bluuebunny/crossref_metadata_2025_split huggingface dataset:
P2-03-03: An Insulin-Like Growth Factor I (IGF-I)-Induced Gene, Solute Carrier Family 7 Member 11 (SLC7A11)/xCT, Mediates IGF-I-Induced Biological Behaviors in Breast Cancer Cells.
Authors: Yang Y , Becker MA , Yee D 
Published: June 2012

Abstract
Our laboratory studied the gene expression profiles of a series of T47D variant cell lines with differential insulin receptor substrate (IRS) adaptor protein expression to develop predictive IGF-I pathway biomarkers. We identified an IGF-I-induced gene, SLC7A11 (or xCT), which is specifically regulated through IRS-1. xCT encodes the cystine/glutamate transporter subunit of the heterodimeric amino acid transport system xc- which is a major plasma membrane transporter for the cellular uptake of cystine in exchange for intracellular glutamate. xCT is involved in the regulations of proliferation, metastasis, and drug resistance in various cancers. However, to date, the linkage between xCT and the IGF-I signaling pathway has not been described. To study the role for xCT in mediating IGF-I-induced biology in breast cancer cell lines, we examined xCT mRNA expression upon IGF-I stimulation in two breast cancer cell lines; the MCF-7 (IRS-1 activated) and MDA-MB-231 (IRS-2 activated) cells. Significant increased xCT expression was observed only in MCF-7 cells after IGF-I treatment. Immunoblots showed that xCT protein expression was elevated after IGF-I treatment and induced glutamate/cystine exchange in MCF-7 cells. shRNA was used to downregulate xCT in MCF-7 and MDA-MB-231 cells. In MCF-7, IGF-I-stimulated cell monolayer growth was suppressed by xCT shRNA or by the xCT inhibitor sulfasalazine (SASP). In MDA-MB-231 cells, xCT downregulation did not affect IGF-mediated Boyden chamber migration. Thus, IGF-I induction of cellular xCT levels is associated with cell growth in the IRS-1 activated MCF-7 cells, while MDA-MB-231 cells were not affected by downregulation of this gene. Therefore, our data imply that xCT may mediate IGF-I induced biological functions in breast cancer cell lines through an IRS-1 dependent pathway.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P2-03-03.
P2-03-04: Novel Pathways Underlying the Initiation and Transition of DCIS to IDC of HER2−Overexpressing Breast Cancer Model.
Authors: Pradeep CR , Koestler W , Lauriola M , Nair H , Rao R , Mills GB , Yarden Y 
Published: June 2012

Abstract
Background: The HER2/Neu -oncogene is amplified in 20–25% percent of human primary breast cancers and this alteration is associated with disease behaviour. The HER2/neu oncogene encodes a receptor-like tyrosine kinase, whose overexpression in breast cancer predicts poor prognosis and resistance to conventional therapies. Whereas signalling pathways emanating from HER2 have been characterized, much less is known about the transcriptionally regulated genes controlled by HER2 that contribute to the initiation of Ductal Carcinoma Insitu (DCIS) and their transition to an invasive ductal carcinoma (IDC).
Materials and Methods: Normal and HER2 overexpressing mammary epithelial cells (MCF10A) were grown in extracellular matrix to form 3D structures, When grown in extracellular matrix as 3-dimensional spheroids, control cells developed a hollow lumen, but HER2−overexpressing cells populated the lumen by evading apoptosis. On the next step, uopon the growth factror stimulation HER2−overexpressing cells grown in extracellular matrix, which protruded invasive outgrowths. Highly variable genes were selected from the described phenotypes using RNA isolated from the 3D structures and hybridized to an Affymetrix HuGene 1.0 ST oligonucleotide array. Results: Using microarrays we analysed transcriptional events responsible for the morphological changes and found several novel sets of genes such as integral proteins, transcription factors, matrix proteases, Notch genes and chemokines were highly altered in the HER2 overexpressing group which were not appreciated before. Using gene annotation we defined molecular-pathways responsible for the phenotypical changes. More specifically, our study proposes a two hit model describes the pathways involved in the initiation of the Ductal Carcinoma Insitu and their transition to Invasive Cancer underlying the HER2 transcriptional network.
Discussion: According to the proposed model, expansion of ductal hyperplasia is limited by intraluminal apoptosis, unless they overexpress HER2, which drives proliferation and forms DCIS due to HER2 induced Notch pathways genes. Secondly, results obtained with the 3D system and their reflection in clinical outcome, we propose that neither HER2 amplification, nor the presence of GFs, is sufficient for development of IDC, but their co-occurrence can instigate metastasis by the activation of genes of integrin-adhesion signaling. The more virulent scenario combines HER2 amplification with GFs, thereby switching a robust, auto-stimulatory program.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P2-03-04.
P2-03-06: Endothelin-1/Endothelin A Receptor Signalling in Breast Cancer.
Authors: Tamkus D , Leece C , Gallo K , Madhukar BV , Dimitrov N 
Published: June 2012

