bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A63: Characterizing the role of ancestry-specific variants of the Duffy Antigen Receptor for Chemokines (DARC) gene in the breast tumor microenvironment
Authors: Martini Rachel N. , Jenkins Brittany D. , Davis Melissa B. 
Published: August 2018

Abstract
Chemokines play an important role in cancer, as they direct infiltrating immune cells and mediate angiogenesis, tumor progression, and direct metastasis to distal sites. This work focuses on an atypical chemokine receptor, named the Duffy Antigen Receptor for Chemokines (DARC). DARC is a nonsignaling receptor that can bind two structural classes of inflammatory chemokines, and mainly acts as a regulator of chemokine homeostasis by removing chemokines from circulation when expressed on red blood cells, or moving them from sites of inflammation into circulation to recruit appropriate immune cell types. The purpose of this study is to investigate how polymorphic variants of the DARC gene found across global populations influence ancestry-specific immune responses, and how these changes in the immune response influence the breast tumor microenvironment. A well-studied example of this is a variant restricted to recent decedents of sub-Saharan Africa, known as the Duffy-Null allele. This variant removes expression of DARC from red blood cells, causing those individuals carrying the Duffy-Null allele to lose the ability to sequester chemokines in circulation. In terms of immune response, Duffy-Null status is shown to be predictive of chronic low white blood cell counts observed in individuals of African descent. By using 1000 Genomes Project variant calling data, we have been able to identify additional gene variants restricted to varying global populations. Our initial study is focused on variants found in the regulatory region of the gene, as these variants will likely change how the DARC gene will be expressed. Preliminarily, using data from the Genotype-Tissue Expression project (GTEx), we have been able to show that our DARC gene variants are also tissue-specific expression quantitative trait loci, showing significant changes in tissue-specific gene expression in association with our variants of interest. By studying these variants with panels of human breast cell lines, ancestry-specific cell lines, and human tissue, we will be able to identify these ancestry-specific changes in immune response, and resulting breast tumor microenvironment.
Citation Format: Rachel N. Martini, Brittany D. Jenkins, Melissa B. Davis. Characterizing the role of ancestry-specific variants of the Duffy Antigen Receptor for Chemokines (DARC) gene in the breast tumor microenvironment [abstract]. In: Proceedings of the AACR Special Conference: Advances in Breast Cancer Research; 2017 Oct 7-10; Hollywood, CA. Philadelphia (PA): AACR; Mol Cancer Res 2018;16(8_Suppl):Abstract nr A63.
Abstract B04: Palbociclib-based combinatorial drug screening in ER-positive cell lines identifies efficacious single agents and novel combinations with synergistic interactions
Authors: Smith Rebecca , Liby Tiera , Gray Joe , Korkola James 
Published: August 2018

Abstract
Estrogen receptor (ER)-positive breast cancer is associated with a good prognosis, but when ER+ breast tumors progress, treatment options are limited. The combination of the CDK inhibitor palbociclib plus the ER degrader fulvestrant was recently approved for patients who have recurrences of ER+ disease. However, durable responses are not typically seen with this combination, and patients eventually progress on therapy. We sought to test other drug combinations using palbociclib as the backbone of therapy. We tested 13 different FDA-approved drugs in combination with palbocilib in a panel of 7 ER+ breast cancer cell lines (600MPE, MDAMB134vii, MDAMB415, ZR75-1, ZR75B, and MCF7). Molecularly, all lines were characterized by amplification of the CCND1 region, high levels of expression of ER, and low RNA expression of EGFR. CAMA1 showed general resistance to the drugs used, never reaching a GR50 (growth rate inhibition of 50%) even at the highest dose tested with palbociclib. CAMA1 was also resistant to the majority of the other 13 drugs, with the exception of panobinostat, vorinostat, and everolimus. Across the entire cell line set, these three compounds were the most effective as single agents. For example, the HDAC inhibitors panobinostat and vorinostat had low nanomolar GR50 values in 7/7 and 4/7 cell lines, respectively. However, significant antagonism was observed between both HDAC inhibitors and palbociclib in MCF7, ZR75B, and ZR75-1, indicating that combining these agents may not be clinically effective. Everolimus plus palbociclib and trametinib plus palbociclib combinations were significantly synergistic in 3/7 cell lines (600MPE, ZR75B, and MCF7 in both cases). Interestingly, CAMA1 and MDAMB134 never showed any evidence of synergistic interactions with any of the combinations tested, suggesting that they may be a distinct subset of ER+ breast cancers. This study indicates that HDAC inhibitors may be effective for treating ER+ tumors that have progressed on antiestrogen therapy, and that combinations of palbociclib plus everolimus or trametinib may also have efficacy.
