bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A20: Decreased nuclear expression of the FRY protein identifies a subset of breast cancers with poor clinical outcomes
Authors: Zarbl Helmut , Graham Jessica C. , Takizawa Norio , Fang Mingzhu , Gong Zhihong , Estrella Brian , Ren Xuefeng 
Published: May 2016

Abstract
The goal of the present study was to determine if decreased nuclear expression of the human FRY protein can serve as a biomaker of breast cancer progression and outcomes. We previously identified the rat Fry gene as a putative mammary carcinoma susceptibility (Mcs) gene. We further demonstrated that FRY expression was decreased in several human breast cancer cell lines. Moreover, ectopic expression of wildtype Fry suppressed tumorigenicity of the triple negative MDA-MD-231 breast cancer cells in vitro and in vivo by promoting epithelial cell differentiation. To evaluate the contribution of altered FRY expression to the clinical progression of human breast cancer, we first compared FRY mRNA expression in &gt;4,800 clinically annotated human breast cancers using DNA microarray data from 19 distinct cohorts available from the Oncomine 3.0 Cancer Profiling Database. The analysis indicated that decreased FRY mRNA was significantly correlated with poorly differentiated tumor histopathology, increased Elston tumor grade, and triple negative status (loss of estrogen, progesterone and Her2 receptors). Using commercially available breast cancer tissue microarrays, we used semi-quantitative immunohistochemistry and quantitative image analysis to compare FRY protein expression in normal mammary tissue and tumors. The results indicated that loss of FRY expression was a frequent event during progression of mammary carcinomas. We therefore analyzed &gt;1200 clinically annotated breast cancers represented on tissue microarrays from commercial suppliers and the National Cancer Institute (NCI) Cancer Diagnosis Program, including the Breast Cancer Diagnosis and Progression panels. FRY protein expression was evaluated by immunohistochemical staining and was graded on a scale of 0 to 4 (0, +, ++, +++, ++++). The analysis indicated that decreased nuclear expression of the FRY protein was significantly correlated with poorly differentiated histopathologies, increasing Elston grade and loss of the estrogen receptor. Tumors with decreased FRY expression were also more likely to metastasize and were associated with decreased tumor-free survival. These findings indicated that loss of nuclear FRY expression identifies a subset of breast cancer with poor clinical outcomes, suggesting that FRY may serve as an early biomarker for breast cancer progression and prognosis.
Citation Format: Helmut Zarbl, Jessica C. Graham, Norio Takizawa, Mingzhu Fang, Zhihong Gong, Brian Estrella, Xuefeng Ren. Decreased nuclear expression of the FRY protein identifies a subset of breast cancers with poor clinical outcomes. [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 A20.
Abstract A40: ESR1 gene alterations in the metastatic breast cancer with resistance to aromatase inhibitor
Authors: Iwase Hirotaka , Takeshita Takashi , Yamamoto-Ibusuki Mutsuko , Inao Touko , sueta Aiko , Fujiwara Saori 
Published: May 2016

Abstract
Background: Estrogen receptor (ER) positive breast cancer can be treated by endocrine therapy; however a certain population of ER-positive patients becomes resistant to endocrine therapy after long-term estrogen deprivation treatment. ESR1 gene alterations, mutations, translocation and amplification, have been reported as one of the reasons.
Patients and Methods: We successfully obtained metastatic tissue samples from 30 patients with resistance to aromatase inhibitor (AI), and 7 patients with resistance to ethinylestradiol (EE2). ER and PgR expression by immunohistochemistry, and ESR1 gene amplification using FISH and copy number variation (CNV) by PCR, and ESR1 gene mutation including Y537N, Y537C, Y 537S and D538G by droplet digital PCR, were examined, in order to evaluate the endocrine responsiveness.
