bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A07: Spontaneous canine mammary cancers: A much-needed model for human basal-like breast cancer and an ideal system to understand myoepithelial cells
Authors: Liu Deli , Xiong Huan , Ellis Angela E. , Northrup Nicole C. , Rodriguez Carlos O. , O'Regan Ruth M. , Dalton Stephen , Zhao Shaying 
Published: May 2016

Abstract
Spontaneous canine mammary cancer represents an excellent model of human breast cancer but is greatly understudied. To better utilize this valuable resource, we performed the first comprehensive characterization of the genome, transcriptome and epigenome of 12 canine mammary cancer cases, including 7 simple carcinomas and 4 complex carcinomas (1).
Simple carcinomas, which histologically match human breast carcinomas, harbor extensive genomic aberrations, many of which faithfully recapitulate key features of human breast cancer. Notably, these tumors closely cluster with human basal-like breast carcinomas from TCGA (2), but not with other intrinsic subtypes, in PAM50 classification with human breast carcinomas. Furthermore, these tumors match the basal-like cancer profile, including MYC amplification, PTEN deletion, BRCA1 mutation, etc. Our results indicate canine simple carcinomas could serve as a much-needed spontaneous cancer model of basal-like breast cancer by effectively bridging the gap between preclinical research and human trials, speeding up drug discovery for the worst subtype of breast cancer.
Canine complex carcinomas, characterized by proliferation of both luminal and myoepithelial cells (rare in human breast cancer), appear to lack genomic abnormalities. Instead, these tumors have ~35 chromatin-modification genes downregulated, and are abnormally enriched with active histone modification H4-acetylation while depleted with repressive histone modification H3K9me3. Our findings indicate that these tumors likely originate from epigenomic alterations instead of genomic lesions. Canine complex carcinomas offer an ideal system to study myoepithelial cells, the second major yet significantly understudied cell lineage of the mammary gland.
References:
1. Liu D, Xiong H, Ellis AE, Northrup NC, Rodriguez CO, Jr., O'Regan RM, et al. Molecular homology and difference between spontaneous canine mammary cancer and human breast cancer. Cancer research. 2014.
2. Cancer Genome Atlas N. Comprehensive molecular portraits of human breast tumours. Nature. 2012;490:61-70.
Citation Format: Deli Liu, Huan Xiong, Angela E. Ellis, Nicole C. Northrup, Carlos O. Rodriguez Jr, Ruth M. O'Regan, Stephen Dalton, Shaying Zhao. Spontaneous canine mammary cancers: A much-needed model for human basal-like breast cancer and an ideal system to understand myoepithelial cells. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research; Oct 17-20, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(2_Suppl):Abstract nr A07.
Abstract A31: Integrative differential allelic expression analysis efficiently reveals the biology underlying risk to breast cancer
Authors: Xavier Joana , Russell Roslin , Almeida Bernardo P. , Rosli Nordiana , Rocha Catia , Samarajiwa Shamith , Chin Suet-Feung , Caldas Carlos , Ponder Bruce AJ , Maia Ana-Teresa 
Published: May 2016

Abstract
Breast cancer is the most common cancer affecting women in the developed world. However, the current knowledge of breast cancer genetic risk cannot explain as much as two-thirds of cases. While successful, GWAS have not: (1) contributed to explain the genetic causality of risk; (2) provided an indication of the biological mechanisms involved.
Based on our previous results demonstrating that cis-regulatory variation is involved in breast cancer risk, we have performed whole-genome differential allelic expression (DAE) analysis of sixty-four normal breast tissue samples. We integrated this genome-wide DAE map with published breast cancer GWAS risk loci according to chromosome location, and linkage disequilibrium between DAE SNPs and GWAS associated SNPs.
We found 15 loci (20%) displaying GWAS associated SNPs in strong linkage disequilibrium with SNPs displaying DAE. Potential regulatory SNPs in top two candidate loci are being currently mapped and functionally studied.
We are now integrating the DAE whole-genome map with unpublished GWAS data, to test the efficiency of this approach to help prioritise loci for further risk-association validation. The large overlap between GWAS and DAE data confirms the importance of cis-regulation in the biology of breast cancer risk and provides a new powerful tool to prioritise and functionally analyse risk loci identified through GWAS.
Citation Format: Joana Xavier, Roslin Russell, Bernardo P. Almeida, Nordiana Rosli, Catia Rocha, Shamith Samarajiwa, Suet-Feung Chin, Carlos Caldas, Bruce AJ Ponder, Ana-Teresa Maia. Integrative differential allelic expression analysis efficiently reveals the biology underlying risk to breast cancer. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research; Oct 17-20, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(2_Suppl):Abstract nr A31.
Abstract A34: BRCA1 and BRCA2 mutation spectrum across 5, 509 high-risk individuals identifies pathogenic variants associated with ethnicity, age of diagnosis, and type of cancer
Authors: Girgis Andrew H. , Wang Marina , Fine Alexa , Zakoor Kathleen-Rose , Khalouei Sam , Charames George , Lerner-Ellis Jordan 
Published: May 2016

