bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract P1-03-01: Evidence for the Warburg effect in mammary atypia from high-risk African American women.
Authors: Seewaldt V , Hoffman A , Ibarra-Drendall C 
Published: August 2014

Abstract
Background: Aggressive cancers are known to consume glucose avidly and produce lactic acid (rather than fully metabolize glucose via the Tricarboxylic Acid (TCA) cycle). This shift toward lactate production, even in the presence of adequate oxygen, is termed the Warburg effect. The Warburg effect is thought to be a late event in breast cancer, however, our studies in high-risk women provide evidence that the Warburg effect occurs during cancer initiation. This is an important observation as glucose-signaling can be readily targeted for breast cancer prevention with minimal toxicity. Here we investigated the role of the Warburg effect in breast cancer initiation in young high-risk women.
Methods and Results: Similar to fluorodeoxyglucose, 2-(N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino)-2-deoxyglucose (2-NBDG) is a fluorescent glucose analog that can be used to track glucose uptake and glycolysis. 2-NBDG spectroscopy provides a means to track glucose metabolism in live mammary epithelial cells from high-risk women. We used 2-NBDG spectroscopy to measure glucose uptake in ER− breast cancer and live atypical mammary epithelial cells from high-risk premenopausal women. We observe that both triple-negative breast cancer and a subset of atypia exhibits accumulation of 2-NBDG.
There is growing recognition that phosphoprotein signaling networks (rather than single genes) play a key role in breast cancer initiation and progression. Our team used Reverse Phase Proteomic Microarray (RPPM) profiling to test for activation of phosphoprotein signaling networks in atypical RPFNA cytology from high-risk premenopausal women in our cohort. RPFNA were obtained from two independent sets of 39 and 38 high-risk premenopausal women; 45% of these women were African American. The signaling network most highly expressed in precancerous cells contained activated signaling proteins associated with the Warburg effect (AKT/mTOR/PI3K), insulin signaling (pACC, IRS1) and epithelial to mesenchymal transition (EMT) IL6/Stat3/vimentin.
Conclusions: This is the first evidence that abnormal glucose uptake and the Warburg effect occurs during breast cancer initiation in high-risk premenopausal women. These studies demonstrate our ability to identify abnormal glucose and activated signaling networks associated with the Warbug effect in atypical mammary cells from high-risk women.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P1-03-01.
Abstract P1-03-03: milk deposition in women's mammary duct has been a potential risk factor of breast tumor
Authors: Xu Z , Gu Y , Gong G , Zhang Y 
Published: August 2014

Abstract
Background: According to the pathology and general resection specimens, so many patients have breast tumors together with deposited milk. Therefore, we performed this retrospective study to determine the distribution and characteristics of breast diseases in women undergoing mammary ductoscopy and explore the clinical values and implications of mammary ductoscopy in the management of the breast diseases.
Materials & Methods: Total of 10,082 women(20,082 breasts) with a mean age of 39.2 years old (ranging from 12 to 84 years old) underwent mammary ductoscopy from 2002 to 2011. We studied NSND in contrast with SND duct, specially focused on the situation of duct with intraductal mass. Comparing with the pathology, we studied the relationship between duct milk deposition and epithelial hyperplasia.
Results: From this study we concluded that duct milk deposition was a common disease in 25–59 years old women, it occupied 42.89% cases of the mammary ductal disease and almost 46% are NSND. The character of deposited milk became solid from liquid with the age growing up. Duct milk deposition 476/1431(33.26%)was mostly associated with intraductal masses(total 1431 cases), followed by duct dilatation 517/1431(36.13%). Pathology of patients diagnosed by FDS for duct milk deposition are epithelial hyperplasia(100%), adenosis(86.5%), chronic inflammation(8.8%), metaplasia(16.9), florid hyperplasia(10.8%), tumor-like hyperplasia (57.2%), intraductal tumor or fibroadenoma (27.8%), dysplasia (3.0%), breast cancer (11.7%).