Results: High expression of ER (median; 90%) and low expression of PgR (median 5%) were seen in majority of the patients treated by AI. Signal enhancement of DNA-FISH (&gt; 2.0 fold) was seen in 2 (8%) of 25 patients, and signal gain (1.0&lt; ≤2.0 fold) was seen in 11 (44%) of 25 patients. The increasing of DNA-CNV of ESR1 gene was seen in 3 cases of the 25 examined cases. There was no relationship between DNA-FISH and CNV of ESR1. High frequent ESR1 mutations were seen in 7 (28%) at Y537N, 4 (16%) at Y537C, 11 (44%) at Y 537S, and 2 (8%) at D538G. Double mutation, Y537N/S, was seen in 6 (24%) patients, who tended to unresponsive to subsequent endocrine therapy. After EE2 treatment, ER expression was decreased and PgR expression was increased, but there was no relationship between EE2 treatment and ESR1 gene alteration.
Conclusion: In the patients with resistance to AI, high ER / low PgR expression was frequently seen, which was no correlation to ESR1 DNA-amplification. The long non-coding RNA in ESR1 gene locus might be related to this discrepancy (Tomita et al; Nat Commun. 2015). Furthermore, accumulation of ESR1 gene mutations tended to be related to endocrine unresponsiveness.
Citation Format: Hirotaka Iwase, Takashi Takeshita, Mutsuko Yamamoto-Ibusuki, Touko Inao, Aiko sueta, Saori Fujiwara. ESR1 gene alterations in the metastatic breast cancer with resistance to aromatase inhibitor. [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 A40.
Abstract A59: Prognostic relevance of PTEN and TP53 deletion in breast cancer
Authors: Kluth Martina , Lebeau Anette , Witzel Isabell , Mahner Sven , Woelber Linn , Geist Stefan , Paluchowski Peter , Wilke Christian , Heilenkoetter Uwe , Mueller Volkmar , Simon Ronald , Sauter Guido , Terracciano Luigi , Krech Rainer , Assen Albert von der , Burandt Eike , Lebok Patrick 
Published: May 2016

Abstract
Inactivation of PTEN and TP53 have been suggested to promote unfavorable phenotypes in various cancers, including breast cancer. Chromosomal deletion is one well established mechanism for inactivation of these genes. In breast cancer, deletions of TP53 and PTEN are known to occur, but systematic analyses of its clinical relevance are lacking. We thus analyzed a tissue microarray (TMA) with 2,197 breast cancers by fluorescence in-situ hybridization (FISH) using specific probes against TP53 and PTEN in combination with respective centromere probes. We found, that TP53 deletion (29%/1026 cancers) occur more frequent in breast cancers than deletions of PTEN (19%/1,239 cancers). The frequency of PTEN deletion varied between histological subtypes with highest deletion rate in medullary cancers (18 of 39, 46%) and lowest deletion rate in mucinous cancers (1 of 28; 3%; p&lt;0.0001) for mucinous vs. medullary). PTEN deletions were significantly linked to various unfavorable tumor features, including advanced tumor stage (p=0.0054), high-grade (p&lt;0.0001), high tumor cell proliferation (Ki67 Labeling Index; p&lt;0.0001), and shortened overall survival (p=0.0090). Deletions of TP53 were significantly linked to high-grade (p&lt;0.0001) and high tumor cell proliferation (p=0,0193) but unrelated to histological subtypes, tumor stage, nodal status, and patient survival. Deletion of PTEN and TP53 were unrelated to each other (p=0.6469). Combined analysis of PTEN and TP53 deletions showed that TP53 deletion had no additional effect on patient prognosis in cancers with or without PTEN deletion. In conclusion, our data support a role of PTEN and TP53 deletions in breast cancer. However, only PTEN deletion is inked to aggressive tumor behavior, while TP53 deletion has no prognostic relevance in breast cancer.
Citation Format: Martina Kluth, Anette Lebeau, Isabell Witzel, Sven Mahner, Linn Woelber, Stefan Geist, Peter Paluchowski, Christian Wilke, Uwe Heilenkoetter, Volkmar Mueller, Ronald Simon, Guido Sauter, Luigi Terracciano, Rainer Krech, Albert von der Assen, Eike Burandt, Patrick Lebok. Prognostic relevance of PTEN and TP53 deletion in 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 A59.
