bluuebunny/crossref_metadata_2025_split huggingface dataset:
P2-02-05: Molecular Mechanism for Src Homology Phosphotyrosyl Phosphatase 2 Regulation of Cell Motility and Migration.
Authors: Hartman ZR , Agazie YM 
Published: June 2012

Abstract
Background: The Src homology phosphotyrosyl phosphatase 2 (SHP2) acts as a transducer of mitogenic and cell survival signaling downstream of receptor tyrosine kinases, cytokine receptors and integrins. As such, SHP2 promotes cell growth, transformation, survival, and motility, among other processes. Recent studies suggest that SHP2 is overexpressed in breast cancer and is essential for the maintenance of the transformed phenotype both in the HER2−positive and the basal-type/triple-negative breast cancer (BTBC) cells.
Materials and Methods: The expression of SHP2 in BTBC cells was suppressed constitutively by lenti virus-mediated transduction of specific shRNA. Impact of SHP2 inhibition on cell migration was determined by the monolayer wound healing assay. The SHP2 substrate-trapping mutant was used to identify FAK as an SHP2 substrate. Site-directed mutagenesis, binding studies and phosphatase assays were employed to further characterize FAK as a bona fide SHP2 substrate. Immunofluorescence microscopy was conducted to visualize the amounts of phosphorylated FAK and its location in the cell after adhesion.
Results: We demonstrate that SHP2 is essential for the migration of BTBC cells as evidenced by loss of the enhanced migratory behavior upon its inhibition. Using the SHP2 substrate-trapping mutant, FAK was identified as a biological substrate of SHP2. Site-directed mutagenesis, binding studies and phosphatase assays confirmed that SHP2 indeed associates with and dephosphorylates FAK at the pY397 site, a site known to promote the focal adhesion activity of FAK. Immunofluorescence of breast cancer cells with SHP2 inhibition were found to have higher levels of FAK pY397 further confirming that FAK is an SHP2 substrate. The increase in pY397 level correlated with loss of cell polarity, enhanced focal adhesion formation, and acquisition of non-transformed morphology.
Discussion: These results suggest that dephosphorylation of pY397 of FAK by SHP2 is the major mechanism by which it is able to modulate cancer cell migration. Together with previous findings, the current studies show that SHP2 is a suitable target for therapeutic intervention to combat breast cancer metastasis.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P2-02-05.
P2-02-10: Differential Targeting of the RB-Pathway To Expand the Therapeutic Index in the Treatment of Triple Negative Breast Cancer.
Authors: Knudsen ES , Dean J , Thangavel C , Ertel A , Witkiewicz AK , McClendon AK 
Published: June 2012

Abstract
Background: The retinoblastoma tumor suppressor (RB) is inactivated in a significant fraction of triple negative breast cancers (TNBC). RB loss is believed to contribute to tumor initiation and progression, and provocative data suggest that RB loss is associated with improved response to cytotoxic chemotherapy. Unfortunately, such therapies have significant side effects that impinge on patient quality of life. Here we explored the ability to specifically target RB loss in TNBC to expand the therapeutic index by protecting against undesired side-effects of chemotherapy.
Experimental Design: A combination of cell culture and xenograft models of triple negative breast cancer were used to evaluate how RB-status impinges on sensitivity to chemotherapy. These models were complemented by the analyses of clinical specimens from patients treated with chemotherapy. Parallel use of agents that activate RB function with high specificity were interrogated as potential tissue protectors to ameliorate side effect of chemotherapy.
Results: RB loss in preclinical models is associated with increased sensitivity to conventional cytotoxic chemotherapies that are frequently employed in the treatment of TNBC. The findings were recapitulated through the analyses of clinical specimens, and suggest that the loss of RB could be particularly useful in defining TNBC patients with improved response to chemotherapy. Combination studies of pharmacological activation of the RB pathway and cytotoxic chemotherapies commonly used to treat TNBC demonstrated that activation of RB can modulate the efficacy of cytotoxic compounds in the treatment of TNBC. Importantly, functional studies indicated that RB pathway activation limits cardiotoxicity associated with anthracycline based treatments and correspondingly improve cardiac function in animal studies.
Conclusions: Combined, these studies indicate that RB pathway status could be utilized in the clinic to direct combination treatments that would exploit the sensitivity of RB-deficient tumors to cytotoxic chemotherapies while simultaneously providing protection for normal tissues.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P2-02-10.
P2-05-02: PGC1, Peroxisome Proliferator Activated Receptor-gamma (PPAR-gamma) Coactivator-1, Is Necessary in PPAR-gamma Modulated Angiogenesis.
Authors: Jiang WG , Li X , Mansel RE 
Published: June 2012

