bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract P4-08-10: Systematic expression analysis of the genes related to drug-resistance in isogenic docetaxel- and adriamycin-resistance breast cancer cell lines.
Authors: Tang J , Li W , Zhong S , Xu J , Zhao J 
Published: August 2014

Abstract
Background: Docetaxel (Doc) and Adriamycin (Adr) are two of the most effective chemotherapeutic agents in the treatment of breast cancer. However, their efficacy is often limited by the emergence of multidrug resistance (MDR). The purpose of this study was to investigate MDR mechanisms through analyzing systematically the expression changes of genes related to MDR in the induction process of isogenic drug resistant MCF-7 cell lines.
Material and Methods: Isogenic resistant sublines selected at 100 and 200nM docetaxel (MCF-7/100nM Doc and MCF-7/200nM Doc) or at 500 and 1500 nM adriamycin (MCF-7/500nM Adr and MCF-7/1500nM) were developed from human breast cancer parental cell line MCF-7/S, by exposing MCF-7/S to gradually increasing concentrations of docetaxel or adriamycin in vitro. Flow cytometry, MTT cytotoxicity assay and cell growth curves were preformed to demonstrate the MDR characteristics developed in sublines. Some key genes on the pathways related to drug resistance (including drug-transporters: MDR1, MRP1 and BCRP; drug metabolizing-enzymes: CYP3A4 and GST pi; target gene: Topo IIα and β-tubulin III; apoptosis genes: Bcl-2 and Bax) were analyzed at RNA and protein expression levels by real time RT-qPCR and western blot, respectively.
Results: MCF-7/100nM Doc and MCF-7/200nM Doc was 22- and 37-fold resistant to docetaxel, and 18- and 32-fold to adriamycin, respectively. MCF-7/500nM Adr and MCF-7/1500nM Adr was 61- and 274-fold resistant to adriamycin, and 3- and 12-fold to docetaxel, respectively. Meantime, they also showed cross-resistance to the other anticancer drugs in different degree. Compared to sensitive MCF-7/S, RT-qPCR and Western blot results revealed that the expression of MDR1, MRP1, BCRP, Bcl-2 were elevated in both MCF-7/Doc and MCF-7/Adr, and Topo IIα, Bax were down-regulated in both the sublines, while CYP3A4 and β-tubulin III were increased only in MCF-7/Doc and GST pi was increased only in MCF-7/Adr. Furthermore, these changes above were dose-dependent, i.e. acquirement of MDR is dependent on docetaxel or adriamycin concentrations in breast carcer model resistant MCF-7 cells.
Conclusions: The established MCF-7/Doc or MCF-7/Adr has the typical MDR characteristics, which can be used as the models for resistance mechanism study. The acquired process of MCF-7/S resistance to docetaxel or adriamycin is gradual, and is also complicated with the various pathways involved in. There are some common mechanisms as well as drug-special mechanisms between MCF-7/Doc and MCF-7/Adr.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P4-08-10.
Abstract P4-09-08: HOXB9, a gene promoting tumor angiogenesis and proliferation, is significantly associated with poor clincal outcomes in ER-positive breast cancer patients
Authors: Seki H , Hayashida T , Jinno H , Takahashi M , Suzuki K , Kaneda M , Hara H , Osaku M , Asanuma F , Yamada Y , Mukai M , Kitagawa Y 
Published: August 2014