Discussion: Diagnosis of duct milk deposition, which may not necessarily presented by nipple discharge, is the most common finding and associated with proliferation and thus intraductal mass, etc. we should noticed 30–50 years old women groups, cause they have have stopped breast-feeding for years but still had yellow or brown, liquid or solid milk-like things in their lactiferous ducts. We predict duct milk deposition may be related with breast carcinogenesis. It is a kind of long time mechanical stimulation in the duct, both the physico-chemical properties and the acid-alkaline environment had changes by years. Still, the deposited milk would be a best medium for microbial and virus, which would cause the genesis of hyperplasia even breast cancer. Therefore, we should go on the research of deposited milk and the changes of the microenvironment of the duct to find the pathogenesis of breast disease.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P1-03-03.
Abstract P1-04-03: Knocking down Suppressor of Cytokine Signaling 7 in breast cancer: The role in Insulin-like Growth Factor - I/Phospholipase Cγ-1 signaling
Authors: Sasi W , Ye L , Jiang WG , Mokbel K , Sharma A 
Published: August 2014

Abstract
BACKGROUND: Suppressor of Cytokine Signaling 7 (SOCS7) is a member of the SOCS family and is known to interact with Phospholipase Cγ-1 (PLCγ-1), one of the Insulin like Growth Factor - I (IGF-I) receptor downstream molecules. In the present study, we sought to examine the effect of knocking down SOCS7 gene on breast cancer cells growth and migration and to elucidate whether this has involved IGF-I — PLCγ-1 signaling using the PLCγ-1 blocker U73122.
METHODS: Suitable breast cancer cells (MCF7 and MDA-MB-231) were transfected with anti-SOCS7 ribozymal transgene, to create sublines with SOCS7 knockdown that was verified by RT-PCR. The growth and migration of the cells were evaluated in the presence or absence of IGF-I and PLCγ-1 inhibitor using in vitro growth assay and Electrical Cell Impedance Sensing (ECIS) migration assay.
RESULTS: MCF7ΔSOCS7 and MDA-MB-231ΔSOCS7 (SOCS7 knockdown) were constructed. Both sublines showed a higher rate of growth compared to control cells with and without IGF-I stimulation. U73122 treatment did not appear to change this growth outcome. Using ECIS migration assay, it was shown that knocking down SOCS7 had a significant positive effect on the migration of MCF7 and MDA-MB-231 cells, and that both IGF-I treatment and SOCS7 knockdown had a synergistic positive influence on their migration (p &lt; 0.05). We further demonstrated that the impact of U73122 on the IGF-I migratory effect was dependent upon SOCS7 knockdown as it has significantly blocked the stimulatory effect of IGF-I on MCF7ΔSOCS7 and MDA-MB-231ΔSOCS7 migration but not that of the control cells. While SOCS7 has acted to control the IGF-I effect, it appeared to cancel the inhibitory function of U73122, indicating a specific anti - PLCγ-1 role for SOCS7 in IGF-I induced breast cancer cellular migration.
CONCLUSION: SOCS7 loss resulted in increased growth and migration of breast cancer cells and this had a synergistic effect on their response to IGF-I. This role could be related to its interaction with PLCγ-1 during the cellular migration but not the growth. It may be possible that SOCS7 acts through different mechanism to control the cellular growth.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P1-04-03.
Abstract P1-04-05: Role of the Rb and p53 Tumor Suppressor Pathways in Mammary Tumorigenesis
Authors: Jones RA , Liu JC , Zhe J , Schimmer AA , Eldad Z 
Published: August 2014