Abstract
Background. Peroxisome proliferator activated receptor- gamma (PPAR-gamma), a nuclear hormone receptor, has been shown to be an important regulator of gene expression. PPAR-gamma agonists have been shown to have anti-cancer properties by ways of inducing expression of tumour suppressor genes. It has been indicated that this action of PPAR-gamma is manifested by forming a complex with the PPAR-gamma coactivators (PGC1 &2) and in association with other transcription factors such as SRC-1 and CREB binding proteins. Both PPAR-gamma and PGC-1 have been shown to be aberrantly expressed in human cancer including human breast cancer (1). PPAR-gamma also plays a role in regulating angiogenesis and that PPAR-gamma agonists have been shown to have anti-angiogenic functions. In the present study, we investigated the role of PGC-1 in PPAR-gamma mediated actions on vascular endothelial cells. Materials and methods. Mammalian expression systems for human full length PGC-1 ereonstructed. Anti-PGC-1 transgenes were constructed again using human mammalian expression vector in order to knock down PGC-1 transcript from the cells. Human vascular endothelial cell, HECV, was used in the study. Cell functions linked to angiogenesis including cell adhesion and cellular migration was evaluated using the electric cell impedance sensing method. PPAR-gamma agonists and antagonists were used in the cell models during the analyses.
Results. HECV cells weakly expressed PGC-1 and PPAR-gamma. Using the transgenes created, sublines over-expressing PGC1 (HECVPGC1exp) or with PGC-1 expression knockdown (HECVPGC1KD) were established. Loss of PGC1 showed marked increase in both adhesion and cellular migration, opposite was true forHECVPGC1exp cells. PPAR-gamma agonist, pioglitizone and ciglitizone, reduced the adhesion of control cells. In contrast, PPAR-gamma antagonist SR202 exhibited a concentration dependent stimulation of both adhesion and migration of the control cells. Knocking down PGC1 in endothelial cells rendered cells lost response to SR202.
Conclusions. PGC-1 is essential in during the modulation of endothelial cells by PPAR-gamma. Together with the aberrant expression of both PPAR-gamma and PGC-1 in breast cancer, it is concluded that PGC-1 is a central player in PPAR-gamma mediated action in both cancer cells and angiogenesis.
1. Jiang WG, Douglas-Jones A, Mansel RE. Expression of peroxisome-proliferator activated receptor-gamma (PPARgamma) and the PPARgamma co-activator, PGC-1, in human breast cancer correlates with clinical outcomes. Int J Cancer. 2003, 106(5):752–757.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P2-05-02.
P2-05-03: Is Breast Cancer Tryptase a Novel Anti-Angiogenetic Molecular Target?
Authors: Ranieri G , Gadaleta-Caldarola G , Misino A , Patruno R , Goffredo V , Di Lecce V , Vinciarelli G , Valerio P , Zito A , Gadaleta CD 
Published: June 2012

Abstract
Tryptase, a serine protease stored and released from mast cells granules has been identified as a new non-classical angiogenetic factor. Tryptase is an agonist of proteinase-activated receptor-2 a G protein involved in cellular proliferation and angiogenesis. On the other hand mast cells can release tryptase following c-Kit receptor activation. We have evaluated the correlations among the number of MCs positive to tryptase (MCDPT), the number of c-Kit receptor expressing cells (C-KREC) and microvascular density (MVD) in a series of 91 primary T1-3, N0-2 M0 female breast cancer by means of immunohistochemistry and image analysis methods. Six-micrometers thick serial sections of formalin-fixed and paraffin-embedded bioptic tumor samples were microwaved at 500 W for 10 min. and treated with a 3% hydrogen peroxide solution. Sections were incubated with primary antibodies: anti-tryptase (AA1; Dako, Glostrup, Denmark), anti-c-Kit receptor (A4502; Dako, Glostrup, Denmark) and anti-CD34 (QB-END 10; Bio-Optica Milan, Italy). In serial sections MVD, MCDPT and C-KREC were counted by means of image analysis (Quantimet 500 Leica) at x400 microscopic fields. Data demonstrated a significantly (r= ranging from 0.72 to 0.91; p: ranging from 0.001 to 0.003 by Pearson's analysis respectively) correlation between MVD, MCDPT and C-KREC to each other. Published in vitro data suggest that tryptase induce angiogenesis in vascular endothelial cells and breast cancer cells lines. According to these data we shown that MVD, MCDPT and C-KREC paralleled to each other suggesting a role in in vivo breast cancer angiogenesis. In this context the inhibition of c-Kit mast cells tryptase degranulation by several tyrosin kinase inhibitors might be evaluated in clinical trials. Finally available tryptase inhibitors such as gabexate mesilate or nafamostat mesilate might be evaluated in clinical trials as a new antiangiogenetic approach.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P2-05-03.
P2-06-03: Differential Expression of Breast Cancer-Associated Genes between Stage- and Age-Matched Tumor Specimens from African- and Caucasian-American Women Diagnosed with Breast Cancer.
Authors: Grizzle WE , Steg AD , He Q , Steciuk MR , Byan-Parker S , Johnson MR , Grunda JM 
Published: June 2012