Abstract A61: Cell cycle regulated centrosome orientation during directed migration requires Aurora Kinase A
Authors: Chu Tony LH , Won Jennifer , Nemirovsky Oksana , Fotovati Abbas , Nielsen Torsten , Maxwell Christopher A 
Published: May 2016

Abstract
Cell cycle progression and the acquisition of a migratory phenotype are hallmarks of human carcinoma cells. Here we report a strong correlation between cell cycle progression into G2 phase and an increased migratory velocity for non-malignant, immortalized mammary epithelia nMuMG (Mus musculus mammary gland) cells, or malignant cervical carcinoma HeLa cells, expressing a fluorescent ubiquitin cell cycle indicator and quantified in wound closure assays with high content multi-parameter live cell imaging. Cells at the wound edge exhibited elevated microtubule nucleation capacity at centrosomes, and a reduction of this capacity through inhibition of aurora kinase A was sufficient to impair migration velocity without affecting cell cycle dynamics. In migratory cells, active aurora kinase A at the centrosome correlated with nucleation capacity. In clinically annotated mammary carcinoma tissues (n=3,992), aurora kinase A activity, as assessed by the abundance of phosphorylated-RHAMM (Receptor for Hyaluronan Mediated Motility) was a significant predictor of breast cancer specific survival and relapse free survival in patients with estrogen receptor negative breast cancer (n= 941), triple negative phenotype breast cancer (n= 538) or basal-like subtype breast cancer (n= 293), but not in those patients with estrogen receptor positive breast cancer (n= 2,218). In estrogen receptor negative tumors from patients that received no adjuvant systemic therapy (n= 453), the levels of phosphorylated-RHAMM associated with the presence of distal nodal metastasis and predicted a subset of patients at high risk of recurrence. Together, these data identify aurora kinase A activity as a regulatory pathway that intersects cell cycle progression and cell migration, with potential to influence the metastasis of estrogen receptor negative breast tumors and patient survival.
Citation Format: Tony LH Chu, Jennifer Won, Oksana Nemirovsky, Abbas Fotovati, Torsten Nielsen, Christopher A Maxwell. Cell cycle regulated centrosome orientation during directed migration requires Aurora Kinase A. [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 A61.
Abstract A72: The E3-ligase E6AP represses breast cancer metastasis through regulation of ECT2-Rho-GTPases signaling
Authors: Mansour Mariam , Haupt Sue , Chan Ai-Leen , Godde Nathan , Rizzitelli Alexandra , Loi Sherene , Caramia Franco , Deb Siddartha , Takano Elena A. , Bishton Mark , Johnstone Cameron , Levav-Cohen Yarra , Jiang Yong-Hui , Yap Alpha S. , Fox Stephen , Bernard Ora , Anderson Robin , Haupt Ygal 
Published: May 2016

Abstract
Metastatic disease is the major cause of breast cancer related death and despite many advances, current therapies are rarely curative. Tumor cell migration and invasion require actin cytoskeletal reorganisation, to endow cells with capacity to disseminate and initiate the formation of secondary tumors. However, it is still unclear how these migratory cells colonise distant tissues to form macrometastases. The E6-associated protein, E6AP, acts both as an E3 ubiquitin-protein ligase and as a coactivator of steroid hormone receptors. We report that E6AP suppresses breast cancer invasiveness, colonisation and metastasis in mice and in breast cancer patients, loss of E6AP associates with poor prognosis, particularly for with basal breast cancer. E6AP regulates actin cytoskeletal remodelling via regulation of Rho-GTPases, acting as a negative regulator of ECT2, a GEF required for activation of Rho-GTPases. E6AP promotes ubiquitination and proteasomal degradation of ECT2 for which high expression predicts poor prognosis in breast cancer patients. We conclude that E6AP suppresses breast cancer metastasis by regulating actin cytoskeleton remodelling through the control of ECT2 and Rho-GTPase activity. These findings establish E6AP as a novel suppressor of metastasis and provide a compelling rationale for inhibition of ECT2 as a therapeutic approach for patients with metastatic breast cancer.
Note: This abstract was not presented at the conference.