Citation Format: Rebecca Smith, Tiera Liby, Joe Gray, James Korkola. Palbociclib-based combinatorial drug screening in ER-positive cell lines identifies efficacious single agents and novel combinations with synergistic interactions [abstract]. In: Proceedings of the AACR Special Conference: Advances in Breast Cancer Research; 2017 Oct 7-10; Hollywood, CA. Philadelphia (PA): AACR; Mol Cancer Res 2018;16(8_Suppl):Abstract nr B04.
Abstract B05: Pathologic complete response is an independent prognostic factor for locoregional recurrence in locally advanced breast cancer patients after neoadjuvant chemotherapy
Authors: Chou Hsu-Huan , Chen Shin-Che 
Published: August 2018

Abstract
Background: Neoadjuvant chemotherapy (NAC) has been the standard approach for downstaging in locally advanced breast cancer and can improve breast conservation rates. Pathologic complete response (pCR) after NAC has been reported to have favorable long-term outcome. However, there is still high locoregional recurrence (LRR) rate after NAC. The aim of this study is to analyze the relationship of pCR and LRR.
Method: A retrospective study was analyzed from 2002 to 2011, and a total of 263 invasive breast cancer patients had NAC and, following mastectomy or breast conserving surgery (BCS) at Linkou Chang Gung Memorial Hospital, were enrolled. Concurrent weekly epirubicin and docetaxel was standard NAC regimen and adjuvant therapy including hormone therapy, radiotherapy, and target therapy was started postoperatively according to the pathologic characters.
Result: The median age was 48 years old (range 18-75). The mean tumor size at diagnosis was 6.0 cm (range 2.0-22.0). The median follow-up time was 54.6 months (range 9.2-126.9). After neoadjuvant chemotherapy, 200 (76%) patients underwent mastectomy and 63 (24%) patients underwent BCS. 29 (11%) patients achieved pCR in this study. In univariate analysis, age&lt;50, negative ER, negative PR, positive HER2, luminal B (HER2 positive) and HER2 overexpression, triple-negative subtype were factors to predict pCR. In multivariate analysis, age &lt;50, luminal B (HER2 positive), HER2 overexpression, and triple-negative subtype were factors to predict pCR. No patients in pCR group developed LRR compared with 31 (13.2%) patients with LRR in non-pCR group. In multivariate analysis, pCR and age &lt;50 were independent prognostic factors for LRR.
Conclusion: Our findings suggested that pCR and younger age are independent prognostic factors for LRR in breast cancer patients after NAC with concurrent eprubicin and docetaxel.
Citation Format: Hsu-Huan Chou, Shin-Che Chen. Pathologic complete response is an independent prognostic factor for locoregional recurrence in locally advanced breast cancer patients after neoadjuvant chemotherapy [abstract]. In: Proceedings of the AACR Special Conference: Advances in Breast Cancer Research; 2017 Oct 7-10; Hollywood, CA. Philadelphia (PA): AACR; Mol Cancer Res 2018;16(8_Suppl):Abstract nr B05.