Abstract
Hereditary Breast and Ovarian Cancer Sydrome (HBOC) accounts for approximately 5-10% of breast and ovarian cancer cases and germline mutations of the BRCA1 and BRCA2 genes confer substantially increased risk. However, the risk of developing cancer, the type of cancer and the associated age at diagnosis vary depending on the type of mutation carried and the individual's ethnic background and gender. Screening of BRCA1 and BRCA2 mutations was conducted on 5, 512 high-risk individuals with a prior probability of carrying a pathogenic mutation (&gt;10% chance) from the Advanced Molecular Diagnostics Laboratory (AMDL) (Mount Sinai Hospital, Toronto). Information on age, type of cancer diagnosed and age at diagnosis, ethnicity and family history were collected. Cumulative incidence competing risk and Fine-Gray proportional hazard regression analyses were generated to determine factors associated with earlier diagnosis of cancer. Among 5,029 women and 480 men who underwent testing, a total of 845 unique variants were identified of which, 289 (34.2%) are pathogenic. There were 603 female mutation carriers, of these, 303 were affected with breast or ovarian cancer (50%), 16 with another cancer (2.25%) and 284 were unaffected (47.1%). We also identified 20 different ethnic groups presenting with at least 3 unique variants. Six ethnic groups carried at least one variant associated with an earlier diagnosis of cancer and differential breast or ovarian cancer incidence. For instance, among the Ashkenazi Jewish cohort, the c.68_69del variant was associated with significantly earlier age at diagnosis for ovarian cancer incidence (Gray's test = 40.6; Fine-Gray HR = 1.12, 95% CI = 1.05 – 1.31). By screening a diverse cohort of high-risk individuals for BRCA1 and BRCA2 mutations, we identified pathogenic variants associated with an earlier age of diagnosis and differential incidence of breast or ovarian cancer among unique ethnic groups.
Citation Format: Andrew H. Girgis, Marina Wang, Alexa Fine Kathleen-Rose ZakoorSam Khalouei, George Charames, Jordan Lerner-Ellis. BRCA1 and BRCA2 mutation spectrum across 5, 509 high-risk individuals identifies pathogenic variants associated with ethnicity, age of diagnosis, and type of cancer. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research; Oct 17-20, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(2_Suppl):Abstract nr A34.
Abstract A44: Clinical significance of ESR1 mutations by cell-free DNA in recurrent/metastatic breast cancer
Authors: Takeshita Takashi , Yamamoto Yutaka , Yamamoto-Ibusuki Mutsuko , Inao Toko , Sueta Aiko , Fujiwara Saori , Iwase Hirotaka 
Published: May 2016

