cancer cells in the attached, anchored environment, whereas p52 is required for growth in unattached 3-D environment. These studies reveal novel information about the role of IKKε in TNBC and highlight the adaptability of NF-κB signaling in maintaining cancer cell survival under different growth conditions. Current studies are underway to clarify the mechanism of IKKε regulation of p52. A better understanding of the diversity of NF-κB signaling may ultimately improve the development of novel therapeutic regimens for TNBC.
Citation Format: Carrie D. House, Valentina Grajales, Michelle Ozaki, Elizabeth Jordan, Helmae Wubneh, Danielle Kimble, Marianne Kim, Christina M. Annunziata. IKK-epsilon supports anchorage independent growth via alternative NF-kB signaling in triple-negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5470.