bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract P5-04-03: Epithelial-mesenchymal transition is associated with in situ to invasive transition of basal-like breast cancer
Authors: Park SY , Choi Y , Kim EJ , Lee HE , Lee HJ , Kang E , Kim S-W 
Published: August 2014

Abstract
BACKGROUND: Epithelial-mesenchymal transition (EMT) is known to play an important role in breast cancer invasion and metastatic progression and to be associated with cancer stem cells and basal-like subtype. However, its role in the progression of in situ to invasive breast carcinoma is uncertain. To investigate this question, we evaluated the difference in the expression of EMT-related markers between pure ductal carcinoma in situ (DCIS) and invasive carcinomas according to molecular subtype.
METHODS: We performed immunohistochemical analyses of EMT-related markers [expression of vimentin, smooth muscle actin (SMA), osteonectin and N-cadherin, translocation of β-catenin and loss of E-cadherin] and breast cancer stem cell markers (CD44+/CD24−, ALDH1) in 320 invasive carcinomas and 179 pure DCIS of breast using tissue microarrays. We also analyzed 39 basal-like invasive cancers with adjacent DCIS component to determine the difference in the expression of EMT-related markers in the invasive and DICS component within individual cases.
RESULTS: In invasive carcinomas, vimentin, SMA and osteonectin were highly expressed in basal-like subtype. In addition, loss of E-cadherin and translocation of β-catenin were most frequently found in basal-like subtype. Furthermore, there were positive correlations between the expression of EMT-related markers and stem cell markers (CD44+/CD24- and ALDH1). However, there was no significant difference in the expression of EMT-related markers according to molecular subtype in pure DCIS. When comparing invasive carcinoma with pure DCIS, expression of EMT-related markers was significantly higher in invasive carcinoma than in pure DCIS. Subgroup analysis revealed higher expression of EMT-related markers in invasive carcinoma than in DCIS in basal-like subtype, but not in non-basal-like subtypes. Moreover, in 39 basal-like invasive cancers with adjacent DCIS, expression of mesenchymal markers was increased in invasive component compared to DCIS component.
CONCLUSIONS: Our study confirmed that EMT is an intrinsic characteristic of basal-like subtype and is associated with breast cancer with stem cell phenotype. However, increased expression of EMT-related markers in invasive carcinoma compared to pure DCIS, especially in basal-like subtype, and in the invasive component of basal-like invasive carcinoma with DCIS component also suggests a role of EMT in the transition of in situ- to invasive carcinoma in basal-like breast cancer.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P5-04-03.
Abstract P5-04-09: Squamous Cell Carcinoma Antigen 1 (SCCA1) Upregulation Causes Epithelial to Mesenchymal Transition (EMT) and Promotes Mammary Tumorigenesis
Authors: Sheshadri N , Ullman E , Catanzaro J , Chen E , Zong W-X 
Published: August 2014

Abstract
SCCA1, a member of the family of serine protease inhibitors, was first identified as a serological marker for cervical cancer but has since been shown to be upregulated in several other cancers including lung, head and neck, liver, skin, and breast. SCCA1 is believed to protect cells from unscheduled cathepsin release and activation upon lysosomal injury. In order to understand the molecular role of SCCA in cancer, we ectopically expressed it in the immortalized yet non-tumorigenic mammary epithelial cell line MCF10A. Expression of SCCA1 impairs the efficiency of lysosomal as well as proteasomal protein degradation pathways. Transcriptional profiling of SCCA expressing cells by microarray demonstrates an altered gene expression pattern that resembles EMT. Phenotypically, SCCA1 expression leads to spindle shaped cell morphology, increased migratory potential, resistance to anoikis, and the ability to form colonies in soft agar. SCCA1-expressing MCF10A cells can form tumors when injected into the mammary fat pad of immune-compromised mice. Correlative to the transforming activity, SCCA1 expressing cells have enhanced Erk and Akt signaling pathways, and have bypassed the requirement of growth factors and hormones that are essential for proliferation of MCF10A cells. In a transgenic mouse model, where SCCA1 is conditionally expressed in mammary epithelial cells under the control of MMTV promoter, increased mammary gland ductal branching and hyperplasia are observed. These findings indicate a previously unknown role of SCCA1 in promoting EMT and tumorigenesis, possibly by inducing chronic misfolded protein stress that contributes to enhance tumor-promoting signaling.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P5-04-09.
Abstract P5-05-03: The 5p12 breast cancer susceptibility locus is associated with MRPS30 expression in estrogen receptor - positive tumors
Authors: Quigley DA , Van Loo P , Alnæs GG , Tost J , Zelenika D , Balmain A , Børresen-Dale A-L , Kristensen VN 
Published: August 2014