Abstract B11: HDAC6 as a therapeutic target in human breast cancer
Authors: Craig Justin M. , Schauwecker Suzanne M. , Clevenger Charles V. 
Published: August 2018

Abstract
Stat5 is a transcription factor utilized by several cytokine/hormone receptor signaling pathways that promotes transcription of genes associated with proliferation, differentiation, and survival of cancer cells. However, there are currently no clinically approved therapies that target Stat5, despite ample evidence that it contributes to breast cancer pathogenesis. Previous research in our lab has shown that the high mobility group nucleosome binding domain 2 (HGMN2) protein serves as a Stat5 co-activator. The activity of HMGN2 has been previously shown to be regulated by acetylation. Here, we show that deacetylation of HMGN2 on lysine residue K2 by histone deacetylase 6 (HDAC6) promotes Stat5-mediated transcription and breast cancer growth. Conversely, in vitro HDAC6 inhibition by pharmacologic and knockdown approaches enhanced HMGN2 acetylation with a concomitant reduction of in vitro Stat5-mediated signaling and global gene expression, and breast cancer growth. These data, combined with global in silico ChIP-Seq analysis, indicate that HDAC6 serves as a regulator of the pioneer function of HMGN2 for Stat5 transcriptional function. In vitro and in vivo treatment of traditional and patient-derived xenograft models with HDAC6 inhibitors resulted in a highly significant reduction of tumor growth. Translationally, it was also found that high levels of acetylated K2 were present in normal human breast tissue, which was lost in primary breast cancers and lymph node metastases. This suggests that blockade of HMGN2 deacetylation as described above is a novel treatment for breast cancer, given that existing HDAC6 inhibitors have a favorable toxicity profile in phase I trials of other tumor types. Altogether, these results reveal a novel mechanism through which HDAC6 regulates the transcription of Stat5 target genes and demonstrates the utility of HDAC6 inhibition as a potential breast cancer therapeutic.
Citation Format: Justin M. Craig, Suzanne M. Schauwecker, Charles V. Clevenger. HDAC6 as a therapeutic target in human breast cancer [abstract]. In: Proceedings of the AACR Special Conference: Advances in Breast Cancer Research; 2017 Oct 7-10; Hollywood, CA. Philadelphia (PA): AACR; Mol Cancer Res 2018;16(8_Suppl):Abstract nr B11.
Abstract B54: Investigating semaphorin 7a in hormone receptor-positive breast cancer progression
Authors: Crump Lyndsey , Elder Alan , Tarullo Sarah , Franz Paris , Lyons Traci 
Published: August 2018

Abstract
While antiestrogen-based treatments are initially effective for hormone receptor-positive (HR+) breast cancer, these tumors often recur, metastasize, and lose responsiveness to endocrine therapies, emphasizing the need for additional therapeutic targets in HR+ disease. We observe that semaphorin 7a (SEMA7A) expression in HR+ patients in the METABRIC dataset confers significantly decreased survival rates by Kaplan-Meier analysis. Thus, we hypothesize that SEMA7A is a potential biomarker for aggressive disease and/or a novel therapeutic target for recurrent HR+ breast cancer. Utilizing multiple 2D and 3D in vitro approaches with human and mouse HR+ tumor cells, we show that shRNA-mediated knockdown (KD) of SEMA7A results in cell growth defects and reduced invasive potential. Loss of SEMA7A also increases apoptosis in attached and forced suspension culture conditions. Finally, we demonstrate that expression of SEMA7A is regulated by the ovarian hormones estrogen and progesterone in a receptor-dependent mechanism. However, we also observe increased expression of SEMA7A with stabilization of HIF1α, suggesting its expression may be context dependent. Overall, these data support SEMA7A as an important driver of multiple hallmarks of cancer in HR+ breast cancer, including cell growth, invasion, and resisting death. As SEMA7A expression is low in normal breast cells, it may be a novel therapeutic target with low toxic side effects.
