bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract P4-03-03: Lower Vitamin D Levels Are Highly Prevalent in Women with Breast Cancer
Authors: Li SP , Moule RN , Seah M-L , Rainbow S , Bhatti R , Steer KA , Windmill E , Makris A. 
Published: April 2011

Abstract
Purpose: The objectives of this study were to determine the prevalence of vitamin D insufficiency or deficiency as measured by serum 25-hydroxyvitamin D (25-OHD) in women with breast cancer and relate this to age, ethnic group, disease stage, and seasonal variation. Methods: Levels of serum 25-OHD were requested on blood samples collected from 129 female patients with histologically-proven breast cancer (median age 61 years; range, 30-88). Vitamin D deficiency was defined as serum 25-OHD less than 12.5 nmol/L, insufficiency as 12.5 to 50 nmol/L, and sufficient levels as greater than 50 nmol/L. The prevalence of inadequate (insufficient or deficient) vitamin D levels and median 25-OHD values were calculated for the cohort as a whole and analysed according to age, ethnicity (Asian (Indian/Pakistani), White and other), disease stage (early versus metastatic), and seasons. Statistical analysis was performed using non-parametric methods and a significance level set at a two-tailed p-value &lt; 0.05.
Results: Overall 52% of women had inadequate levels of 25-OHD (45% deficient, 7% insufficient; median 29 nmol/L). There was no relationship with age. Lower levels were more common in Asian women (n=56) (64%; 16% deficient, 48% insufficient) compared with white women (n=65) (40%; all insufficient) and other (n=8) (62.5%; all insufficient). 25-OHD levels were significantly lower overall in Asian women in comparison with white women (median 36.5 versus 60 nmol/L; p=0.0002). When disease stage was considered, 54% of women with early breast cancer had inadequate 25-OHD levels (n=103) (7% deficient, 47% insufficient) in comparison with 42% of women with metastatic disease (n=26) (8% deficient, 34% insufficient) although overall levels were not significantly different between groups. There was no seasonal variation in 25-OHD levels.
Conclusion: The prevalence of insufficient or deficient vitamin D levels as assessed by 25-OHD in women with breast cancer, especially in the Asian population, is high. Our findings suggest that all patients with breast cancer should have routine testing of vitamin D status and if appropriate, offered adequate vitamin D supplementation.
Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P4-03-03.
Abstract P4-03-04: Body Mass Index as a Predictive Factor of Pathological Complete Response to Neoadjuvant Chemotherapy in Breast Cancer Patients
Authors: Bellet Ezquerra M , Perez Garcia JM , Muñoz Couselo E , SauraManich C , Gomez Pardo P , Vidal M , Argiles G , De Mattos L , Cortes Castan J , Baselga Torres J. 
Published: April 2011

Abstract
Background: Obesity has been associated with worse pathological complete response (pCR) to neoadjuvant chemotherapy (NACT) and overall outcome in breast cancer patients (pts). Our aim was to retrospectively evaluate body mass index (BMI) as a predictive factor of pCR to NACT in pts treated at our institution, taking into account tumor HER2 status and CT dose adjustment.
Pts and methods: Pts with invasive breast cancer who received NACT followed by surgery at Vall d'Hebron University Hospital from January 2004 to December 2008 were analyzed. Pts were categorized as normal/underweight (BMI &lt; 25 kg/m2), overweight (BMI of 25 to &lt; 30 kg/m2), and obese (BMI ≥30 kg/m2). The overweight and obese groups were combined (BMI-high) and then compared with the normal/underweight group. Univariate and multivariate analyses were performed to assess the association between BMI and pCR (no invasive tumor in breast and nodes).
Results: 256 consecutive pts were included. Median age was 52.5 years. According to BMI, 38.7% were normal/underweight and 59.4% were BMI-high. 23.4% of the pts had HER2 positive tumors (n=60), 84% received anthracyclines-and taxanes-based CT, and 46.6% of the HER2 positive pts were treated with trastuzumab. Drug dose was reduced in only five pts with a body surface area &gt; 2m2. No statistically significant association was found between BMI and any tumor characteristics. In the univariate analysis, BMI-high was associated with worse pCR in the whole population (p=0.017), as well as in HER2 positive pts (p=0.013). In the multivariate analysis, BMI did not significantly predict pCR in the total population, although a trend was observed (p=0.098). In the HER2 positive subgroup, however, BMI was an independent predictive factor of pCR (p=0.001). Among luminal A [estrogen receptor positive and/or progesterone receptor positive and (Ki67 &lt; 20% and histological grade 1 or 2)], luminal B [estrogen receptor positive and/or progesterone receptor positive and (Ki67 ≥20% or histological grade 3)], and triple negative tumors, BMI was not a predictive factor of pCR.
Conclusions: Our results suggest that higher BMI is likely associated with worse pCR, particularly in HER2 positive pts. A better understanding of the molecular links between obesity and breast cancer is necessary to identify new predictive factors of pCR to NACT.
Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P4-03-04.
Abstract P4-03-05: The Warburg Effect and RUNX2-Regulated Metabolic Switching in Breast Cancer: A New Therapeutic Target?
Authors: Passaniti T , Chumsri S , Girnun G , Brodie A , Choe M. 
Published: April 2011