Abstract
Genome-wide association studies (GWAS) have identified numerous loci linked to breast cancer susceptibility, but few of these loci have been convincingly linked to causal variants. We identified genes whose mRNA expression is linked to germline variation in normal mammary tissue and breast tumors by performing a genome-wide expression Quantitative Trait Locus (eQTL) analysis in 97 samples of normal mammary tissue and 286 breast adenocarcinomas. In the tumors we found 164 cis-acting loci, which affect expression of nearby genes. Twenty nine of these loci are previously unreported in other eQTL studies, including a cis-acting locus at 5p12 affecting expression of the mitochondrial ribosomal 28S subunit protein MRPS30 in estrogen receptor-positive but not estrogen receptor-negative tumors. This locus has been associated with susceptibility to estrogen receptor-positive breast cancer in several GWAS, with MRPS30 being the suggested candidate gene. One of these studies found that the rs771660 variant was most significantly associated with breast cancer in the 5p12 region, and we found that rs771660 was most strongly associated with MRPS30 gene expression. We provide the first evidence that this breast cancer susceptibility locus affects MRPS30 expression specifically in estrogen receptor-positive tumors and suggest a mechanism for estrogen activation of MRPS30 via proteins in the AP-1 complex.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P5-05-03.
Abstract P5-05-04: Intraductal delivery of RNAi-based therapeutics to gene targets identified through computational systems modeling
Authors: Brock A , Krause S , Li H , Kowalski M , Collins J , Ingber D 
Published: August 2014

Abstract
We utilize a computational systems biology approach to identify gene targets with the potential to serve as targets for therapeutic RNAi. Inferred gene regulatory network models were constructed using whole transcriptome expression profiling for progressive stages of mammary tumorigenesis in FVB C3(1)-SV40Tag mice. These computational models predicted key mediator transcription factors that are critical for hyperplasia and ductal filling in the early stages of disease progression. Putative mediator transcription factors were targeted by RNAi first in a mammary spheroid assay. Based on their ability to restore lumen formation and normal apical-basal polarization to mammary tumor cells, two transcription factors, Hoxa1 and Hoxb13, were selected for validation in vivo. siRNA targeting each of these transcription factors was formulated with lipidoid nanoparticles and delivered to the mammary gland via intraductal injection. Silencing Hoxa1 resulted in a significant reduction in tumor incidence in FVB C3(1)-SV40Tag. This represents a novel strategy to achieve localized silencing of a target gene in the mammary epithelium.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P5-05-04.
Abstract P5-05-05: Computational modeling of breast cancer growth and spread: the role of matrix degrading enzymes
Authors: Deakin NE , Thompson AM , Chaplain MAJ 
Published: August 2014