Abstract
Purpose: We aimed to develop a droplet digital Polymerase Chain Reaction (ddPCR)-based method for the sensitive detection of estrogen receptor (ER) α (ESR1) mutations of tumor tissues and the corresponding cell-free DNA (cfDNA) in recurrent/ metastatic breast cancer.
Experimental Design: We investigated a total of 325 tumor specimens (270 primary breast cancer specimens and 55 ER-positive recurrent/metastatic tumor specimens, in which 33 recurrent/ metastatic tumor specimens had the corresponding plasma). We investigated the quantification of rare ESR1 mutations, four representative types, Y537S, Y537N, Y537C, and D538G in 33 extracted genomic DNA (gDNA) and its corresponding cfDNA using ddPCR system that simultaneously performed thousands of PCRs on a nanoliter scale.
Results: A total of 33 (60 %) of 55 recurrent/ metastatic breast cancer specimens had the corresponding plasma which were evaluated for ESR1 mutations' analysis for cfDNA. We verified the correlation of each ESR1 mutation between cfDNA and tissue gDNA. Only ESR1 Y537C was correlated between cfDNA and tissue gDNA (r = 0.56, P = 0.0006). ESR1 Y537S in tissue gDNA were tend to be correlated Y537N in cfDNA (r = 0.35, P = 0.043). CEA (Carcinoembryonic antigen), which is one of the representative breast cancer tumor markers, was correlated with ESR1 Y537S in cfDNA (r = 0.74, P &lt; 0.0001) and tend to be correlated with Y537S in tissue gDNA (r = 0.36, P = 0.033) and D538G in cfDNA (r = 0.54, P = 0.0011). We also evaluated the correlation between the presence of ESR1 mutations and best overall response (BOR) to post-endocrine therapy. BOR to post-endocrine therapy was 25 stable disease (SD) and 8 progressive disease (PD) in 33 patients. Using each selected cut-off, a total of 4 (50%) of 8 PD patients had ESR1 cfDNA mutations as follow: each patient had Y537S, Y537N, D538G, and double mutations (Y537S and D538G). The presence of ESR1 cfDNA mutations was much higher in PD group, compared with SD group (P = 0.0073)
Conclusions: We demonstrated the sensitive detection and accurate quantification of low frequency ESR1 mutations in 33 tumor tissues and the corresponding cell-free DNA (cfDNA) using ddPCR assay in recurrent/ metastatic breast cancer. Our results highlight that ESR1 mutations may be of clinical relevance for metastatic breast cancer patient.
Citation Format: Takashi Takeshita, Yutaka Yamamoto, Mutsuko Yamamoto-Ibusuki, Toko Inao, Aiko Sueta, Saori Fujiwara, Hirotaka Iwase. Clinical significance of ESR1 mutations by cell-free DNA in recurrent/metastatic breast cancer. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research; Oct 17-20, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(2_Suppl):Abstract nr A44.
Abstract A54: Met and its ligand HGF predict radiotherapy response in premenopausal breast cancer patients
Authors: Veenstra Cynthia , Pérez-Tenorio Gizeh , Nordensköljd Bo , Fornander Tommy , Stål Olle 
Published: May 2016

Abstract
Post-operative radiotherapy effectively decreases the risk for loco-regional recurrence in breast cancer. However, some patients display signs of radioresistance. There are few biomarkers used in the clinic today to predict response to radiotherapy, and patients continue to receive unnecessary treatment. Studies propose a role for the receptor tyrosine kinase Met and its ligand HGF in radioresistance. Therefore, it was aimed in this study to determine MET and HGF copy numbers, Met and HGF expression, and phosphorylated Met expression in breast cancers to elucidate Met and HGF's role in radiotherapy response. MET and HGF copy numbers were determined by digital droplet PCR in 205 pre-menopausal patients, randomized to receive either radio- or chemotherapy. Immunohistochemical staining of Met, phosphorylated Met, and HGF could be performed on 228 tumor tissue samples in this cohort. Increased MET and HGF copy numbers, more than two copies, were detected in 33% and 21% of the tumors, respectively. MET and HGF amplification, more than three copies, was detected in 8% and 7% of the tumors, respectively. Interestingly, patients with tumours with MET amplification tended to relapse at a higher rate than patients without amplification. This was more prominent in patients with triple-negative breast cancer, where both MET amplification and increased copy number were correlated with a shorter recurrence-free survival. High stromal HGF expression, but not HGF copy number, was also shown to be correlated with shorter survival. Both high cytoplasmic phosphorylated Met and high cytoplasmic HGF predicted better response to radiotherapy, compared with low expression. Similar results were seen for MET and HGF increased copy number. A tendency of opposite results were obtained with total membranous Met and stromal HGF. Patients with tumors expressing low levels of these proteins had more benefit from radiotherapy. This suggests that MET and HGF copy gain is not enough for a favorable radiotherapy response, the status of the resulting proteins is additionally of importance.
Citation Format: Cynthia Veenstra, Gizeh Pérez-Tenorio, Bo Nordensköljd, Tommy Fornander, Olle Stål. Met and its ligand HGF predict radiotherapy response in premenopausal breast cancer patients. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research; Oct 17-20, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(2_Suppl):Abstract nr A54.
Abstract B40: Transcription factor Snail mediates EMT by altering vesicular trafficking protein Rab25
Authors: Mitra Shreya , Federico Lorenzo , Mills Gordon B. 
Published: May 2016