Abstract
The retinoblastoma (Rb) and p53 tumor suppressor pathways are frequently altered in human malignancies including breast cancer. To investigate the role of these pathways in mammary tumorigenesis, we crossed mice expressing Cre recombinase in the mammary epithelium (MMTV-Cre) with mice harboring Rb and p53 floxed alleles to generate MMTV-Cre:Rbf/f:p53f/f mutant mice. Combined somatic loss of Rb and p53 led to the formation of aggressive triple-negative tumors (ER−, PR−, HER2−) that often displayed features of an epithelial to mesenchymal transition (EMT) including sarcomatoid differentiation and high expression of the mesenchymal marker N-Cadherin. Molecular profiling revealed Rb/p53 deficient tumors shared similar gene expression profiles with mouse and human claudin-low breast cancers. Interstingly, limiting dilution transplantation analysis also suggests that Rb/p53 deficient claudin-low tumors are enriched for tumor-initiating cells (TICs).
To investigate the cellular origin of claudin-low tumors, the Rbf/f and p53f/f alleles were deleted within the luminal and basal compartments of the mammary gland using a Cre-expressing adenovirus (Ad-Cre) and CD24-CD49f-based FACS analysis. The different cellular fractions were then transplanted into the cleared mammary fat pad of recipient mice which are currently being monitored for tumor development.
Finally, primary cell lines isolated from Rb/p53 deficient mammary tumors were used in conjunction with high-throughput chemical and genetic screens to identify new therapeutic targets. A primary screen of 260 kinase inhibitors and 312 FDA-approved off-patent drugs has identified novel candidates and a genome wide negative selection (‘drop-out’) screen is currently in progress.
Ultimately, the results of this research will provide important insight into the biology of triple-negative breast cancer and will lead to the identification of novel therapeutic targets for the treatment of patients living with this disease.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P1-04-05.
Abstract P1-04-10: PDGFRA signaling in Inflammatory breast cancer.
Authors: Joglekar M , van Golen K 
Published: August 2014

Abstract
Inflammatory breast cancer is the most lethal form of locally advanced breast cancer. It is clear from the recent research advancements in IBC that it is entirely a different entity, not only in its clinical presentation but also in its molecular expression profile. Therefore, it is essential to carry out molecular expression studies in IBC compared to non-IBC as well as to pursue these differences to study their effects on IBC phenotype.
In collaboration with the Translational Cancer Research group in Antwerp Belgium, our lab has recently found that PDGFRA is significantly over expressed in IBC patient samples (between 15–36%) compared to non-IBC patient samples. This project focuses on identifying the PDGFRA activation signature in SUM149 IBC cells. Upon ligand stimulation, PDGFR can either homo or heterodimerize (AA, AB, BB) and produce an array of signaling events responsible for cell growth, cell proliferation, cell differentiation in normal cells as well as in several cancer cells. SUM149 and SUM190 cells lack ER, PR and HER-2 expression and hence are named triple negative IBC cells. Triple negative breast cancers are highly aggressive in nature and therefore suffer from poor prognosis. We seek to determine if signaling via over expressed PDGFRA could be a potential surviving factor in producing such fast growing and highly invasive IBC tumors. Preliminary data on immunostaining of PDGFRA with and without permeabilization suggests intracellular localization of PDGFRA. We also know that SUM149s and SUM190s express all four PDGF ligands (A, B, C, D). This unusual expression of all the PDGF lignads suggests the self-sufficiency of these cells for PDGFRA signaling. In other words, these cells maintain constitutively active PDGFRA via intracrine/autocrine loop. Protein expression of active PDGFRA was studied by using two different phospho specific PDGFRA antibodies (Tyr 1018 and Tyr 849) without any prior stimulation by PDGF ligands. Moreover our data shows that PDGFR- activation in IBC, unlike in n-IBC, is PDGF-C driven.
Possibility of such intracrine/autocrine loop could significantly increase the overall PDGFRA signaling in IBC cells and hence can produce fast growing aggressive IBC tumors. Thus targeting PDGFRA, an important biomarker in IBC could stand as a novel and systematic therapeutic approach.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P1-04-10.
Abstract P1-05-02: Epithelial-to-epithelial transition precedes collective breast cancer invasion
Authors: Cheung KJ , Ewald AJ 
Published: August 2014