Abstract
Background: A “hallmark” of cancer growth and metastatic spread is the process of local invasion of the surrounding tissue. Cancer cells achieve this by the secretion of enzymes involved in proteolysis (tissue degradation) including matrix metalloproteinases (MMPs). These over-expressed proteolytic enzymes then proceed to degrade the host tissue allowing the cancer cells to disseminate throughout the microenvironment by active migration and interaction with components of the extracellular matrix such as collagen. The implications of MMP-2 activation by MMP-14 and the tissue inhibitor of metalloproteinases-2 (TIMP2) can be considered alongside the suitability of the matrix to be invaded. The suitability of the matrix incorporates pore size, since in some highly dense collagen structures such as breast tissue, the cancer cells are unable to physically fit through a porous region and rely on membrane-bound MMPs to forge a path through which degradation by other MMPs and movement of cancer cells can occur.
Method: We have developed a multi-scale mathematical model of breast cancer cell invasion of host tissue by combining both micro- (cell) and macro- (tissue) scale dynamics. The model considers cancer cells and two matrix-degrading enzymes from the MMP family of differing mechanistic actions, namely MMP-2 and the membrane bound MMP-14 (also called MT1-MMP), and their interaction with, and effect on, the extracellular matrix (ECM) in a 2-D spatial domain.
For the macro-scale we use a system of reaction-diffusion-taxis partial differential equations to capture the qualitative dynamics of the migratory response of the cancer cells. The micro-scale operates over a smaller spatial and temporal scale, and as such allows us to explicitly examine the stochastic role which is inherent within the region of enzyme operation. Computational simulations of the equations predict the spatio-temporal evolution of the cancer cell density, the concentration levels of the various enzymes and the density of the extracellular matrix.
Results: The model exhibits a rich range of dynamic and heterogeneous spatio-temporal solutions, which qualitatively match experimental and clinically observed results for aggressive breast carcinoma invasion and can be used to determine the speed of invasion through a variety of structured mediums such as the highly dense collagen constitution of some peritumoral stroma. Using the “worst case” scenario, an estimate for the maximum region of invasion over time from the initial data can be obtained suggesting the likely extent of breast cancer cell invasion into the surrounding tissue.
Conclusion: This modeling is most relevant to and informs the biological processes occurring in early stage breast cancer, in which local invasion is a crucial aspect of tumor behavior.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P5-05-05.
Abstract P5-06-02: The Role of Breast Tumor Kinase (Brk) in Cell Cycle Control
Authors: Nimnual AS , Chan E 
Published: August 2014

Abstract
Brk promotes cell proliferation and has been associated with multiple mitogenic pathways. However, the role of Brk in the cell cycle is still elusive. Here, we present a mechanism of Brk-induced cell cycle progression. Brk downregulates the cell cycle inhibitor p27 by altering its transcription factor FoxO3a subcellular localization. p27 is a key component of the G1/S cell cycle checkpoint and downregulation of p27 promotes S phase entry. The progression of the cell from G1 to S phase, induced by Brk, is independent of growth factors suggesting a role for Brk in malignant transformation. FoxO3a appears to be a major component in p27 down-regulation by Brk as the effect of Brk on p27 expression is significantly abrogated in cells transfected with siRNA targeting FoxO3a. The induction of FoxO3a nuclear exclusion by Brk is inhibited by LY294002 indicating that the mechanism is mediated by the PI3-kinase/Akt pathway. The mechanism underlying PI3-kinase mediated Brk function is still under investigation with evidence suggesting the involvement of the translocation of epidermal growth factor receptor. These data suggest that perturbation of p27 expression induced by Brk causes S phase entrance. Deregulation of the cell cycle is a key event in neoplasia, and thus, the mechanism presented here likely contributes to breast cancer development.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P5-06-02.
Abstract P5-07-02: Analysis of a novel synergistic relationship between the FK506 binding protein FKBP52 and beta catenin in androgen receptor signaling pathways
Authors: Storer CL , Olivares K , Fletterick RJ , Webb P , Cox MB 
Published: August 2014