Citation Format: Lyndsey Crump, Alan Elder, Sarah Tarullo, Paris Franz, Traci Lyons. Investigating semaphorin 7a in hormone receptor-positive breast cancer progression [abstract]. In: Proceedings of the AACR Special Conference: Advances in Breast Cancer Research; 2017 Oct 7-10; Hollywood, CA. Philadelphia (PA): AACR; Mol Cancer Res 2018;16(8_Suppl):Abstract nr B54.
Abstract B55: Investigating the role of semaphorin 7a in triple-negative breast cancer cell invasion
Authors: Tarullo Sarah Elizabeth , Elder Alan , Hill Ryan , Hansen Kirk , Lyons Traci 
Published: August 2018

Abstract
Despite new targeted therapies and improved screening, breast cancer is the second leading cause of cancer-related death of women in the United States. This emphasizes the need to better understand the molecular pathways contributing to breast cancer progression and metastasis and the need for identification of novel therapeutic targets. This is especially true for triple-negative breast cancers (TNBCs), which in comparison to hormone receptor-positive (ER+/PR+) and HER2+ subtypes lack a targeted therapy. Without targeted therapy TNBC patients have limited options for treatment, resulting in decreased overall survival. Our lab identified semaphorin 7a (SEMA7A) as a novel protein that promotes TNBC progression. SEMA7A is a member of the semaphorin family, a group of proteins originally described for their developmental roles in axon guidance. SEMA7A is a unique member of the semaphorin family as it is the only GPI-linked semaphorin and can be shed into the extracellular space. Since breast cancer patients mainly die from metastatic disease, we aim to uncover the role of SEMA7A in TNBC cell invasion and metastasis. To study the role SEMA7A may have in promoting cellular invasion, we utilized an shRNA-mediated knockdown of SEMA7A in human TNBC cell lines. Our results show that SEMA7A plays an important role in many steps of the metastatic cascade, with shSEMA7A cells showing increased cell death in both attached and force suspension conditions (anoikis), reduced mesenchymal phenotypes, and less invasion in 3D matrices. We also observed decreased growth and invasion of shSEMA7A tumors in vivo and decreased synthesis of fibronectin and matrix-metalloproteinase 2 ex vivo from shSEMA7A tumors. Taken together, these results show that SEMA7A is a critical molecule for cellular invasion by modulating not only intrinsic cellular pathways, but also the tumor microenvironment.
Citation Format: Sarah Elizabeth Tarullo, Alan Elder, Ryan Hill, Kirk Hansen, Traci Lyons. Investigating the role of semaphorin 7a in triple-negative breast cancer cell invasion [abstract]. In: Proceedings of the AACR Special Conference: Advances in Breast Cancer Research; 2017 Oct 7-10; Hollywood, CA. Philadelphia (PA): AACR; Mol Cancer Res 2018;16(8_Suppl):Abstract nr B55.
Abstract B67: The DLK1-DIO3 imprinted region regulates long-term proliferation in normal and malignant breast epithelium
Authors: Zabala Maider , Lobo Neethan A. , Seoane Jose A. , Stelzer Yonatan , Luong An V. , Isobe Taichi , Zarnegar Mark A. , Watanabe Nicholas , Antoñana Sonia , Lam Jessica , Qian Dalong , Sikandar Shaheen S. , Kuo Angera H. , Heitink Luuk S. , Shimono Yohei , Scheeren Ferenc A. , Cai Shang , Hisamori Shigeo , Sahoo Debashis , Dirbas Frederick M. , Somlo George , Jaenisch Rudolf , Christina Curtis , Clarke Michael F. 