Abstract
Background: Endothelin-1 (ET-1) and endothelin A receptor (ETAR) are implicated in breast cancer growth and progression. ET-1 is secreted by both tumor cells and stroma (macrophages, endothelial cells). The purpose of this study is to evaluate ET-1/ETAR role on cell proliferation and its effects on EGFR signaling pathway. Materials and Methods: Two breast cancer cell lines: MCF-7 and MDA-MB-231 were stimulated with ET-1. Proliferation of breast cancer cells was analyzed using MTT assay. Protein expression (EGFR, pEGFR, AKT, pAKT, ERK, pERK) was evaluated by Western blot. siRNA knockdown of endothelin A receptor (ETAR) was performed in MCF-7 and MDA-MB-231.
Results: ET-1 stimulated proliferation in both cell lines. Interestingly, at higher ET-1 concentrations cell proliferation was more pronounced in MCF-7 when compared with MDA-MB-231. Stimulation with ET-1 activated EGFR and downstream signaling proteins (pAKT and pERK) in both cell lines. Incubation of breast cancer cells with ET-1 for 48 hours had different effect on total EGFR level: 3 fold increase of total EGFR was seen in MCF-7, while no change was detected in MDA-MB-231. siRNA against ETAR decreased ET-1 induced cell proliferation and reduced total EGFR level in MCF-7.
Conclusions: These observations suggest that ET-1/ETAR plays an important role in survival and proliferation of breast cancer cells. However, those effects are diverse in different subtypes of breast cancer. Our results may represent an improved selective targeted treatment strategy, especially for estrogen receptor positive breast cancer.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P2-03-06.
P2-04-02: Identification of a Novel Glycosyltransferase-Like Gene as an Autophagic Inducer in Human Mammary Carcinoma Cells Via Down Regulation of BCL-2.
Authors: Shastri BG , Jung Y , Steiner M , Perry JK , Lobie PE , Liu D-X 
Published: June 2012

Abstract
Here we report the identification of a previously undescribed glycosyltransferase-like gene, GLTx, and its cellular effect on mammary carcinoma cells. GLTx codes for a novel human protein which is highly conserved in primates. Data obtained from the mRNA expression database Oncomine, demonstrate that GLTx is differentially expressed in a variety of cancers including breast cancer. Western blot analysis of a multiple human tissue blot using a rabbit polyclonal antibody against GLTx demonstrated that GLTx was highly expressed in liver, moderately in kidney, intestine and stomach and undetectable in any other tissues. To functionally characterize GLTx, we attempted to establish stable cell lines with forced expression. However, forced expression of GLTx was completely lethal and resulted in severe cell death in the mammary carcinoma cell lines, MCF-7 and BT549, as well as in any other cell lines tested. Staining of MCF-7 cells transiently transfected with a GLTx expression plasmid by either Hoechst 33258 or fluorescein isothiocyanate-conjugated annexin V and propidium iodide confirmed that the observed cell death was not caused by apoptosis. Further investigation confirmed that GLTx expressing cells exhibited cytoplasmic accumulation of autophagosomes, consistent with the induction of autophagy, as measured by the fluorescently labelled autophagosome marker LC3. In addition we have shown that GLTx downregulated BCL-2, an inhibitor of autophagy, as measured by BCL-2 gene promoter luciferase activity assay and western blot assay following transient transfection of a GLTx expressing plasmid. Thus, we have demonstrated that GLTx is a novel autophagic inducer that causes cell death by down regulating BCL-2.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P2-04-02.
P2-05-07: Combined Antiangiogenic and Anti-Estrogen Therapy in Breast Cancer. Molecular Mechanisms Involved.
Authors: de la Haba J , Berciano M , Cañabate M , Porras I , Valverde A , Cañas A , Rodriguez A , Aranda E 
Published: June 2012