Abstract
Background: Studies have suggested that HOXB9 expression in breast cancer cells promotes cellular invasiveness, metastatic ability, and tumor neovascularization in the surrounding tissue in in vitro and in vivo assays. These findings imply that HOXB9 overexpression may alter tumor-specific cell fates and the tumor stromal microenvironment, contributing to breast cancer progression (Hayashida et al., PNAS 2010). We previously reported that clinical outcomes were significantly decreased in HOXB9-positive patients (Seki et al., Ann Surg Oncol. 2012). In this study, it was demonstrated that HER2 type and basal-like breast cancers were more associated with HOXB9 positivity than the luminal type. Therefore, it is required to identify more detail clinicopathological features most likely to be associated with HOXB9 overexpression. We investigated the correlation between HOXB9 overexpression and clinicopathological variables, and clinical outcomes in estrogen receptor (ER)-positive breast cancer patients.
Patients and methods: A consecutive series of 118 ER-positive breast cancer patients who underwent surgical treatment were examined. HOXB9 expression was analyzed immunohistochemically using the anti-human HOXB9 polyclonal antibody. Immunostaining of Ki-67 and CD31 were also performed to evaluate tumor proliferation and angiogenesis.
Results: The median age was 59 years and median observation period was 62 months. Of 118 tumor specimens immunostained for HOXB9, 49 specimens (41.5%) were positive staining. Univariate logistic regression revealed high nuclear grade (p &lt; 0.001), lymph node metastasis (p = 0.019), the number of micro vessel density (p &lt; 0.001) and the Ki-67 ratio (p = 0.019) as significant variables associated with HOXB9 positive. The disease-free survival (DFS) was significantly decreased in HOXB9-positive patients (HR = 4.262, 95% CI = 1.531 — 11.869, p = 0.006) A Multivariate analysis indicated that HOXB9 expression was the only independent prognostic factor for DFS (HR = 3.380 95% CI=1.160 — 9.849, p = 0.026).

Conclusions: Our results suggest that HOXB9 expression promoting the cellular proliferation and the angiogenesis in tumor microenvironment is a significant prognostic factor for clinical outcomes in ER-positive breast cancer patients. Further study might help to determine the application of anti-angiogenic therapy for metastatic ER-positive breast cancer patients.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P4-09-08.
Abstract P4-12-05: Enrichment of aldosterone synthase (CYP11B2) gene C-allele carriers in women at high risk in the OncoVue® polyfactorial risk model
Authors: Jupe ER , Pugh TW , Knowlton NS , DeFreese DC 
Published: August 2014

Abstract
Background: Models for accurately assessing breast cancer risk are utilized for guiding clinical decisions regarding early detection and prevention. We developed a polyfactorial risk model (PFRM; OncoVue) from analysis of a large case-control database including both functional gene polymorphism and clinical factor data. A multivariate logistic regression based statistical protocol was used to derive a single risk model consisting of 22 single nucleotide polymorphisms (SNPs) in 19 genes and 5 traditional risk factors. Several studies have shown that the PFRM is significantly improved in individualized risk estimation compared to the Breast Cancer Risk Assessment Tool (BCRAT) or Gail model. Here we have examined the genotype frequencies of women placed in the highest decile of risk by the PFRM compared to both the overall control population and to women in the control population placed at the lowest decile of risk.
Materials and Methods: Analyses were performed on 1671 breast cancer cases and 3351 controls that enrolled in a case-control study conducted in six regions of the United States. DNAs were genotyped for the 22 genetic polymorphisms and combined with clinical risk factor information to calculate PFRM risk estimates for the individual participants. The PFRM lifetime scores were used to stratify the upper and lower deciles of risk. The genotype frequencies for these stratified risk groups were determined and compared to the overall control population and to each other (upper vs. lower decile). Odds Ratios (OR) were determined for the CYP11B2 genotypes because they exhibited the largest differences in frequency among the groups.
Results: For CYP11B2 comparison of the genotype frequencies in the highest decile risk group to the overall genotype frequencies of controls identified significant enrichment of the C-allele carriers in the highest risk group. The OR for C-allele carriers (C/C+C/T) compared to the most common T/T genotype was 3.0 (1.9, 4.8; 95% C.I.) with a p-value &lt;0.0001. Similarly for the upper decile risk group compared to the lower decile risk group the association of C-allele carriers was even stronger with OR = 11.0 (6.6,18.4; p &lt;0.0001). In the upper decile of risk 86% of the individuals were C-allele carriers compared to only 38% in the lower decile of risk.
Conclusions: Our previous studies have shown an age dependent association of the CYP11B2 C/C and C/T genotypes with breast cancer risk. The enrichment of these genotypes in women in the upper decile risk group as determined by the PFRM further reinforces the role of this genotype in influencing breast cancer risk and suggests that intervention in the aldosterone synthase pathway be explored as a method of breast cancer prevention.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P4-12-05.
Abstract P4-13-01: Racial Disparities in the Incidence of Dose-limiting Chemotherapy Induced Peripheral Neuropathy
Authors: Speck RM , Sammel MD , Farrar JT , Hennessy S , Mao JJ , Stineman MG , DeMichele A 
Published: August 2014

