bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract P3-10-01: Epidemiological risk factors and normal breast tissue markers in inflammatory breast cancer
Authors: Atkinson RL , Sexton KR , Ueno NT , El-Zein R , Brewster AM , Krishnamurthy SA , Woodward WA 
Published: August 2014

Abstract
Background: Inflammatory breast cancer (IBC) is a rare form of aggressive breast cancer with no existing identifiers for screening or prevention strategies. Women with triple-negative (TNBC, ER–, PR–, Her2–) non-inflammatory breast cancer are less likely to breastfeed, and we have shown in adjacent normal breast tissue that this tissue has more foci of stem cells compared to non-TNBC cancers. A disproportionately higher percentage of women with IBC have TNBC relative to women with non-IBC. We hypothesized that adjacent normal tissue in TNBC IBC vs. TN non-IBC may also display unique biological features based on epidemiologic characteristics.
Methods: We examined epidemiologic factors by breast cancer receptor subtype in 144 patients diagnosed with IBC in 1991–2011 at MD Anderson Cancer Center. Breast cancer risk factors including parity and breastfeeding were compared between patients with TN and non-TN IBC with chi-square or Wilcoxon rank sum tests. Normal adjacent tissues were stained for stem cell markers CD44+CD49f+CD133/2+ and macrophage marker CD68.
Results: The mean age at diagnosis was 52.3 years (range = 23–80) and 83% of patients were non-Hispanic white, 80% were overweight or obese (BMI &gt;25), and 36% were TN IBC. Patients with TN IBC had significantly lower frequency of breastfeeding compared with non-TN IBC, 28% vs. 55%, (p = 0.01). No differences were found in the frequency of other breast cancer risk factors. All 8 IBC adjacent tissue samples showed a distinct spatial distribution of stem cell staining, not limited to the triple negative patients. Compared with 0/60 non-IBC cases, 0/8 triple negative non-IBC, (p = 0.001 Pearson chi-square). Given the high BMI among IBC patients, we further examined normal tissues for the presence of CD68+ cells distributed individually or as clusters exhibiting a “crown-like” pattern (multiple CD 68+ macrophages found around dead adipocytes), and found that 7 of the 8 IBC adjacent tissues were CD68+. Benign biopsies collected from 2 patients at 10 years before diagnosis displayed similar staining, including both stem cell and CD68 staining. Compared with 12/60 non-IBC adjacent tissues were positive for CD68, with 1/8 TN non-IBC, (p = 0.001 Pearson chi-square).
Conclusion: We describe for the first time a stem-cell staining pattern unique to IBC present in all IBC tissues examined, including pre-cancer biopsies. Tissue samples from additional patients will be examined to further explore the relationship between stem cells and CD68 positivity with IBC subtypes.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P3-10-01.
Abstract P3-14-03: Differences in pathological and biological factors between DCIS, DCIS with microinvasion (DCIS-MI) and DCIS with concomitant invasive ductal carcinoma (DCIS-IDC).
Authors: MacGrogan G , Baranzelli MC , Picquenot JM , Penault-Llorca F , Mathieu MC , Tas P , Fermeaux V , Mery E , Sagan C , Blanc-Fournier C , Brabencova E , Arnould L , Jacquemier J , Ettore F , Velasco V , Gonzalves B , Brouste V , Tunon de Lara C 
Published: August 2014

Abstract
Background: Specific pathological and biological factors differentiating pure DCIS, DCIS with microinvasion (DCIS-MI) and DCIS with concomitant invasive ductal carcinoma (DCIS-IDC) are currently unknown. Identification of such factors would enable us to better understand the transition from an in situ to an invasive carcinoma and improve patient management for patients diagnosed with extensive DCIS.