Abstract
Background: Recent studies suggest that the poorer outcome of breast cancer patients observed in African-American women (AAW) may, in part, result from underlying genetic factors. The purpose of this study was to investigate gene expression differences between Caucasian-American women (CAW) and AAW that may contribute to this poorer prognosis.
Methods: The expression of genes involved in breast carcinoma prognosis, response to therapy, estrogen signaling, and tumor aggressiveness was assessed in age- and stage-matched CAW and AAW paraffin-embedded breast cancer specimens. The Wilcoxon-Mann-Whitney Test was used to identify genes with a significant difference in expression between CAW and AAW. To determine if the differentially expressed genes could segregate between the CAW and AAW, we performed semi-supervised principle component analysis (SSPCA).
Results: Twenty genes were differentially expressed between AAW and CAW. SSPCA incorporating these 20 genes separated AAW and CAW into two distinct groups. AAW were significantly (p &lt; 0.05) more likely to display aberrations in G1/S cell-cycle regulatory genes, decreased expression of cell-adhesion genes, and low to no expression of ESR1, PGR, ERBB2 and estrogen pathway targets.
Conclusions: The gene expression differences identified between AAW and CAW may contribute to more aggressive disease, resistance to therapy, enhanced metastatic potential and poor clinical outcome. Impact: These findings support the hypothesis that breast cancer specimens collected from AAW display distinct genetic differences compared to similar tissues obtained from CAW. Additional population-based studies are necessary to determine if these genetic variations contribute to the highly aggressive and treatment-resistant breast cancer phenotype frequently observed in AAW.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P2-06-03.
P2-07-02: Germline Genetic Variants Disturbing the Let-7/LIN28 Double-Negative Feedback Loop Alter Breast Cancer Susceptibility.
Authors: Yu K-D , Shao Z-M , Chen A-X 
Published: June 2012

Abstract
Previous studies have shown that let-7 can repress the post-transcriptional translation of LIN28, and LIN28, in turn, could block the maturation of let-7, forming a double-negative feedback loop. In this study, we investigated the effect of germline genetic variants on regulation of the homeostasis of the let-7/LIN28 loop and breast cancer risk. We initially demonstrated that the T/C variants of rs3811463, a single nucleotide polymorphism (SNP) located near the let-7 binding site in LIN28, could lead to differential regulation of LIN28 by let-7. Specifically, the C allele of rs3811463 weakened let-7-induced repression of LIN28 mRNA, resulting in increased production of LIN28 protein, which could in turn downregulate the level of mature let-7. This effect was then validated at the tissue level in that the normal breast tissue of individuals with the rs3811463-TC genotype expressed significantly lower levels of let-7 and higher levels of LIN28 protein than those individuals with the rs3811463-TT genotype. Because previous in vitro and ex vivo experiments have consistently suggested that LIN28 could promote cellular transformation, we then systematically evaluated the relationship between rs3811463 as well as other common LIN28 SNPs and the risk of breast cancer in a stepwise manner. The first hospital-based association study (n = 2,300) demonstrated that two SNPs were significantly associated with breast cancer risk, one of which was rs3811463, while the other was rs6697410. The C allele of the rs3811463 SNP corresponded to an increased risk of breast cancer with an odds ratio (OR) of 1.25 (P = 0.0091), which was successfully replicated in a second independent study (n = 1,156) with community-based controls. The combined P-value of the two studies was 8.0 × 10−5. Taken together, our study demonstrates that host genetic variants could disturb the regulation of the let-7/LIN28 double-negative feedback loop and alter breast cancer risk.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P2-07-02.
P2-07-03: Collective Evidence Suggests Neutrality for BRCA1 V1687I, a Novel Sequence Variant in the Conserved THV Motif of the First BRCT Repeat.
Authors: Cortesi L , De Nicolo A , Medici V , Marino M , Turchetti D , Pradella LM , Rossi G , Parisini E , Federico M 
Published: June 2012