Abstract
Objective: To determine the incidence of and risk factors for dose-limiting chemotherapy induced peripheral neuropathy (CIPN) in non-metastatic breast cancer.
Methods: This retrospective cohort study included 488 women with an adjuvant or neoadjuvant treatment plan with docetaxel or paclitaxel from June 1, 2009 to December 31, 2011. Exclusion criteria were: metastatic disease, previous neurotoxic chemotherapy, pre-existing neuropathy, pregnant or within 3 months post-partum, and prosthetic limb. The primary outcome was dose-limiting CIPN, defined as a treatment modification event (dose delay, dose reduction, or treatment discontinuation) attributed to CIPN. The primary risk factor of interest was obesity (BMI≥30). Covariates included race, age, menopausal status, diabetes, and other comorbidities, node status, tumor size, regimen, and oncologist. With 80% power and 0.05 type I error rate, the study could detect a risk ratio of 1.8 in the obese versus non-obese.
Results: Fifty (10.2%) women had a treatment modification event attributed to CIPN (TM-CIPN). TM-CIPN incidence differed significantly by agent (docetaxel = 2.4% (N = 5/209), paclitaxel=16.1% (N = 45/279); p &lt; 0.001). In analyses restricted to patients treated with paclitaxel with complete covariate data (N = 273), the odds of TM-CIPN did not differ by obesity, OR = 1.17 (95% CI 0.59–2.35). After adjusting for black race, menopausal status, disease severity, and type II diabetes the TM-CIPN and obesity association was attenuated. The attenuation occurred after adjustment for black race, which was a confounder of the obesity and TM-CIPN relationship, and associated with obesity (OR = 3.78, p = &lt;0.001). Post-menopausal status, disease severity, and type II diabetes were associated with obesity, but were not confounders. Compared to whites, and after controlling for disease severity, menopausal status, and oncologist, blacks and other non-whites had significantly increased odds of CIPN-TM (OR = 2.5, p &lt; 0.02; OR = 4.8, p &lt; 0.01; respectively). Tests of homogeneity indicated the race and TM-CIPN association was not modified by oncologist or disease severity.
Conclusion: Obese and non-obese women have a comparable likelihood of having their treatment modified due to CIPN. Women of racial minorities had over 2-to 4-fold increased odds of TM-CIPN compared to white women. Investigations addressing the mechanistic explanations for this association are warranted.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P4-13-01.
Abstract P4-13-06: Association of Age, Obesity and Incident Breast Cancer Phenotypes
Authors: Scheri R , Power S , Marks J , Seewaldt V , Marcom K , Hwang S 
Published: August 2014

Abstract
Background: Obesity has been shown to be associated with increased risk of breast cancer in postmenopausal women. However, it is unclear whether this risk is isolated to a specific phenotype. We hypothesized that the increased levels of insulin, IGF-1 and estrogens associated with obesity preferentially drive an increased proportion of the luminal A phenotype of breast cancer.
Methods: Between 2008 and 2011, 1001 women were diagnosed with invasive breast cancer at Duke University Medical Center and had weight and height recorded at the time of diagnosis. Tumor phenotypes were based on hormone receptor (HR: ER− and/or PR-positive) and Her2 testing with subtypes defined as follows: Luminal A: HR(+), Her2(−); Luminal B: HR(+), Her2(−); Her2: HR(−), Her2(+); triple negative: HR(−), Her2(−).
Results: Median age of the cohort was 55.7 years; median BMI was 27.7. As expected, increasing BMI was associated with older age, with BMI almost evenly distributed between three groups: ≤ 25, 25–30, and &gt;30. In the overall group, proportion of luminal B, Her2, and triple negative subtypes did not differ by BMI; however the proportion of patients with luminal A cancer increased from 65% for the lowest BMI group to 70% for the highest BMI group. Analysis stratified by age ≤ 40, 40 to 59, and ≥60 years showed a lower proportion of the triple-negative (19% vs. 6% vs. 4%, p &lt; 0.001) and higher proportion of the luminal A (11% vs. 23% vs. 32%; p &lt; 0.001) phenotype with older age group. This finding was limited to women with higher BMI only.
Conclusions: Although there were no trends observed between BMI and incident phenotype in the overall cohort, age stratified analysis revealed striking correlations. High BMI was associated with triple negative phenotype in the youngest age group and luminal A phenotype in older age groups. These results suggest that obesity likely exerts different effects on tumor progression based on patient age and/or menopausal status.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P4-13-06.
Abstract P5-01-16: Value of ultrasonography appearance of breast mass in prediction of histologic type
Authors: Xu Z , Sun L , Yang H , Song Y , Sun G 
Published: August 2014