Abstract
Hormone-dependent cancers depend largely on folding and regulation by a chaperone-steroid receptor complex. The final stage of the receptor-chaperone complex consists of a receptor, a heat shock protein 90 (Hsp90) dimer, p23, and an immunophilin. Hormone-dependent prostate cancer progresses due to key interactions between the androgen receptor complex and the ligand dihydrotestosterone. While current treatments block androgen receptor-ligand interactions, these therapies are no longer effective in advanced stage, hormone independent prostate cancer (HRPC), when the receptor is activated even in miniscule levels of hormone. Therefore, we are interested in targeting other members of the androgen receptor complex and signaling cascade, namely the immunophilin FK506 binding protein (FKBP52) and the Wnt cell signaling protein β-catenin. FKBP52 has the ability to potentiate activity of the androgen, progesterone, and glucocorticoid receptors and is a prostate cancer biomarker. β-catenin is a member of the cellular adhesion complex with E-cadherin in healthy cells, but in aberrant situations, β-catenin actively promotes progression and invasion in a number of cancers. Our data from FKBP52 knockout mouse embryonic fibroblast cell lines suggests that FKBP52 and β-catenin work in tandem to synergize androgen receptor (AR) transcriptional activity with the probasin promoter. When AR, FKBP52, and β-catenin are co-transfected, a synergistic up-regulation of AR signaling is observed, as assessed by luciferase reporter assays. According to pull down assays, FKBP52 and β-catenin can interact in the absence of other proteins. Luciferase assays of mutant FKBP52 proteins suggest that FKBP52's binding to β-catenin involves the FKBP52 proline-rich loop and may act independently of Hsp90 binding. Interestingly, it appears that this synergistic effect is promoter-specific, suggesting that regulation by these proteins occurs at the transcriptional level. We have successfully abrogated the synergism of these proteins using the FKBP52-specific inhibitor MJC13, a small molecule developed for use in our laboratory. According to surface plasmon resonance studies, this molecule binds the androgen receptor at the BF-3 regulatory surface, the interaction surface for FKBP52 regulation of receptor. According to recent findings, AR, Wnt, and Human Epidermal Growth Factor Receptor 2 signaling pathways are linked in molecular apocrine breast cancer progression. We therefore hypothesize that our findings could be relevant to breast cancer as well as prostate cancer.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P5-07-02.
Abstract P5-07-05: Insulin-like growth factor binding protein-3 is a key component of the breast cancer cell response to DNA-damaging therapy
Authors: Baxter RC , Lin MZ , Marzec KA , Martin JL 
Published: August 2014

Abstract
Introduction. Breast cancer cells frequently develop resistance to DNA-damaging therapies, such as radiation and the cytotoxic drugs doxorubicin and etoposide, and activation of the epidermal growth factor receptor (EGFR) may play an important role in this process. However many estrogen receptor (ER)-negative breast tumors respond poorly to DNA-damaging drugs even when combined with an EGFR inhibitor. EGFR can modulate the repair of DNA double strand breaks (DSB) by non-homologous end-joining (NHEJ), by forming protein complexes that include the catalytic subunit of DNA-dependent protein kinase (DNA-PKcs). In previous studies we have shown that the growth-regulatory protein, insulin-like growth factor binding protein-3 (IGFBP-3), can translocate to the nucleus, is a substrate for DNA-PKcs, and can transactivate EGFR. The aim of this study was to delineate the role of IGFBP-3 in the response of breast cancer cells to DSB-inducing chemotherapeutic agents.
Results. In the triple-negative breast cancer cell lines MDA-MB-468 and Hs578T, which express IGFBP-3 highly, nuclear localization of EGFR and IGFBP-3, and of their complex as measured by coimmunoprecipitation (coIP), was enhanced by exposure to etoposide or doxorubicin, peaking 2 h after etoposide treatment. This effect was blocked by the EGFR kinase inhibitor gefitinib. Concomitantly, the co-location of EGFR-IGFBP-3 complexes with lipid rafts, visualized by proximity ligation assay (PLA) and confocal microscopy, decreased in response to drug treatment, consistent with the loss of this complex from the plasma membrane. Similar to the nuclear DNA-PKcs-EGFR complex, the nuclear DNA-PKcs-IGFBP-3 complex (seen by both coIP and PLA) was greatest 4 h after treatment. DNA-PKcs activation at serine-2056, required for the repair of DNA DSB and stimulated by etoposide treatment, was decreased by IGFBP-3 downregulation using two separate siRNAs, and this treatment also attenuated the enhanced DNA-PKcs-EGFR complexes seen in response to etoposide. Collectively these data suggest that IGFBP-3 has an obligatory role in the DNA repair response to DNA-damaging therapy through its interactions with EGFR and DNA-PKcs.
Conclusion. IGFBP-3 co-translocation to the nucleus of breast cancer cells and its complex formation with DNA-PKcs and EGFR in response to DNA damage demonstrate its previously unrecognized involvement in the regulation of DNA DSB repair by NHEJ. These novel findings suggests the possibility of a therapeutic approach for sensitizing ER-negative breast cancers to chemo- or radiotherapy by targeting the DNA repair function of IGFBP-3. Supported by the Australian Research Council.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P5-07-05.
Abstract P5-09-01: Evaluation of BCL2 sequence variant in Iranian women patients with Breast cancer
Authors: Motahari B , Ghaffarpour M , Javadi GH , Houshmand M 
Published: August 2014