Abstract
Breast cancer (BC) is the leading cause of cancer deaths among women in North America and Western Europe. Numerous studies have shown that breast tumor progression is associated with a switch from mitochondrial oxidative phosphorylation (OxPhos) to increased utilization of glucose and aerobic glycolysis (Warburg effect). Uncovering underlying mechanisms regulating this progression may lead to innovative approaches for treatment. The RUNX2 DNA-binding transcription factor is expressed in highly aggressive BC and regulates bone metastasis in animal models. We observed increased expression of RUNX2 in primary human ductal carcinoma in situ (DCIS), which correlated with grade and proliferative index (Ki67 staining), decreased estrogen receptor/progesterone receptor expression (ER/PR status), increased glucose uptake values by PET scanning, and increased expression of the glucose transporter, GLUT1. Further, more than 80% (9 out of 11) of triple-negative BC cell lines examined expressed RUNX2. Therefore, to test the hypothesis that RUNX2 may alter the metabolic status of breast cancers and increase their dependence on glycolysis during tumor progression, we have generated a Tet-OFF model system using MCF7 cells with inducible RUNX2 expression. RUNX2-positive MCF7 cells exhibited increased cell death under conditions of glucose depletion or when treated with 2-deoxy-glucose, a competitive inhibitor of hexokinase II. Conversely, RUNX2-positive cells were more resistant to OxPhos inhibitors (rotenone, oligomycin) than RUNX2-negative cells. We also observed higher expression levels of GLUT1 and pAKT in RUNX2-positive MCF7 cells. Hypoxia-inducible factor-α (HIF1α) is a transcription factor that regulates cancer metabolism through its activation of glycolytic genes, while SIRT6, an NAD-dependent deacetylase, is a negative regulator of HIF1α activity. This occurs, in part, via inhibition of HIF1α transcriptional activity. RUNX2-positive or negative cells expressed HIF1α in response to glucose but RUNX2-positive cells exhibited lower SIRT6 expression than RUNX2-negative cells, suggesting that with the loss of SIRT6, HIF1α might be more active in promoting glycolysis in the presence of RUNX2. These results suggest that RUNX2 may have clinical diagnostic value as an indicator of BC metabolic stress and predictor of poor prognosis. Current strategies are utilizing computer-assisted drug design to develop RUNX-specific inhibitors to target BC glycolysis and tumor growth.
Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P4-03-05.
Abstract P4-04-02: Isolation and Characterization of Adult Mammary Stem Cells from the Periphery of Breast Cancer
Authors: Shi A , Xu N , Fan Z , Jiang Y , Fu S. 
Published: April 2011

Abstract
Background: Normal adult mammary stem cells (AMSCs) provide promising cell sources for breast reconstruction, especially after the resection of breast tumors. However, the potential targeting by carcinogenic events may convert normal AMSCs to cancer stem cells, posing a safety issue for applying the AMSCs for tissue regeneration in clinic. Objective: In the current study, we characterized a population of AMSCs isolated from the normal tissue at the periphery of human breast tumors and provided evidence that these AMSCs remain normal but not cancerous phenotypes and therefore, could be candidates for breast reconstruction. Methods: A population of AMSCs was isolated from the normal tissue surrounding primary breast tumors using immunomagnetic sorting. The stemness of these cells were examined by differentiation analysis and the gene expression profile compared to that of the cancer cells by microarray, with several differentially expressed candidate genes confirmed by both RT-PCR and Western blot assays. The in vivo tumorigenic capability of these cells were also investigated and compared to that of MCF-7 cell line. Results: The AMSCs were positive for stem cell markers, epithelial specific antigen (ESA) and keratin 19 (K19). When stimulated with the differentiation agent, basic fibroblast growth factor (bFGF), these AMSCs formed lobuloalveolar structure with myoepithelium that are positive for CALLA. The gene expression profiles revealed that compared to the cancer cells, see Table 1,2. AMSCs were low in oncogenes such as c-myc, Ras and c-erbB-2, but high in tumor suppressor genes including Rb1, Pten and CDKN2A, see table 1,2 and fig 1,2. When injected into nude mice, the AMSCs formed no tumors but regular mammary ductal structures. Conclusion: The AMSCs isolated from the normal tissue surrounding the primary breast cancers present features of normal mammary stem cells, therefore, are promising candidates for mammary reconstruction after breast tumor resection.
Gene expression by western blot
(sample 1, 2, 3 were breast cancer; sample 4,5 were mammary stem cells)
CerbB2 rtranscription
(sample 1, 2, 3 were breast cancer; sample 4,5 were mammary stem cells)