Abstract
Background: Much is known about the mechanisms involved in the response to anti-hormonal treatment or those involved in the response to antiangiogenic therapy. It is also known the association between angiogenesis and hormonal status, both in physiological and pathological settings. However, the molecular and cellular mechanisms contributing to the efficacy of combined antiangiogenic-antihormonal therapy in breast cancer are still unknown. This combination is currently in clinical trials, but unfortunately there are scarce preclinical studies contributing to the rationale of combining antiangiogenic and antihormonal therapies.
Aims: To define the mechanisms involved in the response to combined antiangiogenic-antihormonal treatments in breast cancer cells. Methods: Breast cancer cell lines with different estrogen dependence (MCF-7, BT-474, MDA-MB-231) were subjected to an estrogen gradient (estradiol), and treated with fulvestrant (antiestrogen), plus bevacizumab (anti-angiogenic). Cellular proliferation and apoptosis were determined using the corresponding kits. Proliferation and survival intracellular signaling pathways, estrogen alpha and VEGF receptors activation and COX-2 expression were analyzed by western-blot using specific antibodies.
Results: In estrogen-dependent breast cancer cells (MCF-7 and BT-474) the pro-proliferative effect of estradiol decreased after bevacizumab treatment.

Furthermore, the combination of the antiangiogenic with an antiestrogen enhanced this antiproliferative effect, that was also related to the reduction in the levels of VEGF-A in the culture medium and to diminished ER alpha phosphorylation. The combined treatment also altered the phosphorylation of Akt and Erk1/2 signaling kinases. Interestingly, bevacizumab treatment augmented COX-2 activity in MCF-7.
Conclusions: Our results suggest that in estrogen dependent breast cancer cells the anti-proliferative effect of bevacizumab depends on estradiol concentration, that in turn affects VEGF production levels, using a different mechanism to apoptosis. The combination of bevacizumab with antiestrogens enhances this antitumoral effect, altering intracellular signaling pathways of proliferation and survival.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P2-05-07.
P2-08-13: Does Routine Use of Preoperative Magnetic Resonance Imaging (MRI) in Breast Cancer Influence the Outcome?
Authors: Große R , Kantelhardt EJ , Steer S , Spinda AK , Vetter M , Ruschke K , Thomssen C 
Published: June 2012