Abstract
Introduction: Despite recent advancements in the treatment and management of cancers, Breast cancer still remains the most common malignancy and second leading cause of cancer-related deaths among women in Iran. Apoptosis and cellular proliferation play role an important role during normal mammary development and carcinogenesis of the mammary gland. In normal tissues, the homeostasis between apoptosis and cell proliferation is regulated by Bcl-2 family proteins. Tumor cells tend to interfere with the mechanism of Apoptosis by activating anti apoptotic genes such as bcl-2. BCL-2 gene, located at 18q21.3 and consists of three exons and two promoters (P1 and P2), which have different functions. The second promoter, P2, is located 1,400 bp upstream of the translation initiation site and functions as a negative regulatory element to the P1 promoter. Bcl-2 is the one of the most important anti apoptotic genes. It has been shown that the −938AA genotype s associated with higher Bcl-2 expression levels in B-CLL and poor prognosis. Bcl2 gene has been also demonstrated with breast cancer development and a single nucleotide polymorphism (SNP-938C &gt;A) has been identified recently and can provide a susceptible factor for causing breast cancer.
The main objective of this study was to evaluation of the frequency of specific genetic alterations in the BCL-2 gene (−938,-758 and 21) and the risk of breast cancer in Iranian women patients with Breast cancer.
Materials and Methods: Patients; 27 paired Fresh tumor and adjacent normal samples were obtained from consecutive patients with BC who underwent surgery for mama mastroctomy from IRANIAN National Tumor Bank, National Cancer Institute, Imam Khomeini Hospital Complexes, Medical Tehran University, Tehran, Iran. Histopathological examinations were performed, and all tumors were confirmed as adenocarcinoma.
Mutational analysis: Fresh tumors and their adjacent were extracted for genomic DNA using the QIA amp Mini Kit according to the manufacturer's instructions. We searched DNA samples of Iranian patients for identification of SNP; −938C&gt;A, −758T insertion in the inhibitory P2 promoter and 21A/G in exon 2 of the BCL-2 gene by means of PCR sequencing.
Results and conclusions: In All cases, the frequency of genetic alterations in the BCL-2 gene (−938, −758 and 21) was 16 of 27 (59.29%) heterozygous in −938(C, A) and 5 of 27(18.51%) SNP-938 C&gt;A, 0 of 27(0%)and 8 of 23(34.78%)heterozygous in +21(A, G)and 2 of 23(8.69%)SNP 21A&gt;G respectively. According to our findings, point mutation in −938C and 21A alleles displayed a positive relation with increasing tumorgenesis in breast cancer. Our result indicated that the regulatory BCL2 promoter polymorphism (−938C, A) and coding BCl2 gene (21A, G) may be useful as a tumor marker for increasing tumorgenesis in Iranian women breast cancer.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P5-09-01.