bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 3568: Progression from benign breast disease to cancer in women with a family history of breast cancer
Authors: Israel Sarah , Warzecha Hind , Gross Amy L. , Tatsas Armanda , Lee Andrew , May Betty , Axilbund Jennifer , Khouri Nagi , Jacobs Lisa , Armstrong Deborah , Visvanathan Kala
Published: August 2012

Background: In the general population, benign breast disease (BBD) is an established risk factor for breast cancer, with increased risks ranging from 20 to 50% for atypical proliferative subtypes. There is limited data on the incidence of atypical hyperplasia (AH) and its association with breast cancer risk specifically among women with a strong family history (FH). Methods: In an ongoing, prospective cohort of women with a FH of breast cancer and/or a BRCA1/2 mutation who attend the Breast and Ovarian Surveillance Service (BOSS) at Johns Hopkins (N=1,132), we identified 259 pathology confirmed incident BBD cases diagnosed between 1959 to 2010. Slides were obtained for re-review and evaluation of specific histologic features. Cox proportional hazards models were used to estimate the risk of breast cancer relative to BBD subtype. Results: Of the incident BBD diagnoses, 61.4% were non-proliferative, 26.3% were proliferative without atypia, and 12.4% were AH. AH cases were diagnosed at an older age (p-value=0.04) and were less likely to have a strong FH (p-value=0.01) as compared to non-atypical subtypes. Sixty-one BBD cases progressed to cancer and the median time to diagnosis was significantly shorter for cases of AH (4.2 years) than for non-proliferative disease (8.8 years) (p<0.01). Women with AH were 2.36 (95% confidence interval (CI): 1.15, 4.87) times more likely to develop in-situ or invasive breast cancer compared to non-proliferative cases, adjusting for age and year of incident BBD. In models additionally adjusting for BRCA1/2 mutation status and degree of FH, women with AH had a 4.5-fold (95% CI: 2.16, 9.53) increased risk of breast cancer. BBD subtype and degree of FH were found to be independent risk factors for breast cancer. Prophylactic mastectomy and tamoxifen use post BBD diagnosis did not differ by BBD subtype or the total number of BBD diagnoses. Conclusion: Given the high incidence of AH in this cohort and the increased risk of breast cancer associated with this subtype, AH may be a viable target for preventative strategies in women with a FH of breast cancer. Further, AH does not seem to track with a stronger FH, suggesting two different breast cancer pathways.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3568. doi:1538-7445.AM2012-3568
Abstract 3586: Epigenetic influence on ethnic disparities in non-small cell lung cancer
Authors: Buckingham Lela E. , Sekosan Marin , Ferrar Karen , Hadziahmetovic Emira , Lad Thomas
Published: August 2012

African Americans are more likely to develop lung cancer and die from it than any other ethnic group. Complex biological, environmental, political and cultural factors contribute to this disparity. The purpose of the current project is to examine the relationship between epigenetic factors, gender, ethnicity and outcome in a retrospective study of patients with surgically-treated early stage lung cancer. Fixed primary tumor tissues from a private (RMC) and a public (JHS-CCH) institution were analyzed in this study. The RMC group consisted of 132 patients with stage Ib, IIa and IIb NSCLC, 22% African-American (AA) and 52% female. The JHS-CCH group consisted of 88 patients, 62% AA and 43% female. Five year survival was achieved by 85% of women vs 67% of men in the RMC group (Chi square p=0.022). 68% of Caucasians vs 53% AA survived five years in the RMC group (p=0.186). To investigate the role of epigenetic influences on survival, promoter methylation of Ras association domain family protein 1, RASSF1A, was investigated. Associations between inactivation of the RASSF1A tumor suppressor and poor outcome in lung and other cancers have been reported in several studies. Promoter methylation was quantified using pyrosequencing. Percent methylation of RASSF1 at cytosine position –36 (A of ATG=+1) was more frequent in AA (41% of cases) than in Caucasians (20% of cases) in the RMC group (p=0.023) compared to 69% of cases in the JHS-CCH group. Methylation levels of RASSF1 at all CpG sites tested were higher in the JHS-CCH group than in the RMC group. Kaplan-Meier analysis was performed on dichotomized hypermethylation status compared to five-year survival (5YS). Promoter hypermethylation of RASSF1 was significantly associated with shortened 5YS in AA (p=0.005), compared to Caucasians (p=0.197) in the RMC group. Although 5YS was marginally shortened with hypermethylation of RASSF1 in men in the RMC group (p=0.123), no significant effects were seen with regard to gender. These results suggest that biomarkers can have differential effects, based on genetic background and support analysis of epigenetic biomarkers to address disparities and develop more personalized treatment strategies for individual patients.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3586. doi:1538-7445.AM2012-3586
Abstract 3589: Comparative expression profile of transmembrane mucin MUC1 in breast cancer from American Indian and Caucasian women
Authors: Maher Diane M. , Stephenson Phillip , Gupta Brij K. , Bauer Nichole A. , Koch Michael , Eliason Susan , Jaggi Meena , Chauhan Subhash C.
Published: August 2012