Abstract
Introduction: The role of routine preoperative breast MRI in patients diagnosed with breast cancer is still under discussion. In a milestone review, Houssami et al. (CA Cancer J Clin 2009;59;290) did not demonstrate an advantage with regard to DFS or OS. We reviewed our case series (n=793) in order to add evidence to the current discussion of whether or not preoperative MRI would influence the outcome.
Material and Methods: In our database we identified four years of diagnosis (2004-07) in which a high percentage (72%) of patients (349 of 483) with histologically confirmed invasive breast cancer received preoperative MRI. In the following years (2008/09), MRI was still done in 31% of the cases (97 of 309). All pts were treated according to national guidelines; however, patients with additional lesions in MRI were subjected to an additional MRI-guided needle biopsy or additional wire-guided excision. The median follow-up time was 31.5 months (0-81). The patients were followed clinically. In most cases local surveillance was done by mammography.
Results: In the total cohort, 20% of the patients had additional needle biopsies and/or wire-localisation due to MRI-findings. By MRI, lesions that subsequently led to an additional preoperative needle biopsy were found in 82 pts. Interestingly, only ten contralateral second cancers were found. In 357 pts, MRI was used as guidance during the operation with (n=118) or without MRI-supported wire localization (n=238). The percentage of additional MRI-needle biopsy or MRI-supported localisation did not differ between invasive ductal (n=655) and lobular cancer (n=91): 10% versus 13% needle biopsies and 15% versus 20% wire localisations. The number of surgical procedures to achieve tumor-free margins did not differ between patients with or without preoperative MRI. In this series, 69 of 100 patients who received neoadjuvant chemotherapy, also had MRI-imaging. Considering the patient cohort with follow-up available (n=737), no significant difference of DFS probability was observed between pts with and without preoperative MRI.
Discussion: This retrospective analysis did not demonstrate any advantage for routine preoperative MRI with regard to local treatment and DFS probability. The observed rate of 20% additional operative procedures corresponds to similar published data (16% additional multicentric or multifocal lesions found by MRI, Solin, Breast. 2010;19:7).
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P2-08-13.
P2-09-03: Breast Cancer Detection Using a Novel Functional Imaging Device Equipped with Multiparametric Computer Analysis.
Authors: Sella T , Sklair-Levy M , Maya C , Rozin M , Tanir A , Maira S , Libson E , Izhaky D 
Published: June 2012

Abstract
Introduction: A novel prototype system performing functional three-dimensional (3D) infrared imaging (RUTH), coupled with multi-parametric computer analysis (MIRA), was evaluated for non-invasive breast cancer detection. The technique utilizes non-ionizing radiation and automatically provides risk assessment based on parameters derived from a clinically known training set.
Materials and methods: Following IRB approval, prospective multi-center, two-armed blinded evaluation, was performed on 102 women, which included 43 patients with biopsy proven breast cancer and 59 women with a normal (BI-RADS 1) mammogram. RUTH imaging (Real Imaging Ltd, Israel) was acquired on a continuous temporal timeline for 5 minutes during which a cold-stress test was applied for one minute. Acquired data were analyzed using multiple computed algorithms (MIRA) which were combined to develop a master algorithm for risk assessment of breast cancer. Analysis was blinded to the clinical status. Results were displayed as risk assessment scale with 100 being suspicious for breast cancer and −100 inferring normal healthy breasts.
Results Thirty-nine of 43 cancers (91.7%) were identified using this novel technology. The sensitivity and specificity of RUTH coupled with MIRA for detecting breast cancer were 90.7% and 67.8% respectively. The AUC defined by the ROC curve was 0.832. Twenty-seven of the 39 (70%) detected cancers were smaller than 20mm in size.
Conclusions: This preliminary study shows adequate performance of the novel technology examined for detecting breast cancer. Performance is comparable to the reported performance of new adjunctive breast imaging technologies such as tomosynthesis and contrast-enhanced mammography, and superior to the published sensitivity of mammography. Our results warrant further evaluation of the RUTH and MIRA technologies in detecting and characterizing breast cancer.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P2-09-03.
P2-09-12: High Resolution Diffusion MRI Characterizes Tumor Stromal Boundaries.
Authors: McLaughlin RL , Newitt DC , Wilmes LJ , Sinha S , Wisner DJ , Hylton NM 
Published: June 2012