Abstract
BACKGROUND: Invasion represents a fundamental step in tumor progression and is a driving force for metastasis and cancer-related mortality. Invasion has been studied largely in the context of single cells, but in vivo, most tumor cells are not found in isolation, but rather are found as ensembles of cells with substantial molecular heterogeneity. It remains poorly understood in this context which cells are invasive, how these cells arise or how these cells interact collectively to accomplish invasion.
RESULTS: We developed an ex-vivo 3D culture assay enabling us to distinguish invasive from non-invasive cells and to interrogate their molecular phenotype. In two mouse models of luminal breast cancer, we find that invasive cells express markers of basal epithelium including cytokeratin K14, p63 and P-cadherin. Invasive K14+ cells were also molecularly and functionally distinct from normal myoepithelial cells and co-expressed luminal K8 and E-cadherin. In vivo, K14+ cells were localized to tumor-stromal interfaces in the primary tumor and in lung micro and macro-metastases. Using a molecular biosensor and time-lapse microscopy, we observed that K14+ invasive cells were derived from K14-negative luminal tumor cells by direct phenotypic conversion. Interestingly, the capacity of luminal tumor cells to acquire basal markers varied by model, with few K14+ cells in MMTV-Her2 and many K14+ cells in MMTV-PyMT mice, correlating with the known in vivo kinetics of tumor progression in these models. To block this epithelial to epithelial transition, we tested the activity of an inhibitor of ribosome S6 kinase (RSK), which has been shown previously to inhibit myoepithelial differentiation in normal mammary epithelium. RSK inhibition caused relative depletion of K14+ tumor cells in 3D culture and abrogation of invasion. Finally, our assay revealed that in fresh primary tissue from human ER+ luminal breast cancers, invasive cells also expressed basal epithelial markers.
CONCLUSIONS: Taken together, these data suggest that an epithelial-to-epithelial transition precedes collective invasion in luminal breast cancers. Because we observe K14+ leader cells independent of tumor estrogen receptor status, these data may be generally applicable to breast cancer invasion across subtypes. Because many epithelial tissues have basal populations, K14+ tumor cells may also lead invasion in other cancers.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P1-05-02.
Abstract P1-05-04: Expression of Quiescin Sulfhydryl Oxidase 1 is associated with a highly invasive phenotype and correlates with a poor prognosis in Luminal B breast cancer.
Authors: Katchman BA , Ocal T , Hostetter G , Cunliffe HE , Wantanabe A , Lake DF 
Published: August 2014

Abstract
Quiescin sulfhydryl oxidase 1 (QSOX1) oxidizes sulfhydryl groups to form disulfide bonds in proteins. Informatic analysis using the newly available “Gene Expression Based Outcome for Breast Cancer Online” (GOBO) tool indicated high levels of QSOX1 expression in Estrogen Receptor positive (ER+) subtypes of breast cancer. We confirmed this finding by evaluation of QSOX1 protein expression in breast tumors and in a panel of breast cancer cell lines. In addition, Kaplan Meyer analyses revealed QSOX1 as a significant predictive marker for both relapse and poor overall survival in Luminal B tumors, but not in other intrinsic subtypes. To investigate malignant cell mechanisms in which QSOX1 might play a key role, we suppressed QSOX1 protein expression using short hairpin (sh) RNA in ER+ MCF7 and ER− BT549 breast cancer cell lines. Suppression of QSOX1 protein dramatically slowed cell proliferation but did not significantly effect apoptosis or cell cycle regulation. Inhibition of QSOX1 did however dramatically inhibit MCF7 and BT549 breast tumor cells from invading through Matrigel in a modified Boyden chamber assay. Inhibition of invasion could be rescued by the exogenous addition of recombinant QSOX1. Gelatin zymography indicated that QSOX1 plays an important role in activation of MMP-9 a key mediator of breast cancer invasive behavior. Taken together, our results suggest that QSOX1 is a novel biomarker for risk of relapse and poor survival in Luminal B breast cancer, and has a pro-invasive role in malignant progression through post-translational activation of MMP-9.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P1-05-04.
Abstract P1-05-05: Podocalyxin is a key regulator of breast cancer progression and metastasis.
Authors: Snyder KA , Hughes MR , Graves M , Roskelly C , McNagny KM 
Published: August 2014