Methods: We previously performed a prospective surgical study demonstrating the benefit of performing upfront sentinel lymph node (SLN) biopsy in patients with extensive DCIS or DCIS-MI undergoing mastectomy. In that study, 196 DCIS and 31 DCIS-MI diagnosed on vacuum-assisted macrobiopsies underwent mastectomy and SLN biopsy. Final pathological status after mastectomy examination revealed 117 DCIS, 38 DCIS-MI, 69 DCIS-IDC, and in 3 cases no residual disease was found. The mastectomy specimens of 216 cases (111 DCIS, 37 DCIS-MI, 68 DCIS-IDC) were available for central pathological review and a TMA containing DCIS lesions of 214 cases (110 DCIS, 36 DCIS-MI, 68 DCIS-IDC) was performed. DCIS morphological features (histological size, nuclear grade, comedo necrosis, inflammation) and immunohistochemical factors (ER, PR, Ki-67 and Her2) were assessed in each of the three groups and compared using Chi2 or Wilcoxon tests.
Results: Median histological DCIS sizes did not significantly differ between DCIS and DCIS-MI groups (70mm [4–160] and 60mm [4–180], respectively, p = 0.33), nor between DCIS and DCIS-IDC (70mm [4–160] and 65 mm [10–140], respectively, p = 0.98). DCIS nuclear grade was significantly higher in DCIS-MI compared to DCIS (p = 0.01), but there was no difference in nuclear grade between DCIS and DCIS-IDC (p = 0.22). Comedo necrosis was more often present in DCIS-MI compared to DCIS (p = 0.04), and no such difference was found between DCIS and DCIS-IDC (p = 0.81). Stromal inflammation surrounding DCIS was more often found in DCIS-MI and DCIS-IDC compared to DCIS (p = 0.03 and p &lt; 0.001, respectively). DCIS-MI was more often ER-negative than DCIS (p = 0.009), and no such difference was found between DCIS and DCIS-IDC (p = 0.6). No other significant differences concerning PR and Her2 status or Ki-67 index were found between the 3 groups.
Conclusions: In patients with extensive DCIS there are few morphological or current immunohistochemical factors differentiating in situ cases from those that have associated microinvasion or invasive ductal carcinoma. DCIS-MI cases have more aggressive histological features than DCIS. Stromal inflammation surrounding DCIS was the only feature distinguishing DCIS from DCIS-IDC.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P3-14-03.
Abstract P4-03-10: Sonographic-pathological correlation in contrast-enhanced ultrasonography in the diagnosis of breast cancers.
Authors: Kato K , Miyamoto Y , Kamio M , Nogi H , Imawari Y , Mimoto R , Toriumi Y , Nakata N , Takeyama H , Uchida K 
Published: August 2014

Abstract
Background: As contrast-enhanced ultrasonography (CEUS) in the diagnosis of breast masses has been performed less frequently than other imaging modalities, it's efficacy evaluation has not been established. CEUS with Sonazoid, which is microbubble-based contrast agent, allows visualization of the mass bloodstream, therefore the classification of enhancement patterns in CEUS could increase diagnostic yield for breast masses. To achieve this, a clear standard for the CEUS evaluation is needed. The purpose of this study was to identify CEUS findings for malignancies and clarify sonographic-pathological correlation of breast cancers.
Material and Method: Present study included 20 patients with invasive ductal cancer who underwent operation for primary therapy without any chemotherapy or hormonal therapy. We contrasted CEUS features with Sonazoid with surgical specimens retrospectively. As malignant findings, the presence of focal perfusion defects inside masses and enhancement of outside masses were chosen.
Result: All of the 20 cases displayed focal perfusion defects. 9 cases of those could be successfully assessed in the same sections histopathologically and ultrasonographically. Histopathological findings showed those defects to be fibrotic foci inside masses in 7cases (77.7%). While, 6 cases of all (30%) showed stains outside tumor, and only one case was found out to be fibrotic growth with cancer cells.
Conclusion: focal perfusion defects of breast masses in CEUS were considered to be specific for malignancy, and they seemed to be fibrotic foci histopathologically. Desmoplastic reaction has been observed in epithelial solid tumor biology, and if those defects reflect the desmoplasia defects could be the proof of malignancy.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P4-03-10.