Introduction: Considerable disparity exists in breast cancer incidence and mortality among different racial/ethnic populations and geographic locations. For unknown reasons, American Indian women of the Northern Plains have a greater incidence and higher death rate due to breast cancer than Caucasian women living in the same geographical region. Additionally, American Indian women living in the Northern Plains also have a much higher incidence and death rate due to breast cancer than American Indian women living elsewhere in the United States. To investigate the potential molecular basis for this cancer health disparity, we have compared the expression profile of transmembrane mucin, MUC1 on breast cancer cases from American Indian and Caucasian women living on the Northern Plains. MUC1 is known to be overexpressed in breast cancer and nuclear localization of MUC1 can have downstream effects on cell signaling and increase oncogenic phenotypes. We are also exploring the link between smoking, exposure to HPV infection, and the development of breast cancer in American Indian women. Methods: We have examined the expression profile of MUC1 in breast cancer tissue from American Indian (n=40) and Caucasian (n=60) women. The staining was analyzed by experienced pathologists and scored according to intensity (0-4) and percent of cancer cells stained positive (0-4). A composite score was calculated by multiplying the scores of intensity and percent of cells stained. Tissues were categorized by modified Bloom-Richardson's histological grade and the mean composite scores were compared amongst American Indian and Caucasian groups. Results and Conclusions: We have observed that grade 3 breast cancer samples from American Indian women had a higher percent of nuclear MUC1 staining and a lower amount of p53 expression. This result correlates with previous data showing that MUC1 inhibits the expression of p53. In conclusion, breast cancer tissue from American Indian women has a different expression profile of molecular markers and this finding may help to explain the cancer health disparity. Further investigation of these differences may promote understanding of the etiological differences and may identify effective treatment strategies for breast cancer in American Indian women.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3589. doi:1538-7445.AM2012-3589
Abstract 3596: Globally, minorities are at increased risk for lung cancer
Authors: Cox Solange E. , Hulbert Alicia , Brock Malcolm V.
Published: August 2012

Purpose of Study: To determine whether identifiable minority populations in countries of the six regions of the world experience higher incidence rates of lung cancer than do the members of the majority population of those countries. Experimental procedures: The WHO website has codified the world's continents into six regions including Africa, Americas, South East Asia, Europe, The Eastern Mediterranean and the Western Pacific. This definition of world regions was used for this study. Data were available from five of the six regions. Countries were ordered in each region according to population density. In each region, at a minimum, the 10 most densely populated countries were included. A minority population group was defined as a numerically smaller proportion of a population differing from the majority by a specific identifiable characteristic. Minority and majority populations were defined according to the CIA world fact book and the minority rights group international. Each country was evaluated separately for incidence rates of lung cancer within both minority and majority populations. Codified study data were included for a country only if the data met the following specific criteria: (1) the data had to be presented in its original form using a case-control or cohort methodology; (2) lung cancer incidences had to be reported as an outcome. Data were only included for analysis if it were published as a case-control or cohort study with appropriate references in a peer-reviewed journal. No data from non -peer reviewed articles were considered. Results: Table 1: Lung cancer incidence rates in minority and majority populations from countries included in the top ten of the most densely populated of five world regions. Conclusions: Globally, minority populations experience much higher incidence rates for lung cancer within a country than do the majority population. We hypothesize that this is due to marginalization of these minority groups which may lead to increased smoking in the minority group members as a coping mechanism.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3596. doi:1538-7445.AM2012-3596
Abstract 36: The Importance of sticking together; Cdh1 loss in the gastric zymogenic lineage
Authors: Geahlen Jessica Harrison , Swat Filip A. , Mills Jason C.
Published: August 2012