Abstract
Podocalyxin (gene name Podxl) is a CD34-related sialomucin that has been shown to be important in regulating cell adhesion, migration, and polarity of hematopoietic progenitors and vascular endothelia. In breast cancer, we have shown that podocalyxin is overexpressed on a subset of node-negative tumors and its expression is strongly associated with poor overall survival. To determine whether podocalyxin directly regulates breast cancer cell behavior, we ectopically expressed podocalyxin in the human breast cancer cell line, MCF7, which expresses low levels of endogenous podocalyxin, is minimally invasive, and non-metastatic. Upon ectopic expression of podocalyxin, MCF7 “bulge apically”, produce apical and lateral microvilli, are less adhesive in vitro, and are delayed in targeting integrins to the basolateral surface. In contrast to MCF7, MDA-MB-231 is a basal-like breast cancer cell-line, which expresses high levels of endogenous podocalyxin, exhibits poorly polarized monolayer and mammosphere architecture in vitro and forms “metastatic” lung tumors in vivo. Using Podxl-targeted shRNA vectors we show that expression of podocalyxin is required for MDA-MB-231 cells to form distant metastases in a competitive in vivo assay utilizing humanized NOD/SCIDIL-2rγ−/− (NSG) mice. Previously, we observed that Podxl-deficient hematopoietic cells have impaired CXCR4-mediated chemotaxis to CXCL12, a known axis for tumor metastasis. Our current hypothesis is that podocalyxin regulates chemotaxis of tumor-initiating cells (TICs) to the CXCL12-rich tissues of the lungs, liver, and bone marrow. Up-regulation of podocalyxin on breast cancer cells may be a key event in tumor progression and likely enables these cells to sense chemokines and metastasize to peripheral sites.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P1-05-05.
Abstract P1-05-08: Targeting integrin signaling suppresses invasive recurrence in a three-dimensional model of radiation treated ductal carcinoma in situ
Authors: Nam J-M , Ahmed KM , Costes S , Zhang H , Sabe H , Shirato H , Park CC 
Published: August 2014

Abstract
Background: DCIS (ductal carcinoma in situ) is comprised of cancerous cells that are contained within the milk duct and separated from the stroma by a basement membrane. Akt activation is implicated in breast cancer progression and also upregulated in ∼30% of DCIS lesions. We have previously shown that β1-integrin inhibition enhanced the efficacy of ionizing radiation (IR) in invasive breast cancer, via an Akt-mediated effect. Radiation therapy (RT) is commonly used to treat DCIS, resulting in a decrease in recurrence risk by ∼50%. However, DCIS still recurs in a substantial number of patients, and as invasive disease half of the time. This study aimed to identify the effects of IR on Akt-driven DCIS, and possible mechanisms underlying invasive progression in surviving cells.
Materials and Methods: To model DCIS, we took advantage of the ability of non-invasive mammary epithelial cells, MCF10A that form duct-like structures in 3-dimensional laminin-rich extracellular matrix (3D lrECM), and overexpressed an activated myristoylated form of the serine/threonine kinase, Akt. The 3D lrECM cultured MCF10A-Akt cells show filled lumen and retained basal polarity, characteristic of DCIS lesions in vivo. After DCIS structures formed in 3D lrECM, cultures were exposed to 8 Gy IR. Confocal microscopy analysis, western blot analysis, matrigel chemoinvasion assay and matix degradation assay were performed to characterize the IR effect on luminal or basal cells of the DCIS like structures.
Results: MCF10A-Akt structures post-8 Gy IR shows a significant increase in apoptosis measured by cleaved caspase-3 (n = 3, P &lt; 0.05). When we propagated cells post-IR in 3D lrECM, an invasive phenotype emerged in a sub-population of survivors (n = 3, P &lt; 0.01). We also confirmed that inhibitory antibodies to β1-integrin suppressed the invasive phenotype that was induced by 8 Gy IR. In addition to this, invasion activity emerged by 8 Gy IR was inhibited by nuclear factor-kappaB (NF-κB) inhibitor JSH-23 (n = 3, P &lt; 0.01). Finally, inhibition of β1-integrins or NF-κB translocation completely suppresses the formation of invasive colonies.
Discussion: In present study, we found that inhibition of β1-integrins abrogates the emergence of an invasive phenotype among surviving clones. Our current data suggest that regulation of β1-integrin signaling via NF-κB plays an important role in the emergence of invasive disease after radiation, and may be an important clinical target.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P1-05-08.