Abstract
Background: Unequivocal classification of BRCA1 and BRCA2 variants of uncertain significance (VUS) with respect to their effect on protein function is a challenge with consequent implications for clinical decision-making. Currently, integration of different types of evidence derived from independent sources appears to be the most reliable approach to help define disease relevance for each single VUS. During a routine screening for BRCA1 and BRCA2 mutations carried out by the Modena study group for familial breast and ovarian cancer we identified a novel BRCA1 sequence change (c.5178G&gt;A) that causes a valine to isoleucine (V to I) substitution at position 1687. The sequence alteration was found in a patient diagnosed with early onset breast cancer and it was present neither in other breast/ovarian cancer families screened nor in unaffected control individuals. No co-occurrence of the variant with any known clinically relevant BRCA1 mutations was observed.
The C-terminally located BRCA1 V1687I lies in the conserved THV motif of the first BRCT repeat. Disease-causality has previously been suggested for two neighbouring sequence alterations, BRCA1 V1688del, whose repercussions on protein stability and function were also reported (De Nicolo et al., 2009), and BRCA1 H1686Q (Giannini et al, 2008). We aimed at garnering evidence that, together with family and genetic data, could help assess the clinical significance of the V1687I variant.
Methods: We employed a multimodal approach that included immunohistochemistry on tumor sections, in silico analyses, comparative structural modeling, and ascertainment of BRCT-mediated functional associations.
Results: Whereas tumor histology, receptor and HER2/neu status were compatible with a BRCA1-deficient phenotype, most algorithms we used to assess sequence and structure variation based on evolutionary conservation predicted the BRCA1 V1687I variant to be benign. In line with this prediction, analysis of the modeled BRCA1 V1687I BRCT domain did not reveal any major structural changes relative to the wild type counterpart and suggested that BRCA1 V1687I leaves the local architecture and overall stability of the protein largely unaltered. Consistently, the BRCA1 V1687I protein was properly expressed and localized to the nucleus, and it was still capable of binding BRIP1/FANCJ, CtIP and Abraxas, three BRCT-interacting, DNA damage response and repair partner proteins.
Conclusions: Based on our collected evidence, the BRCA1 V1687I amino acid change, although occurring in an evolutionary conserved region, does not seem to affect the function of the correspondingly encoded protein, and hence it is a likely benign sequence alteration.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P2-07-03.
P2-08-02: Magnetic Resonance Imaging as a Predictor of Pathologic Response in Patients Treated with Neoadjuvant Systemic Treatment for Operable Breast Cancer (TBCRC 017).
Authors: De Los Santos J , Cantor A , Mcguire K , Golshan M , Meric-Bernstam F , Horton J , Nanda R , Amos K , Forero A , Hudis C , Meszoely I , Hwang S 
Published: June 2012