Abstract
Objective to determine the relationship of sonographic features to the histological typing and grading of breast mass.
Methods: 292 breast masses were prospectively evaluated with ultrasonography. Sonographic features included irregular shape, microlobulation, spiculated margin, halo, posterior attenuation, microcalcification, ductal distortion. Lesion morphology was analyzed and correlated with histopathologic results, which included tumor typing and grading. Then we make a retrospective analysis and evaluation of patients scanned completely by qualitative and semi-quantitative methods. All patients have signed the informed consent form before the test, together with the recognition of the Ethics Committee.
Resuls: Among these masses, there are breast cancer accounted for 45.89% (134/292), A rounded or lobular mass was strongly associated with ductal carcinoma in situ(DCIS), poorly differential invasive ductal carcinoma(IDC), or some of the specific invasive cancer. Mastitis accounted for 8.22% (24/292), fibroadenoma accounted for 43.84% (128/292), and phyllodes tumor accounted for 2.05% (6/292). In 134 breast cancer cases, 92.70% (127/134)have obviously sonographic features with justled growth was found around the turmor with lamellar necrosis in different extents and lympholeukocytic infiltration, microlobulation, speculated margin, halo, posterior attenuation, microcalcification, ductal distortion, with justled growth was found around the turmor, neoplastic cell array showed as massive nest, patchy and satin ribbon structure, and the membrane of tumor cells was unsharpness with less cytoplasma, round or oval nucleus, great heteromorphism, higher karyoplasmic ratio and common nuclear mitotic figures. Other 7 cases with fibrous tissue hyperplasia under microscope show a regular shape. In fibroadenoma, phyllodes tumor and mastitis team, they shows unobviously sonographic features and the cell morphology contrast with breast cancer are quite different.
Conclusions:Ultrasonography appearance of breast masses is related to pathologic characteristics and can be a predictor of histopathologic pattern preoperatively.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P5-01-16.
Abstract P5-03-10: HIF-1alpha knockout radiosensitizes select Inflammatory Breast Cancer cells through reduction of stem-like cancer cells
Authors: Xu W , Debeb BG , Smith DL , Li JL , Ueno NT , Alvarez de Lacerda LC , Larson RA , Schwba LP , Seagroves TN , Woodward WA 
Published: August 2014