Abstract
Epithelial cells maintain intercellular communication directly by cell-cell, cell-ECM interaction and indirectly by paracrine secretion of extracellular messengers either as free molecules or via exosomes. The vesicular trafficking machinery is an integral part of such communication, paralleling digital cables that transmit the information bytes to the correct hub. During the process of EMT, derailing of the trafficking machinery leads to a systemic breakdown of intra and inter-cellular communication pathways. The purpose of the current study is to elucidate the functional role of Rab25, a key member of the vesicular trafficking machinery in mediating EMT-MET processes during breast cancer progression.
Aberrant endocytosis is a new hallmark of cancer. Rab GTPases are the primary regulators of endocytosis. Many members of this large family are implicated in a wide array of cancers including breast cancer. Specifically, Rab25, a GTPase associated with the recycling endosomes, is deregulated in most epithelial cancers. Rab25 appears to function both as a tumor suppressor and an oncogene in a context dependent manner.
We found that Rab25 is lost in Claudin Low tumors as well as in representative cell lines such as the MDA MB231. Rab25 is a robust and sufficient marker of breast cancers and cell lines with an increased EMT signature. Additionally, in immortalized human mammary epithelial cell lines (HMLE), induction of EMT by overexpression of Snail1 completely obliterates Rab25 protein. Exogenous re-expression of Rab25 dramatically rescues these cells from Snail driven invasion through Matrigel. However this Snail dependent regulation is unique only to TN and Claudin Low tumors and does not hold true for hormone receptor positive tumors. Further, analysis of RNA Seq data from a MMTV mouse model showed that tumors enriched in EMT markers and by corollary with low CDH and claudins, also lost Rab25 transcripts.
Snail mediated transcriptional repression targets recycling endosomal proteins such as Rab25 to decrease delivery of junction proteins that facilitate cell-cell communication to the appropriate compartment. In parallel, it potentially enhances paracrine regulation by secreted exosomes. Overall, our study shows presence and absence of Rab25 markedly alters cell-cell communication, which is essential for maintenance of epithelial features of cells. Rab25 could be a prognostic marker and a therapeutic target for a subset of patients with increased risk of metastatic disease.
Citation Format: Shreya Mitra, Lorenzo Federico, Gordon B. Mills. Transcription factor Snail mediates EMT by altering vesicular trafficking protein Rab25. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research; Oct 17-20, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(2_Suppl):Abstract nr B40.
Abstract IA20: Genomics of a STAT1 knockout mouse model of human ER+ breast cancer
Authors: Mardis Elaine , Griffith Obi L. , Szeman Ruby Chan , Griffith Malachi , Krysiak Kilannin , Skidmore Zachary , Hundal Jasreet , Allen Julie A. , Cora Arthur , Miceli Alexander P. , Schmidt Heather , Trani Lee , Kanchi Krishna-Latha , Miller Christopher A. , Larson David E. , Fulton Robert S. , Wilson Richard K. , Schreiber Robert D. 
Published: May 2016

Abstract
Estrogen receptor alpha positive luminal breast cancers are the most frequent subtype of breast cancer. Previous work has established that Stat1-/- mouse mammary tumor model recapitulates signaling, expression and phenotypic alterations observed in this subtype of human breast cancers. To identify transforming events that contribute to tumorigenesis, we performed whole genome sequencing of 22 Stat1-/- primary mammary tumors and cell lines. We discovered a novel hotspot of somatic mutations in 100% of tumors that resulted in a truncated form of the prolactin receptor (Prlr). Targeted sequence analysis identified similar mutations in 77.8% of ductal carcinoma in situ. Co-expression of truncated and full-length Prlr in normal cells led to activation of oncogenic Stat3 and Stat5 as well as cellular transformation. In conclusion, truncating mutations of Prlr drive tumor development in a model of human ERa+ breast cancer and should be considered as novel antitumor targets.
Citation Format: Elaine Mardis, Obi L. Griffith, Ruby Chan Szeman, Malachi Griffith, Kilannin Krysiak, Zachary Skidmore, Jasreet Hundal, Julie A. Allen, Arthur Cora, Alexander P. Miceli, Heather Schmidt, Lee Trani, Krishna-Latha Kanchi, Christopher A. Miller, David E. Larson, Robert S. Fulton, Richard K. Wilson, Robert D. Schreiber. Genomics of a STAT1 knockout mouse model of human ER+ breast cancer. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research; Oct 17-20, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(2_Suppl):Abstract nr IA20.
Abstract IA30: Insights into metabolome of breast cancer
Authors: Sreekumar Arun 
Published: May 2016