Citation Format: Mariam Mansour, Sue Haupt, Ai-Leen Chan, Nathan Godde, Alexandra Rizzitelli, Sherene Loi, Franco Caramia, Siddartha Deb, Elena A. Takano, Mark Bishton, Cameron Johnstone, Yarra Levav-Cohen, Yong-Hui Jiang, Alpha S. Yap, Stephen Fox, Ora Bernard, Robin Anderson, Ygal Haupt. The E3-ligase E6AP represses breast cancer metastasis through regulation of ECT2-Rho-GTPases signaling. [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 A72.
Abstract B11: A dual PI3K/mTOR inhibitor, BEZ235 blocks tumor-induced angiogenesis: Evidence for an effect on the tumor and endothelial compartment
Authors: De Pradip , Sun Yuliang , Carlson Jennifer H. , Lin Xiaoqian , Dey Nandini , Leyland-Jones Brian 
Published: May 2016

Abstract
Background: Tumor progression including HER2+ breast tumor, particularly in aggressive and malignant tumors, is associated with the angiogenesis. To investigate the effects of BEZ235 on angiogenesis, we evaluated its effects on the hypoxic stabilization or the PI3K-AKT-mTOR pathway-mediated synthesis of hypoxia-inducible factor -1α (HIF-1α) and tumor-induced angiogenesis. Methodology: Here we have studied the in vitro and in vivo effects of BEZ235 in HER2+/T-sensitive (BT474), HER2+/T-resistant (BT474HerR) and HER2+/PIK3CA (HCC1954 & UACC893) mutated models. We assessed in vitro activation status of the PI3K-AKT-mTOR signaling pathway following BEZ235 treatment in HER2+ BC cell lines. We next evaluated the impact of BEZ235 on hypoxia-induced or the PI3K-AKT-mTOR pathway ⊠mediated HIF1α stabilization/synthesis which is a master regulator of angiogenesis and also tumor-induced angiogenesis using xenograft models. Results: The results show that 1) BEZ235 inhibited downstream activation of the PI3K-AKT-mTOR signaling pathway effectors, p-AKT (Ser473, The308), p-P70S6K, p-S6RP and p-4EBP1, 2) unlike other pan-PI3Kinase inhibitor (e.g. LY294002, SF1126), BEZ235 has no effect on hypoxia-mediated stabilization of HIF1α however, heregulin-induced HIF1α synthesis which is an important angiogenic modulator in breast cancer cells, was significantly decreased following the treatment of BEZ235 in HER2+ and HER2+/PIK3CA mutated breast cancer cells, 3) interestingly, BEZ235 mediated abrogation of HIF1α synthesis is more pronounced than mTORC1 inhibition alone, 4) integrin-directed endothelial cell migration is one of the critical steps for tumor-induced angiogenesis. BEZ235 abrogates endothelial cells functions especially integrin-directed HUVEC cells migration on vitronectin (avb3/ avb5) and significantly abrogates endothelial cells tube formation on Matrigel and 5) furthermore, we evaluated the effects of BEZ235 on the capacity of HER2+ and HER2+/PIK3CA mutated breast tumor cells to recruit a blood supply in vivo during thrice weekly treatments with BEZ235. A microvessel density (MVD) in control versus BEZ235-treated tumors showed a significant decrease in MVD (CD31+) and also VEGFR immunostaining in BEZ235 treated tumors. Conclusion: Our data suggest that BEZ235 has potent antiangiogenic activity in three different xenograft models probably via mTOR-HIF1α-VEGF signaling axis.
Citation Format: Pradip De, Yuliang Sun, Jennifer H. Carlson, Xiaoqian Lin, Nandini Dey, Brian Leyland-Jones. A dual PI3K/mTOR inhibitor, BEZ235 blocks tumor-induced angiogenesis: Evidence for an effect on the tumor and endothelial compartment. [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 B11.