Stomach Cancer is the second leading cause of cancer related death worldwide. The adult stomach is a renewing system with cells simultaneously differentiating and migrating along invaginations termed gastric units. One such lineage is the zymogenic lineage in which neck cells differentiate to form mature zymogenic cells at the base of the gastric units. The transcription factor Mist1 plays a key role in this differentiation and is lost in the formation of precancerous metaplasia. Another important protein in proper zymogenic cell formation is the cellular adhesion protein Cdh1. Cdh1 has been characterized as a tumor suppressor protein and is often lost in cancer cells allowing for metastasis. In some forms of Hereditary Diffuse Gastric Cancer, loss of Cdh1 is thought to be an initiating event in tumor formation. I have genetically engineered mice in which I can temporally knock out Cdh1 within zymogenic cells both in the presence and absence of Mist1. It is my hypothesis that cells lacking both of these tumor suppressors will be more likely to develop gastric tumors. Preliminary immune-fluorescence analysis of these stomachs indicates that in absence of both MIST1 and CDH1, fully differentiated and normally post mitotic zymogenic cells show greatly reduced size and increased re-entry into the cell cycle. This data suggests that deletion of both MIST1 and CDH1 disrupts the terminal differentiation program of zymogenic cells and promotes metaplastic growth in a manner that could resemble the origins of gastric cancer.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 36. doi:1538-7445.AM2012-36
Abstract 3605: Effects of antibody-mediated EGF-receptor inhibition on ERK 1/2 isoform phosphorylation in organoid cultures
Authors: Unger Florian T. , Rosenbrock Cordula , Krueger Jana , Schaller Janina , Rabe Birgit , Juhl Hartmut , David Kerstin A.
Published: August 2012

Inhibition of the EGF-receptor activity has been widely integrated into clinical practice for different tumor entities, e.g. non small lung cancer and colorectal cancer. Besides the application of tyrosine kinase inhibitors, anti-EGF-receptor treatment is mainly based on the application of therapeutic antibodies. As a standard procedure, patients are tested for KRAS mutation and only those without mutation are selected for anti-EGF-receptor therapy. Although KRAS testing is used to guide colorectal cancer treatment, clear heterogeneity in responses to treatment has been observed. The molecular mechanisms responsible for this heterogenity are still not fully understood, In the present study, we used a preclinical model based on tumor tissue slices for a more detailed evaluation of antibody-mediated EGF-receptor inhibition. In previous experiments, the diffusion of antibodies into organoid cultures and the detection of their functional effects had been successfully shown. Tumor tissue slices from five colorectal cancer patients have been treated with an anti-EGF-receptor antibody for 48 hours. Using immunohistochemical staining, one patient showed a strong expression of the EGF-receptor, one was weak positive and three displayed a moderate staining. As readout of treatment effects, the expression and phosphorylation levels of selected key proteins from two EGF-receptor downstream pathways, the MAPK-pathway and Akt-pathway, were measured using the multiplex technology platform from Meso Scale Discovery. For a more detailed view, we have integrated the NanoPro technology in our pathway analysis approach. This new method enables the identification of distinct isoform phosphorylations and thus is able to display the complex regulation of phosphorylation patterns in detail. By using both methods, we observed a dose-dependent regulation of total- and phospho-ERK in the organoid cultures after anti-EGF-receptor treatment. Deeper analysis using the NanoPro technology showed that the regulation of isoform phosphorylation patterns of ERK1/2 differed among patients, representing the heterogeneity of individual responses among patients. In summary, the combination of the organoid drug testing platform and the NanoPro technology can potentially be useful to identify predictive phosphorylation patterns of tumor cells within their natural tumor microenvironment. This may facilitate the discovery of predictive biomarker for the response to anti-EGF-receptor treatment and further improve personalized medicine.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3605. doi:1538-7445.AM2012-3605
Abstract 3609: Generation and characterization of a novel monoclonal antibody recognizing both the blood and tissue form of human PCBP-1
Authors: Alper Özge , Vortmeyer Alexander O. , Herrmann Marille , Akoa Achille , Alper Özgül M. , Auerbach Aaron , Chen Cui P.
Published: August 2012