Abstract P4-04-02: Tumor-initiated peripheral myeloid cell expansion is reversed by radiation therapy
Authors: Gough MJ , Savage T , Bahjat KS , Redmond W , Bambina S , Kasiewicz M , Cottam B , Newell P , Crittenden MR 
Published: August 2014

Abstract
Myeloid lineage cells, particularly monocytes and macrophages, have an important role in the development and progression of cancer. Within established tumors, macrophages are critical for angiogenesis, invasion, metastasis, immunosuppression and response to therapy. In addition, both transplantable and transgenic mouse models of mammary cancer are associated with myeloid expansions detectible in the tumor, spleen and peripheral blood, and these myeloid cells are able to suppress T cell activation in vitro. Reducing the tumor burden through chemotherapy and resection has been shown to control the myeloid expansion. However, chemotherapies that reduce tumor burden also have direct effects on myeloid cells, and surgical trauma has been shown to mobilize myeloid cells. Radiation therapy is the third major option to treat cancer, but the consequence of radiation therapy to systemic myeloid populations has not been described. We applied tumor-specific radiation therapy to test the hypothesis that the frequency of myeloid lineage cells correlates with the primary tumor burden. We demonstrate in the MMTV-PyMT model of mammary cancer that myeloid expansion in the blood closely correlates with myeloid involvement in the tumor and with tumor progression. We demonstrate that radiation therapy of 4T1 mammary tumors leads to a decline in myeloid cell numbers in the blood and a decrease in spleen size. The frequency of myeloid cells does not decline to the level seen in tumor-free mice: we demonstrate that metastatic disease can prevent myeloid cell numbers from returning to baseline, and that tumor recurrence from residual disease correlates with re-expansion of myeloid lineage cells. Despite these changes in the frequency of myeloid lineage cells, T cell numbers in the blood and spleen remains constant. However, radiation therapy improves the myeloid cell:CD8+ T cell ratio and results in increased proliferation of T cells in the spleen. Finally, we demonstrate that T cell responses to foreign antigens are not altered by tumor burden or myeloid cell expansion, while T cell responses to tumor-associated antigens are increased after radiation therapy of the tumor. These data demonstrate that myeloid cell numbers are directly linked to primary tumor burden, that this population contracts following radiation therapy, and that radiation therapy may open a therapeutic window for immunotherapy of residual disease.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P4-04-02.
Abstract P4-06-05: NF-κB Upregulates β1-integrin via Increased Transcriptional Activity in Three-dimensional Culture: a Mechanism by which Malignant Breast Cells Acquire Radioresistance
Authors: Ahmed KM , Zhang H , Park CC 
Published: August 2014

Abstract
The molecular mechanisms giving rise to tumor viability after therapeutic radiation remain elusive. We showed previously that β1-integrin is associated with enhanced cell survival of breast cancer cells after exposure to high dose ionizing radiation (IR). Recently, we discovered that a typical binding site for Nuclear factor-κB (NF-κB), a stress-sensitive heterodimeric transcription factor, was located in human β1-integrin promoter, which indicates that β1-integrin-mediated resistance to radiation may be functionally regulated by NF-κB. The aim of the present study was to investigate the relationship between NF-κB and β1-integrin pathways in radioprotection of malignant T4-2 breast cells in three-dimensional laminin-rich extracellular matrix (3D lrECM). We show that NF-κB is required for radiation-induced β1-integrin transactivation. Inhibition of NF-κB activity significantly reduced clonogenic survival with the inhibition of IR-induced total and phosphorylated (Thr 788/789) β1-integrins, correlated with increased DNA binding activity at the β1- integrin promoter. Treatment of T4-2 colonies with NF-κB activation inhibitor before IR resulted in a reduction of the size of colonies, associated with a decrease in proliferation and increase in apoptosis, indicating an increased susceptibility to IR. Further studies revealed that a direct interaction of β1-integrin with α5-integrin was highly induced, but not with NF-κB p65, in T4-2 cells surviving IR. These interactions were found to be oppositely regulated in radiosensitive S1 cells, suggesting that IR induces the formation of α5β1-integrin complexes leading to increased survival post-IR. Together these results provide the first evidence that NF-κB-induced β1-integrin transactivation is responsible for increased survival post IR in breast cancer. Since β1-integrin is shown to activate NF-κB, our data further suggest a loop-like β1-integrin–NF-κB–β1-integrin pathway in tumor radioresistance. This novel pathway may serve as an efficient drug target to re-sensitize radioresistant tumor cells.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P4-06-05.