Abstract
Metabolomics describes the science of quantifying the levels of metabolites (e.g., small molecules &lt;1kDa) that are the byproducts of cellular metabolism. Unlike genomics, transcriptomics and proteomics, metabolomic analysis involves reduced complexity because of fewer endpoints and allows the assay of composite downstream outputs from complex interconnected cellular processes. These aspects both facilitate bioinformatic analysis and may accentuate subtle upstream gene/protein level alterations. Comparisons of metabolomic profiles from tissues or bodily fluids from one diseased state to another permits the identification of pathways and processes that may drive the phenotype in question.
Our recent profiling of 200 metabolites using mass spectrometry in benign and malignant breast tissues from ancestry-verified AA and EA women, revealed altered levels of specific metabolites (or associated pathways) in AA TN BCa compared to EA TN tumors. Key among them was elevated levels of 2- hydroxyglutaric acid (2-HG), a mitochondrial onco-metabolite that was elevated in a subset of predominantly AA TN BCa with poor clinical outcome. Tumors with high 2-HG had a distinct methylation signature exhibiting activation of the MYC oncogene and were associated with elevated levels of fatty acids and lipids. Taken together, we expect these studies help understand the disparity in the clinical behavior of TN BCa. Further, we expect biochemical profiles to be useful in stratifying tumors for various pathway-based treatment regimens.
Citation Format: Arun Sreekumar. Insights into metabolome of breast cancer. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research; Oct 17-20, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(2_Suppl):Abstract nr IA30.
Abstract PR06: Modeling the tumor microenvironment to identify novel loss of function mutations in breast cancer progression
Authors: Peck Barrie , Maguire Sarah , Morrison Eamonn , Wai Patty , Natrajan Rachael 
Published: May 2016

Abstract
Recent next generation sequencing studies have comprehensively mapped the genetic landscape of breast cancer and revealed that only a small number of genes are recurrently mutated in more than 10% of unselected tumors (i.e. TP53, PIK3CA and GATA3), and that the vast majority of recurrent mutations occur at low frequencies. Although some have been shown to be drivers (i.e. confer a selective advantage), such as oncogenic ERBB2 mutations, there is a myriad of significantly altered lower frequency mutations whose functional impact is unknown.
We utilized a functional genomics approach silencing the 200 most frequently mutated genes in breast cancer in 3D spheroid cultures that more accurately recapitulate in vivo like conditions, using the MCF10A progression series cell line panel to identify novel loss of function mutations that affect breast cancer progression from non-malignant to highly invasive disease. Genes whose silencing significantly altered spheroid growth were integrated with comprehensive copy number and mutation data in order to analyze the impact of these genes in concert with additional driver alterations in genes such as TP53 and PIK3CA mutations.
We identified 11 genes whose silencing with siRNA had a significant effect on growth in two or more cell lines in 3D, including FMN2, FOXA1, NIPBL and CREBBP. Silencing of FMN2 increased spheroid growth in the invasive cell lines only, suggesting loss of function mutations are a later event in breast cancer progression. A second targeted validation screen showed that silencing of a cohort of these genes had limited effect under traditional 2D culture conditions, for example, silencing of maltase-glucoamylase (MGAM) resulted in increased growth in AT1 and DCIS.com cells in 3D while having no effect in 2D; an effect that was recapitulated by treating cells with an established MGAM inhibitor. Furthermore, loss of NIPBL significantly increased spheroid growth in cells harboring TP53 nuclear accumulation, and was significantly co-mutated in TP53 mutant primary tumors, suggestive of epistasis. Integrating genes that when silenced decreased spheroid growth with mutation status in the cell lines identified 3D specific oncogenic dependencies with PIK3CA and novel SZT2 mutations.
Using a functional genomic approach in 3D models we have identified recurrently mutated genes whose loss or gain of function contribute to breast cancer progression and furthermore may be epistatic or cooperate with established driver mutations in breast cancer.
Citation Format: Barrie Peck, Sarah Maguire, Eamonn Morrison, Patty Wai, Rachael Natrajan. Modeling the tumor microenvironment to identify novel loss of function mutations in breast cancer progression. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research; Oct 17-20, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(2_Suppl):Abstract nr PR06.