Published: August 2018

Abstract
DNA methylation changes are common in cancers, but their consequences are not fully understood. The DLK1-DIO3 locus, whose transcripts are controlled by the imprinted control region IG-DMR, is hypomethylated in 8% of breast cancer patients. Moreover, breast cancer patients with increased copy number of miR-127, an miR encoded in the DLK1-DIO3 locus, had worse disease-specific survival. IG-DMR reporter mice revealed that the elevated expression of miR-127 in immature normal and malignant mammary epithelial cells is controlled by allele-specific DNA methylation. Aberrant expression of miR-127 led to the de novo acquisition of long-term proliferation by normal and malignant mammary epithelial cells. Mechanistically, miR-127 suppresses translation of SETD8 and subsequent H4K20me1 deposition at LATS2, resulting in an effective activation of the Hippo target genes. Our results demonstrate that the DLK1-DIO3 region epigenetically regulates mammary stem cells, contributing to increased proliferative and tumorigenic capacity partially via regulation of the Hippo signaling pathway.
Citation Format: Maider Zabala, Neethan A. Lobo, Jose A. Seoane, Yonatan Stelzer, An V. Luong, Taichi Isobe, Mark A. Zarnegar, Nicholas Watanabe, Sonia Antoñana, Jessica Lam, Dalong Qian, Shaheen S. Sikandar, Angera H. Kuo, Luuk S. Heitink, Yohei Shimono, Ferenc A. Scheeren, Shang Cai, Shigeo Hisamori, Debashis Sahoo, Frederick M. Dirbas, George Somlo, Rudolf Jaenisch, Curtis Christina, Michael F. Clarke. The DLK1-DIO3 imprinted region regulates long-term proliferation in normal and malignant breast epithelium [abstract]. In: Proceedings of the AACR Special Conference: Advances in Breast Cancer Research; 2017 Oct 7-10; Hollywood, CA. Philadelphia (PA): AACR; Mol Cancer Res 2018;16(8_Suppl):Abstract nr B67.
Abstract IA02: Mapping stem and progenitor cells to decipher the origins of breast cancer
Authors: Fu Nai Yang , Nolan Emma , Vaillant Francois , Joyce Rachel , Lindeman Geoffrey , Visvader Jane 
Published: August 2018

Abstract
Breast cancer is a highly heterogeneous disease at both the molecular and pathologic levels. To understand this heterogeneity and the cells of origin of breast cancer, it is important to dissect the normal mammary epithelial hierarchy. Both transplantation and lineage tracing studies, a strategy for tracking stem and progenitor cell fate in situ, have been implemented to explore the contribution of stem and progenitor cells to postnatal mammary gland development and tissue homeostasis. The combination of lineage tracing with a novel three-dimensional imaging strategy, which enables visualization of large regions of intact tissue at cellular resolution, has provided insights into the normal differentiation hierarchy as well as potential cells of origin of breast cancer. In a further layer of investigation, we have applied single cell RNA-seq analysis to both mouse and human mammary tissue. This type of analysis has revealed unexpected heterogeneity among epithelial cells that reside in the normal mammary gland.
In the context of human tissue, the identification of cells of origin of cancer and deregulated genes/pathways in crucial target cell populations may enable earlier detection of malignancies and lead to preventive therapies for individuals at high risk of developing breast cancer. Towards this end, we recently showed that the RANK receptor marks a small subset of luminal progenitors and this subset is expanded in precancerous tissue from BRCA1 mutation carriers. In preclinical Brca1-deficient mouse models, inhibition of the RANK ligand (RANKL) prevented or delayed tumorigenesis. These data implicate blockade of the RANK-RANKL signaling axis as a promising breast cancer prevention strategy.
Citation Format: Nai Yang Fu, Emma Nolan, Francois Vaillant, Rachel Joyce, Geoffrey Lindeman, Jane Visvader. Mapping stem and progenitor cells to decipher the origins of breast cancer [abstract]. In: Proceedings of the AACR Special Conference: Advances in Breast Cancer Research; 2017 Oct 7-10; Hollywood, CA. Philadelphia (PA): AACR; Mol Cancer Res 2018;16(8_Suppl):Abstract nr IA02.