Abstract P4-06-08: Clinical utility of functional analysis of FGFR kinase family for selecting patients who may benefit from FGFR inhibitors
Authors: Hoe N , Zhou J , Kuy C , Jin K , Srikrishnan R , Soundararajan A , Ma Y , Liu X , Singh S 
Published: August 2014

Abstract
Background: Fibroblast growth factor receptor (FGFR) family of receptor tyrosine kinases (RTKs) are currently under investigation as therapeutic targets for the treatment of breast cancer. Members of this kinase family have been associated with breast cancer progression and resistance to current therapeutics. FGFR1 amplifications range from 7.5–17% in breast cancers and are associated with a shorter overall survival. FGFR1 amplified cell lines drive activation of AKT, ERK, and RSK and are highly sensitive to FGFR1 inhibition, suggesting an oncogenic addiction to FGFR1. FGFR2 is activated in lapatinib-resistant, HER2-positive cells. Likewise, FGFR3 expression levels are elevated in tamoxifen-resistant, ER positive patients. FGFR 4 overexpression correlated with poor response to chemotherapy due to activation of MAPK and increase in B-cell lymphoma extra large (BCL-XL) levels. Using an immuno-microarray system, this study seeks to determine FGFR signal transduction pathway modulation post FGFR inhibitor treatment in breast cancer cell lines expressing varying levels of FGFR1, 2, 3 or 4.
Method: FGFR 1, 2, 3, and 4 amplified cell lines (MDA-MB-134VI (KRAS), SNU16, RT112, and MDA-MB-453) were treated with varying dosages (1, 10, 100, and 1000nM) of several FGFR inhibitors (AZD4547 (pan FGFR), PD173074 (FGFR1,3) and Ponatinib-AP24534 (FGFR1)) either in presence or absence of corresponding FGF (FGF1, FGF7, FGF9, and FGF19) stimulation. Expression and activation of FGFR 1, 2, 3, and 4 and downstream signaling proteins FRS2, AKT, ERK, MEK, and RSK were measured utilizing a proximity based immuno-microarray.
Results: FGFR1, 2, 3, 4 protein expression was detected in each of the corresponding four FGFR1, 2, 3, 4 amplified cell lines. Total protein levels remained unchanged with or without FGFs stimulation. Levels of FGFR1 phosphorylation increased 5 folds in MDA-MB-134VI stimulated with FGF1. FGFR2 and FGFR3 activation increased by 2–3 folds in SNU16 and RT112 stimulated with FGF7, and FGF9 respectively. FGFR4 activation levels in MDA-MB-453 remained unchanged due to Y367C mutation. ERK was activated in both FGF1 stimulated and unstimulated group in MDA-MB134 due to the KRAS mutation. RSK activation increased in both SNU16 and RT112 when stimulated with FGF7, and FGF9 respectively. FGFR inhibitors treated data analysis is currently in progress and will be presented.
Conclusion: We have demonstrated utility of specific FGFR analysis using well defined model systems. FGFR- profiling should be considered during the clinical work-up in order to select patients who may benefit from regimen containing specific FGFR inhibitors.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P4-06-08.
Abstract P4-06-15: Mifepristone modifies the tumor microenvironment increasing the therapeutic efficiency of low doses of Doxorubicin liposomes or paclitaxel-albumin nanoparticles in a murine model of breast cancer.