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P4-04-02.
Abstract P4-05-02: Role of the Atr Protein Kinase and Curcumin in Tumor-Stromal Interactions in Breast Cancer
Authors: Aboussekhra A , Al-Ansari MM , Hendrayani S-F , Al-Tweigeri T. 
Published: April 2011

Abstract
Carcinoma-associated fibroblasts (CAFs) play important roles in the genesis and thrive of various types of epithelial cancers, including breast carcinomas. Indeed, various genetic and epigenetic variations have been identified in stromal fibroblasts, and we have recently shown that CAFs as well as their corresponding counterparts (TCFs) display neoplastic-specific changes (Hawsawi et al., 2008). We have also shown that the levels of the tumor suppressor proteins p53 and p21 are down-regulated in CAFs as compared to TCFs. During the cellular response to DNA damage these genes are under the control of important proteins such as Atr, a protein kinase essential for the maintenance of genomic integrity. To further elucidate the molecular changes that occur in breast cancer-associated fibroblasts we assessed the expression of Atr and have shown that the level of the Atr protein kinase is lower in 7 out of 10 (70%) CAFs as compared to their corresponding TCFs. Using specific ATR-siRNA we have shown that ATR negatively controls the expression of various proteins involved in the stromal-epithelial interactions. These include the stromal cell-derived factor 1 (SDF1), the vascular endothelial growth factor (VEGF) and the matrix metalloproteinase-2 (MMP2). In addition, the ELISA assay was used to show that the level of these proteins was higher in the conditioned media from stromal fibroblasts expressing specific ATR-siRNA as compared to control cells. Importantly, serum-free conditioned media from ATR-defective cells stimulated the proliferation and invasion/migration of cultured human breast cancer cells in an SDF1-dependent manner. These results clearly show the role of the breast stromal fibroblast Atr protein in suppressing tumoregenesis in the breast. Moreover, we have shown that curcumin can normalize the expression/secretion of these factors and therefore reduces the invasion/migration of breast cancer cells in vitro. This indicates that curcumin has potential use as stromal fibroblastnormalizing factor that can be utilized for the inhibition of both cancer initiation and recurrence.
Hawsawi, N. M., Ghebeh, H., Hendrayani, S. F., Tulbah, A., Al-Eid, M., Al-Tweigeri, T., Ajarim, D., Alaiya, A., Dermime, S., and Aboussekhra, A. (2008). Cancer Res 68, 2717-2725.
Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P4-05-02.
Abstract P4-06-02: Systemic Deletion of c-Jun N-Terminal Kinase 1 or 2 Is Protective in Breast Cancer Bone Metastasis
Authors: Nasrazadani A , Van den Berg CL 
Published: April 2011