Abstract IA20: A coding region variant in the TP53 tumor-suppressor gene may underlie cancer disparities in African Americans
Authors: Murphy Maureen E. 
Published: August 2018

Abstract
In addition to being frequently mutated in sporadic cancer, the p53 tumor suppressor also contains several coding region variants that alter function and can contribute to increased cancer risk. We previously published that the Pro47Ser variant of p53 exists in approximately 1-2% of individuals of African descent, and that this variation prevents a key phosphorylation event on p53, and reduces the ability of this protein to induce cell death (1). We recently published a mouse model for this variant, and show that this mouse develops a striking incidence of sporadic cancer, predominantly hepatocellular cancer but also including cancers of the pancreas, stomach, and intestine. In a cohort of African American women with breast cancer, we found evidence for an association of Pro47Ser with pre-menopausal cancer incidence (HR 1.7, p&lt;0.025) (2). Mechanistically, we find that the Pro47Ser variant displays a very selective transcriptional defect compared to wild-type p53, for a subset of target genes involved in ferroptosis and metabolism (3). Metabolic studies on mouse and human cells, as well as our Pro47Ser mouse, indicate that there is a profound difference in metabolism, with cells and mice containing Pro47Ser showing a significant predilection for aerobic glycolysis instead of oxidative phosphorylation. Interestingly, this defect actually leads to an apparent increase in fitness in these mice. We recently conducted a drug screen to search for compounds that may be selectively efficacious in tumors containing the Pro47Ser variant; this analysis revealed several compounds with increased efficacy against Pro47Ser tumors, compared to identical tumors with wild-type p53 (4). Our combined data suggest that the Pro47Ser variant may underlie increased cancer risk in African Americans, and that we may be able to personalize therapy for individuals containing this variant.
1. Li X, Dumont P, Della Pietra A, Shetler C, Murphy ME. The codon 47 polymorphism in p53 is functionally significant. J Biol Chem 2005;280(25):24245-51. PubMed PMID: 15851479.
2. Murphy ME, Liu S, Yao S, et al. A functionally significant SNP in TP53 and breast cancer risk in African-American women. NPJ Breast Cancer 2017;3:5. PubMed Central PMCID: PMC5445618.
3. Jennis M, Kung CP, Basu S, et al. An African-specific polymorphism in the TP53 gene impairs p53 tumor suppressor function in a mouse model. Genes Dev 2016;30(8):918-30. PubMed Central PMCID: PMC4840298.
4. Basu S, Barnoud T, Kung CP, Reiss M, Murphy ME. The African-specific S47 polymorphism of p53 alters chemosensitivity. Cell Cycle 2016;15(19):2557-60. PubMed Central PMCID: PMC5053554.
Citation Format: Maureen E. Murphy. A coding region variant in the TP53 tumor-suppressor gene may underlie cancer disparities in African Americans [abstract]. In: Proceedings of the AACR Special Conference: Advances in Breast Cancer Research; 2017 Oct 7-10; Hollywood, CA. Philadelphia (PA): AACR; Mol Cancer Res 2018;16(8_Suppl):Abstract nr IA20.
Liverpool Merchants in 19th-Century Niger Delta
Authors: Wariboko Nimi 
Published: August 2018

Abstract
How does religion or worldview affect business practices and ethics? This tradition of inquiry goes back, at least, to Max Weber who, in the Protestant Ethic and the Spirit of Capitalism, explored the impact of theological suppositions on capitalist economic development. But the connection can also go the other way. So the focus of inquiry can become: How does business ethics or practices affect ethics in a given nation or corporation? This paper inquires into how the political and economic conditions created and sustained by nineteenth-century trading community in the Niger Delta influenced religious practices or ethics of Christian missionaries. This approach to mission study is necessary not only because we want to further understand the work of Christian missions and also to tease out the effect of business ethics on religious ethics, but also because Christian missionaries came to the Niger Delta in the nineteenth century behind foreign merchants.