Abstract
Independent of the tumor stroma, HIF-1α regulates tumor cell metabolism, cell proliferation and DNA repair pathways, which may produce conflicting responses to radiation, promoting either radioresistance or radiosensitization. Recently, HIF-1α was shown to increase tumor initiating cells (TICs) activity in normoxic tumor cells derived from the MMTV-PyMT trasngenic mouse model of luminal-like breast cancer. While TICs have been reported to be relatively radio-resistant, the role of HIF-1α in mediating the radation response in breast cancer TICs remains unknown. Herein, we examined radiosenstitivity of TICs derived from either PyMT HIF-1α knock out (KO) tumor cells or human breast cancer cell lines transduced with a HIF-1α dominant negative (DN) construct. Consistent prior results that loss of HIF-1 activity reduces TIC frequency, down-regulation of HIF-1 activity through the HIF DN construct reduced mammosphere formation in SUM-159, SUM-149 and MCF-7 cells (by 5.0-, 2.0-, and 2.0-fold respectively). Moreover, β-catenin expression was down-regulated in SUM-149 and SUM-159 cells transfected with the HIF-1α DN construct. Moreover, SUM-149 cells expressing the HIF-1α DN construct exhibited delayed tumor growth in vivo (p = 0.05). Standard clonogenic assays demonstrated that PyMT HIF-1α KO cells and SUM-149 cells expressing the HIF-1α DN construct were more sensitive to radiation therapy (SF6 of PyMT, HIF-1α:Control, 0.016:0.087), but that the PyMT KO and SUM-149 mammospheres that persisted after radiation were completely radioresistant (SF6 of PyMT, HIF-1 α: Control, 0.48:0.44). In contrast, MCF-7 cells were not radiosensitized in either standard or mammosphere assays. Interestingly, in HIF-1α DN MCF-7 cells, molecular features of IBC were observed, such as the increased expression of E-Cadherin and loss of Wisp3. But, Notch1 protein expression was unchanged between HIF-1α DN MCF7 or SUM149 cells. Moreover, concurrent radiation in the presence of a gamma secretase inhibitor or with a p53-MDM2 inhibitor nutlin failed to radiosensitize HIF KO mammosphere clonogens. We conclude that downregulation of HIF-1 activity selectively radiosensitizes IBC clonogenic cells but fails to radiosensitize the residual mammospheres. These data suggest that the known HIF-1α mediated mechanisms that favor radiosensitivity, such as the promotion of glycolysis and proliferation under stress, may predominate in mammospheres, which ultimately leads to radioresistance in residual mammospheres after HIF inhibition.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P5-03-10.
Abstract P5-03-11: Possible role for cancer stem cells: results from a pilot neoadjuvant trial of HER-2 positive breast cancer patients treated with a combination of (Nab)-paclitaxel and lapatinib.
Authors: Siziopikou KP , Gradishar WJ , Kaklamani VG 
Published: August 2014

Abstract
Background: Lapatinib, a dual kinase inhibitor against both epidermal growth factor (EGFR) and human epidermal factor 2 (HER-2) and nanoparticle albumin bound (nab) paclitaxel was recently used by our group in a pilot study of early stage HER-2 positive breast cancer. We reported that the combination was well tolerated and showed good efficiency in this patient group. Cancer stem cells were recently identified in solid tumors including breast carcinomas. These tumor initiating stem cells are reported to be increased in HER-2 positive breast cancers. Lapatininb is postulated to reduce the percentage of breast cancer stem cells following HER-2 inhibition. This study aimed to investigate such an effect in this patient population of early stage HER-2 positive breast cancer cases uniquely treated by a combination of nab-paclitaxel and lapatininb.
Design: 30 patients with stage I-III HER-2 positive breast cancer were treated in a neoadjuvant setting with lapatinib 1,000mg/day and nab-paclitaxel 260 mg/m2 every 2 weeks for 4 cycles. The expression of the stem cell markers aldehyde dehydroganase (ALDH1) (BD), CD24 and CD44 (both Santa Cruz Biotechnology) was assessed immunohistochemically in breast cancer specimens prior to treatment and at the time of definitive surgery. Staining was considered negative if &lt; or = 1%, and positive if &gt;1%.
Results: Of the 30 patients, 28 underwent surgery and were evaluated for pathologic response. Complete pathologic response (pCR) was observed in 5/28 (17.9%) of the patients. Of the 17 patients for whom pre-treatment material was available 13 (76.5%) were positive for ALDH1 expression and 4 (23.5%) were negative. Of the 22 patients with material available for testing at the time of surgery, 5 showed pCR, 3 were negative and 14 (63.6%) were positive for ALDH-A1 expression. The CD44+/CD24- phenotype was variable and showed no difference between groups.
Conclusions: 1. Combination of lapatinib and nab-paclitaxel resulted in a complete pathologic response in almost 1/5 of the HER-2 positive early stage breast cancer patients. 2. Overall, there is a reduction in the number cancer stem cells following neoadjuvant treatment with lapatinib and nab-paclitaxel. Our results support the hypothesis that lapatinib may have an effect in manipulating the numbers of cancer stem cells in patients with HER-2 positive breast cancer. Additional studies are currently under way to further characterize these findings.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P5-03-11.