Abstract
Background: Increased pathologic complete response (pCR) rates observed with neoadjuvant chemotherapy for invasive breast cancer has prompted interest in whether patients with pCR can be identified preoperatively and potentially spared the morbidity of surgery. This multicenter retrospective study was performed to determine the accuracy of preoperative MRI in predicting pCR in the breast and whether MRI performance differs by molecular subtype, histology, and treatment regimen.
Methods: 770 women from 8 institutions were retrospectively identified as having received neoadjuvant systemic therapy with MRI obtained at baseline and after completion of systemic treatment. Tumor phenotypes were defined on the basis of estrogen and progesterone receptor (ER/PR or HR) and HER2 receptor status. Univariate and multivariate analyses of factors influencing radiographic complete response (rCR) and pCR were recorded, with rCR defined as resolution of any abnormal enhancement, mass, or distortion on MRI, and pCR defined as resolution of both invasive disease and DCIS.
Results: rCR and pCR for the total group were 182/746 (24%) and 179/746 (24%), respectively, with the highest rate of pCR seen among the triple-negative (TN; 57/155; 37%) and HR-/HER2+ (38/101; 38%) subtypes. Covariates significantly associated with rCR included T stage (p=0.0002), tumor grade (p=0.005), IHC phenotype (p=0.005), and chemotherapy regimen (p&lt;0.0001). On multivariate analysis, only tumor phenotype was independently associated with likelihood of rCR, with both TN (OR = 2.00, 95% CI 1.20−3.33) and HR-HER2+ (OR=2.30, 95% CI 1.09–4.83) more likely to achieve rCR than HR+HER- (reference group). Overall accuracy of MRI for prediction of pCR was 74%. Sensitivity, NPV, PPV, and accuracy differed significantly among tumor subtypes, with the greatest NPV in the HR-/HER2+ and TN subtypes (table1). Among patients with rCR, ER- status (OR=6.4, 95% CI 1.1 to 35.6), PR- status (OR=3.8, 95% CI 1.2 to 11.4), and tumor grade of 3 vs 1 or 2 (OR=2.49, 95% CI 1.22−5.07) were independently associated with likelihood of pCR. Discussion: MRI performance for predicting pCR in patients with invasive breast cancer receiving neoadjuvant systemic therapy differed significantly among breast cancer subtypes; however this difference is likely due to subtype differences in frequency of pCR and not to intrinsically better or worse MRI detection. The relatively low NPV of MRI following neoadjuvant systemic therapy does not support using MRI rCR alone to accurately identify those patients that can safely avoid surgery.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P2-08-02.
P2-08-03: Quantitative MRI for Noninvasive Prediction of Prognostic Markers in Breast Cancer.
Authors: Parsian S , Sun R , Kurland BF , Rahbar H , Allison KH , Specht JM , DeMartini WB , Lehman CD , Partridge SC 
Published: June 2012

Abstract
Background: Magnetic resonance imaging (MRI) is a valuable tool for assessing extent of breast cancer and monitoring treatment response. Quantitative measures by diffusion-weighted MRI (DWI) and dynamic contrast-enhanced (DCE) MRI reflect tumor cellularity and vascularity. Tumor grade and some histopathological markers, such as ER, PR, HER-2, Ki67 and P53, are prognostic factors that can also be associated with tumor cellularity and vascularity. DWI and DCE measures may therefore provide a noninvasive means for predicting disease prognosis and stratifying patients to appropriate therapies. The purpose of this study was to investigate the correlation between quantitative MRI features and prognostic pathological factors in patients with invasive breast cancer.
Methods: This IRB-approved retrospective study included patients with biopsy-proven invasive cancer who underwent 1.5T breast MRI (including DCE and DWI) from October 2005 to May 2006 prior to treatment. Pathology data was obtained from pre-treatment biopsy and intrinsic subtype classification was approximated by standard immunohistochemistry characteristics. After excluding cases with missing MRI or pathology data, the final study cohort included 41 invasive cancers (36 ductal and 5 lobular carcinomas) in 36 patients. MRI measures included lesion DCE kinetic features: peak initial enhancement (PE), percent rapid enhancement (RE), and percent washout (WO), and DWI normalized apparent diffusion coefficient values (nADC). Associations between imaging features and pathology markers, cancer grades and intrinsic subtypes were evaluated by Mann-Whitney U test and multivariate logistic regression.
Results: Results of univariate comparisons are summarized in Table 1. One or more DCE-MRI kinetic parameters were significantly predictive (p&lt;0.05) of each of the histopathological markers with the exception of ER, which was marginally associated with WO (p=0.05). Each of the DCE kinetics parameters significantly discriminated grade III tumors from grades I and II and luminal A from luminal B and basal-like intrinsic subtypes. In multivariate regression, both PE and WO were significant independent predictors of tumor grade (p=0.0094, p=0.0005, respectively). WO and nADC were significant independent predictors of PR status (p=0.0054, p=0.0027), while PE was the only significant independent predictor of both Ki67 (p=0.014) and intrinsic subtype (p=0.015).
Conclusion: This preliminary study suggests that quantitative MRI measures are associated with prognostic tumor markers and may provide valuable noninvasive characterization of tumor biology. Larger prospective studies are needed to validate our findings.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P2-08-03.