Abstract
Background: Studies of 3D cell cultures have shown that mammary epithelial cell growth and morphogenesis is regulated by extracellular matrix (ECM) stiffness, linking ECM stiffening to malignant transformation. Tumors are consistently stiffer than normal adjacent tissue, and matrix stiffening is caused by ECM cross-linking and increased deposition of collagen. Some evidence suggests that collagen orientation at tumor boundaries can promote tumor metastasis. Measuring the stiffness of the tumor boundaries and adjacent stromal tissue may give additional information 1) about tumor microenvironment and 2) to guide treatment. Diffusion-weighted imaging (DWI) MRI measures the mobility of water in tissue and may be sensitive to this phenomenon.
Material and Methods: MRI data was collected on patients with locally advance breast cancer enrolled in an IRB-approved study at UCSF and signed informed consent. In addition to a standard dynamic contrast enhanced (DCE) MRI, a high-resolution diffusion-weighted image (HR DWI) was acquired with an echo planar imaging sequence and the following parameters: TR/TE=4000/64.8 ms, b=0,600, FOV=70×140mm, matrix=28×64, and voxel size=0.55×0.55×4.0mm. Apparent diffusion coefficient (ADC) maps were created. HR DWI images were segmented into tumor and non-enhancing, surrounding stromal tissue. A proximity mapping method was used to measure ADC values at the inner edge of tumor and at increasing distances from the tumor boundary on HR DWI. The mean was calculated for the voxels in 1 mm increments, starting at 5 mm into the tumor (−5 mm) and ending at 2.5 cm away from the tumor (25 mm).
Results: The average of the changes per 1 mm shell was largest for the transition of the tumor boundary (Table 1). In Table 1, the −5 to 0 mm, 0 to 5 mm, and 5 to 25 mm columns represent inside the tumor, tumor boundary, and outside the tumor, respectively. In general, ADC values were consistently lower inside the tumor than outside. The greatest changes per 1 mm shell was seen in the transition from inside to outside tumor, although the values varied among tumor types. Each of the three cases analyzed had different patterns of ADC values.

Discussion: These preliminary studies show that water mobility measurements change at the tumor boundary, with different patterns observed among individual patients. We are further investigating the influence of density and tumor margin morphology on these ADC measurements.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P2-09-12.
P2-09-13: The Value of FDG PET/CT in Screening Detected Breast Cancer Patients.
Authors: Koo HR , Moon WK , Cho N , Chang JM , Kang KW , Yi A 
Published: June 2012

Abstract
Background. To evaluate the diagnostic value of FDG PET/CT for initial staging of screening detected breast cancer.
Methods. Between January 2008 and June 2010, a total of 77 women (mean age 54 years, range 31–77 years) with screening detected primary breast cancer (mean invasive tumor size 1.65cm, range 1–70mm) underwent whole body fluorine-18 fluorodeoxyglucose (FDG) PET/CT for initial staging and were included in this retrospective study. Two patients had bilateral breast cancer. The sensitivity of FDG PET/CT for the detection of primary tumor and the sensitivity, specificity, PPV and NPV for the detection of axillary lymph node metastases were determined. Systemic staging with whole body FDG PET/CT was also performed. For analysis of diagnostic performance of FDG PET/CT, quantitative measurement of the maximum standardized uptake value (SUVmax) criteria 1.0 was used. The final histopathology following surgery served as the gold standard.
Results. The primary tumor was FDG PET/CT positive in 65 of 79 lesions (82%). Depending on the tumor size, there was a variation in diagnostic sensitivity (63% in ≤ 1cm tumor, n=19 vs. 88% in &gt; 1cm tumor, n=60) and the uptake of FDG was significantly higher in &gt; 1cm tumor than in ≤ 1cm tumor (mean SUVmax 2.85 vs. 1.11, p&lt;0.05). The uptake of FDG was significantly higher in ductal carcinomas compared to lobular carcinomas (median SUVmax 2.0, n=72 vs. 1.3, n=7, p&lt;0.05). Of the 77 patients included in this study, 16 patients were found to have axillary node metastasis. The sensitivity, specificity, PPV and NPV of FDG PET/CT for detection of LN metastasis were 63% (10/16), 89% (54/61), 59% (10/17) and 90% (54/60), respectively. FDG PET/CT showed distant uptake in 9 patients and 8 of 9 were false positive results. 4 lesions were confirmed histopathologically as benign and 4 lesions were evaluated with radiologic methods. One of nine was true positive result. Distant involvement was skeletal and visible on the conventional bone scintigraphy. The patient staged as cT1N3M1.
Conclusion. FDG PET/CT has limited value for the initial staging of screening detected breast cancer patients. Considering high costs, radiation exposure and false positivity, FDG PET-CT is not recommended for the preoperative evaluation of screening detected breast cancer patients.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P2-09-13.