Abstract
Growth and survival of metastatic breast cancer cells in the bone is enhanced by the release of growth factors during osteoclast mediated bone resorption. In order to facilitate release of bone degradation products, breast cancer cells continually stimulate osteoblasts, which in turn differentiate osteoclast precursors. Mature osteoclasts are then activated to secrete factors such as tartrate-resistant acid phosphatase (TRAP) and cathepsin K to degrade bone matrix. Identification of molecular targets involved in these signaling pathways may prove beneficial for treatment of aggressive tumor types. Results from our previous studies demonstrated that tumor cell expression of c-Jun N-Terminal Kinases (JNKs) mediate lung and bone metastasis. To determine if systemic JNKs play a role in breast cancer progression, jnk1-/- and jnk2-/- Balb/c mice were used to study host related contributions to bone metastasis. The highly metastatic 4T1.2 syngeneic mammary tumor cells were injected intra-cardiac into jnk1-/-, jnk2-/-, and wild-type mice. Both jnk1-/- and jnk2-/- mice survived significantly longer than wild-type controls, (p=0.0034 and p=0.0459, respectively). Wild-type mice succumbed to symptoms of morbidity as early as 10 days post-injection whereas; 60% of the jnk1-/- and 40% of the jnk2-/- mice remained asymptomatic at day 55 and day 70, respectively. Analysis of ribcage metastases post-mortem revealed a significant decrease in bone lesions in jnk1-/- and jnk2-/- mice compared to wild-type mice (P&lt;0.0001 and p=0.0031, respectively). We then evaluated if jnk1 or 2 expression may inhibit osteoclast differentiation and slow tumor related osteolysis, Raw 264.7 osteoclast precursor cells were employed to knockdown Jnk1 or Jnk2 expression to study their proliferation and differentiation into osteoclasts. Proliferation of JNK1and JNK2 deficient osteoclast precursors (Raw shJNK1 and Raw shJNK2, respectively) was slightly decreased compared to wild-type Raw 264.7. In contrast, Receptor Activator for Nuclear Factor κB Ligand (RANKL) induced osteoclast differentiation was impaired in both Raw shJNK1 and Raw shJNK2 cells. Collectively, our results suggest the involvement of JNK1 and JNK2 in osteoclast differentiation, thus playing a vital role in breast cancer metastasis to the bone. These data suggest that therapeutic inhibition of JNKs may improve the morbidity and mortality associated with bone metastasis in breast cancer patients.
Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P4-06-02.
Abstract P4-06-11: Gene Expression Profiling Identifies Potential Precursor Genes in Lobular Carcinoma In Situ
Authors: Andrade VP , Morrogh M , Qin L-X , Olvera N , Giri D , Brogi E , de Alcantara-Filho P , Paik W , Muhsen S , Morrow M , King TA. 
Published: April 2011

Abstract
INTRODUCTION: Historically lobular carcinoma in situ (LCIS) has been considered a risk marker but not a true precursor of invasive breast cancer. Emerging evidence of clonal relatedness between LCIS and synchronous invasive lobular cancers (ILC) has reopened this debate. We hypothesized that gene expression profiling of LCIS and synchronous ILC could identify genes that confer precursor potential in LCIS.
METHODS: Patients with LCIS +/− ILC undergoing mastectomy were prospectively identified. Mastectomies were sampled to collect fresh frozen normal epithelium (N), LCIS and ILC. Laser Capture Microdissection was used to isolate purify cell populations and total mRNA was subject to Affymetrix HU133 2.0 gene expression array. Transcript abundance was compared across samples in a paired analysis (P&lt;0.001) using the R software. Potential precursor genes (PPG) were defined as those with monotonically increasing or monotonically decreasing expression from N to LCIS to ILC. Cellular functions and pathways were identified using the Ingenuity Pathway Analysis.
RESULTS: Patient matched triplets (N, LCIS, ILC) were available from 23 mastectomies. 206 probe sets (178 genes) fit the PPG definition, 154 probe sets (130 genes) displayed monotonically decreasing expression and 52 probe sets (48 genes) displayed monotonically increasing expression. The table shows the top five cellular functions and canonical pathways related to the (PPG).
The candidates PPGs are distributed across all chromosomes, with the highest frequencies on 1 q (9.6%), 16q (7.3%), 2q (5.06%), 5q (5.06%) and 4q (4.49%). All 13 potential precursor genes identified on 16q and the 9 PPG identified on 5q showed monotonically decreasing expression while 13/17 PPGs identified on 1q showed monotonically increasing expression. Among all upregulated PPG, 27.1% are located at 1q while 10% of all downregulated PPGs are located at 16q.
CONCLUSIONS: Gene expression profiling identified 178 candidate genes with monotonically increasing or monotonically decreasing expression across patient matched samples of N-LCIS-ILC. Top cellular functions and canonical pathways represented by the candidate genes are known to be associated with carcinogenesis, suggesting that dysregulation of these candidate genes may confer precursor potential in LCIS. The abundance of potential precursor genes on chromosomes 1 q and 16q is also consistent with the model of lobular carcinogenesis.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P4-06-11.
Abstract P4-06-13: c-Jun N-Terminal Kinase 1 (JNK1) Inhibits Tumor Progression and Regulates Embryonic Mammary Development
Authors: Ebelt ND , Ven Den Berg CL 
Published: April 2011