Authors: Sequeira GR , Vanzulli SI , Lamb CA , Rojas PA , Lanari C 
Published: August 2014

Abstract
Chemotherapy is the standard treatment for metastatic breast cancer today. To overcome undesired side effects and improve drug efficacy in tumor cells, different nanoparticle formulations have been developed. Paclitaxel has been bound with human albumin (Nab-paclitaxel), and pegylated liposomes have been developed for doxorubicin delivery (PEG-LD). The aim of our study was to evaluate the effect of these therapeutic agents in experimental mammary carcinomas expressing different ratios of progesterone receptor (PR) isoforms and to evaluate the effect of combined treatments of chemotherapeutic agents with the antiprogestin mifepristone (MFP). Nab-paclitaxel (Abraxane, Abraxis), at a dosage of 30 and 60 mg/kg body weight administered in three doses every four days, completely inhibited the growth of the antiprogestin-resistant C4-2-HI mouse mammary carcinoma, which is associated with high levels of PR isoform B (PR-B) expression. C4-HI, an antiprogestin-responsive mouse tumor that shows high levels of PR isoform A (PR-A) expression, was not inhibited by the low Nab-paclitaxel dose. However, the combination of MFP (6 mg silastic pellet) with Nab-paclitaxel improved the efficacy of both single treatments. Similar experiments were conducted using PEG-LD (Doxopeg; Laboratorios Raffo). In this case, all tumors tested (C4-HI, CC4-3-HI, 59–2-HI and C4-2-HI) were all highly responsive to high (18 mg/kg/week) or low (9 mg/kg/week) PEG-LD doses. When PEG-LD concentrations were lowered to 4.5 mg/kg/week and they were combined with MFP, an improved response was observed with combined treatments only in tumors with high PR-A levels (p &lt;0.001). Using BALB/c-GFP mice, we demonstrated that MFP treatment induced tissue remodeling in PR-A positive tumors, increasing the stromal/tumor cell ratio and the number of vessels (as shown by CD31 positive cells; p &lt; 0.001). Taking advantage of doxorubicin's red autofluorescence, we showed increased levels of drug accumulation in tumor cells surrounding the stromal tissue. Using a human albumin antibody we demonstrated nab-paclitaxel accumulation in similar locations. However, because increased areas (p &lt; 0.001) of stromal tissue were observed in the antiprogestin-treated mice, the total amount of PEG-LD or Nab-paclitaxel was much higher in the combined-treated tumors. We propose that antiprogestins have the potential to enhance the efficacy of nanotherapeutics in patients with breast tumors with a high PR-A/PR-B ratio.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P4-06-15.
Abstract P4-09-06: miR-187 is an independent prognostic factor in lymph node-positive breast cancer patients.
Authors: O'Connor DP , Mulrane L , Brennan DJ , Madden S , Gremel G , McGee SF , McNally S , Martin FM , Crown JP , Jirstrom K , Higgins DG , Gallagher W 
Published: August 2014

Abstract
Purpose: MicroRNAs (miRNAs) involved in cancer progression have now become the focus of much attention as they represent a new class of biomarkers and potential drug targets. Here, we describe an integrated bioinformatics, functional analysis and translational pathology approach for the identification of novel miRNAs involved in breast cancer progression.
Experimental Design
Differential gene expression can, in part, be attributed to the activity of specific miRNAs. Given a database of miRNA binding site motifs and gene expression levels determined by transcriptomic profiling, correspondence analysis, between group analysis and co-inertia analysis can be combined to produce a ranked list of miRNAs associated with a specific gene signature and phenotype. Here, using two independent breast cancer cohorts, this approach was employed to produce a ranked list of miRNAs associated with disease progression. Functional studies were subsequently carried out in MCF7 cells assessing for alterations in growth, tumorigenicity and agressiveness and miRNA expression was evaluated in two cohorts of breast cancer patients by locked nucleic acid in situ hybridisation on tissue microarrays.
Results: CIA identified miR-187 as a key miRNA associated with poor outcome in breast cancer.
Ectopic expression of miR-187 in MCF7 cells resulted in a more aggressive phenotype (evidenced by increased anchorage-independent growth, migratory and invasive potential).
In a test cohort (n = 117) breast cancer patients, high expression of miR-187 was associated with a trend towards reduced breast cancer-specific survival (BCSS) (p = 0.058), and a significant association with reduced BCSS in lymph node-positive patients (p = 0.036). In a validation cohort (n = 470), high miR-187 was significantly associated with reduced BCSS in the entire cohort (p = 0.021) and, again, in lymph node-positive patients (p = 0.012).
Multivariate cox regression analysis revealed that miR-187 is an independent prognostic factor in both TMA cohorts (Cohort 1 HR-7.369 (95% CI 2.048–26.509, p = 0.002); Cohort 2 HR-2.798 (95% CI 1.518–5.157, p = 0.001).
Conclusions: miR-187 expression in breast cancer leads to the formation of a more aggressive, invasive phenotype and acts as an independent predictor of outcome.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P4-09-06.