Abstract B26: Identification of genes that predict response to paclitaxel in breast cancer using an in vivo genome-wide knockdown screen
Authors: Sultan Mohammad , Huynh Thomas Tan , Thomas Margaret Lois , Coyle Krysta Mila , Giacomantonio Carman A. , Marcato Paola 
Published: May 2016

Abstract
Treatment decisions for breast cancer are based upon stage, tumor grade and hormone receptor status, and can include surgical resection, hormone receptor antagonists, radiation, and chemotherapy (e.g. paclitaxel). Breast cancer treatment success depends upon avoidance of chemotherapy resistance (i.e. achieving complete response) and prevention of both over- and under-treatment. Increased understanding of the genes which cause resistance and sensitivity to currently used drugs would lead to development of more effective therapeutic strategies that are specifically tailored to patient groups based on molecular profiling of their tumors (i.e. personalized medicine). Being able to identify the genes which when expressed in a tumor predict sensitivity or resistance to treatment prior to administration of paclitaxel would improve treatment efficacy and patient survival. We performed an in vivo shRNA genome-wide screen with MDA-MB-231 tumors treated with paclitaxel for the purpose of identifying genes which determine breast cancer response to paclitaxel. Completion of 6 replicates of the in vivo screen identified 26 putative paclitaxel sensitivity genes and 14 putative paclitaxel resistance genes (e.g. BCL6) for breast cancer. Screen-identified putative paclitaxel resistance were verified by individual knockdown clone generation and comparison of their sensitivity to paclitaxel-induced decreased cell proliferation, cell-cycle arrest, and apoptosis to a shRNA scramble control clone. Upon individual knockdown of the putative resistance genes (e.g. BCL6), MDA-MB-231 cells were more sensitive to paclitaxel and demonstrated increased apoptosis and decreased paclitaxel IC50 concentrations. Finally, expression of a preliminary gene signature generated from the screen-identified hits was tested for its ability to predict response to paclitaxel in two archived patient data sets. The preliminary gene signature predicted response to paclitaxel in the datasets with an accuracy ranging from 70 to 100%. Further confirmation experiments of the remaining potential resistance and sensitivity genes will help to generate a more robust genetic profile which can be used to identify candidate breast cancer patients who would most benefit from paclitaxel treatment as opposed to treatment with other drugs.
Citation Format: Mohammad Sultan, Thomas Tan Huynh, Margaret Lois Thomas, Krysta Mila Coyle, Carman A. Giacomantonio, Paola Marcato. Identification of genes that predict response to paclitaxel in breast cancer using an in vivo genome-wide knockdown screen. [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 B26.
Abstract B43: APOBEC3B upregulation by the PKC-NFκB pathway in breast cancer
Authors: Leonard Brandon , McCann Jennifer , Starrett Gabriel , Kosyakovsky Leah , Amy Molan , Burns Michael , McDougle Rebecca , Parker Peter , Brown William , Harris Reuben 
Published: May 2016

Abstract
Overexpression of the antiviral DNA cytosine deaminase APOBEC3B has been linked to somatic mutagenesis in breast and other cancer. Human papillomavirus (HPV) infection accounts for APOBEC3B upregulation in cervical and head/neck cancers. However, the responsible mechanisms are unclear for non-viral malignancies such as breast cancer. Here, we demonstrate APOBEC3B upregulation through the PKC-NFκB pathway. PKC activation by the diacylglycerol mimic PMA causes specific and dose-responsive increases in APOBEC3B mRNA, protein, and activity levels, which are strongly suppressed by PKC and NFκB inhibition. Induction correlates with RELB (but not RELA) recruitment to the endogenous APOBEC3B gene implicating non-canonical NFκB signaling. Relevance to tumors is supported by PKC inhibitor-mediated APOBEC3B downregulation in multiple breast cancer cell lines. These data establish the first mechanistic link between APOBEC3B and a common signal transduction pathway, suggesting that existing PKC-NFκB inhibitors could be repurposed to suppress cancer mutagenesis, dampen tumor evolution, and decrease the probability of adverse outcomes such as drug resistance and metastases.
Citation Format: Brandon Leonard, Jennifer McCann, Gabriel Starrett, Leah Kosyakovsky, Molan Amy, Michael Burns, Rebecca McDougle, Peter Parker, William Brown, Reuben Harris. APOBEC3B upregulation by the PKC-NFκB pathway in 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 B43.