Abstract
Background: Specification of the murine mammary placode in embryonic development involves pathways that are dysregulated in murine and human breast cancers. Beginning with secretion of Neuregulin 3 (Nrg3) and Wingless-Integrated (Wnt) 10b by the dermal mesenchyme, at embryonic day (E) 10.5, a mammary placode will condense over 48 hours due to signaling through the canonical Wnt pathway as well as through the avian ERythroBlastosis oncogene B (ErbB) receptors 4 and 2. By E15.5 placodes will invade the underlying mesenchyme to form the primary duct. The Wnt and ErbB pathways are also known to cause or promote cancer when dysregulated.
Methods and Materials: Number four mammary glands of female, virgin mice (jnk1+/+ or jnk1-/-) were harvested and stained with carmine alum to observe ducts. Wildtype mice were injected with 4T1.2 cells with shRNA targeted to Jnk1 (shJnk1) or non-targeting shRNA (GipZ). Tumors were palpated for growth changes and lungs were stained with India ink to observe lung metastases. RNA from tumors was compared using microarray fro expression of cancer related genes. Results: We have observed that adult glands from jnk1-/- mice contain multiple primary ducts whereas jnk1+/+ mice contain only one, indicating a possible defect during embryonic placode formation. This phenotype mimics what has been previously reported in models of ectopic NRG3 expression. In a 4T1.2 murine mammary cancer model, shJnk1 results in increased tumor growth as well as increased lung metastasis when compared to cells transfected with GipZ. In the tumors grown from the 4T1.2shJnk1 and 4T1.2GipZ cells, a microarray analysis revealed increases in Nrg3, Wnt targets and ligands, and the ErbB2 and Wnt target ETV5 in 4T1.2shJnk1 cells. An increase in the expression of ETV5, Bcl-9, Cox-2 (an ETV5 target), and ErbB2 (a target of ETV5) in 4T1.2shJnk1 cells vs 4T1.2GipZ cells has been confirmed by RT-PCR and western blotting for ErbB2 (Figure 2). I plan to determine how JNK1 affects the Wnt and ErbB pathways in mouse embryos and mammary tumor models. Since Wnt and ErbB pathways are necessary for placode formation, it is likely that these pathways, which are upregulated in our cancer model, are involved in the embryonic phenotype. I hypothesize that JNK1 loss causes increased signaling through these pathways, resulting in the formation of ectopic mammary placodes as well as a more aggressive tumor phenotype. If my hypothesis is supported by these studies then future studies will evaluate if low jnk1 expression is associated with a higher risk of developing breast cancer or a worse prognosis using publically available microarray datasets derived from human tumor samples.
Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P4-06-13.
Abstract P4-08-03: False Positive HER-2 Testing by Fluorescence In Situ Hybridization in Human Breast Cancer
Authors: Ramsey B , Hanlon Newell A , Troxell M , Olson S , Keenan E , Luoh S-W. 
Published: April 2011

Abstract
Background: Testing for human epidermal growth factor receptor-2 (HER-2) is routinely performed after breast cancer diagnosis by either immunohistochemistry (IHC) or fluorescence in situ hybridization (FISH). FISH is more accurate and reproducible, often considered the gold standard, and a more reliable predictor of a patient's response to HER-2 directed therapies in clinical practice. The growth factor receptor-bound protein-7 gene (GRB7) encodes a multi-domain signal transduction molecule located in close proximity to HER-2 on chromo some 17q11-12 and has been shown to be an independent adverse prognostic marker in breast cancer. Methods: We performed western blotting analysis of protein extracts from 563 annotated frozen breast tumors, collected from 1988 - 1998. GRB7 and HER-2 bands were assigned low or high values compared to specific protein controls, and tubulin bands. HER-2 FISH was performed on a subset of these tumors using an FDA approved Path Vysion kit on 4 μm frozen sections. HER-2 and chromosome 17 centromere (CEP17) signals were enumerated according to ASCO/CAP guidelines. Results: Sixty-six tumors (11.5%) over-expressed HER-2 and GRB7 proteins by Western analysis, 66 (11.5%) over-expressed HER-2 but not GRB7, and 30 (5.5%) over-expressed GRB7 but not HER-2. All 32 tumors (32/32) submitted to FISH analysis that over-expressed both HER-2 and GRB7 proteins demonstrated HER-2 gene amplification, while only one out of thirty-five (1/35) tumors that over-expressed HER-2 without GRB7 protein over-expression were HER-2 amplified. Interestingly, 7 of 28 tumors over-expressing GRB7 but not HER-2 protein were amplified for the HER-2 gene. Clinical laboratory HER-2 IHC testing confirmed the absence of HER-2 protein over-expression in all 7 of these tumors. Conclusions: Our study demonstrates that about ten percent of human breast cancers that test positive with FISH for HER-2 gene amplification do not over-express HER-2 protein, which may influence sensitivity to HER-2 directed therapy. All tumors that show false positive HER-2 gene amplification over-express GRB7 protein, suggesting the presence of GRB7 driven gene amplification in these tumors. Given that the HER-2 FISH probe contains GRB7 sequences, it is possible that HER-2 FISH false positivity may reflect GRB7 gene amplification.
Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P4-08-03.