Background: Poly(rC)-binding protein-1 (PCBP-1) is a nucleic-acid-binding protein that localizes in nucleus and/or cytoplasm of cells. Shuttling between nucleus and cytoplasm has been related to its function in regulation of RNA transcription, translation and also implicated its involvement in cancer metastasis, progression and chemoresistance. In the present study, we investigated the levels and expression of PCBP-1 in breast carcinoma and its potential use as a biomarker in breast carcinoma differential diagnosis. Methods/Results: We generated a novel monoclonal antibody (mAb), AB-PCBP-1 using hybridoma technology and native protein in cell culture medium as immunogen. This mAb is of IgG1 (kappa) type. It specifically recognized both native and denatured human PCBP-1 protein and displayed high affinity as assessed by ELISA, immunohistochemistry assay, western blot and flow cytometry applications. Using this mAb in competitive ELISA, we showed for the first time that soluble PCBP-1 level is significantly increased in the plasma of metastatic breast cancer patients’ plasma. PCBP-1 is also expressed in metastatic breast carcinoma tissue by immunohistochemistry. Seventy percent of normal breast ducts and lobules expressed strong nuclear staining whereas cytoplasmic staining was less specific and found in most cancer tissues. We examined 90 cases of breast carcinoma tissues classified as either ductal and lobular carcinoma. To evaluate the immunoreactivity of PCBP-1, the staining intensity and intracellular distribution were compared and scored as 0, 1+, 2+ and 3+ based on intensity. Seventy nine % (60 out of 76) of ductal carcinomas showed strong cytoplasmic staining (2+ and 3+) and 45% also exhibited strong nuclear localization for PCBP-1. Lobular carcinomas (n=14), on the other hand, showed an exclusively nuclear staining pattern.Conclusion: AB-PCBP-1 mAb showed high performance in blood and tissue assays. PCBP-1 levels were significantly increased in blood and demonstrated a distinct pattern of expression related to histological tumor types, suggesting that PCBP-1 may be involved in a regulatory mechanism that differs in various subtypes of breast carcinoma. The results suggest the potential clinical use of PCBP-1 as a therapeutic target and/or a biomarker in blood and tissue for the diagnosis and prognosis of breast carcinoma.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3609. doi:1538-7445.AM2012-3609
Abstract 3629: HOXA10 expression profiles in prostate cancer
Authors: Hatanaka Yuji , De Velasco Marco A. , Kura Yurie , Yamamoto Yuji , Kodama Mitsumasa , Nozawa Masahiro , Shimizu Nobutaka , Yoshimura Kazuhiro , Yoshikawa Kazuhiro , Nishio Kazuto , Uemura Hirotsugu
Published: August 2012

HOXA10 is a member of the homeobox gene family and is a transcription factor primarily involved in embryonic development. Perturbed HOX gene expression has been identified in numerous cancers and thus suggests that these genes may play important roles in diagnosis and treatment of cancer. We initially identified altered HOXA10 expression in prostate tumors form prostate-specific PTEN conditional knockout mice. HOXA10 is highly expressed in the normal prostate glands from wildtype and PTEN-mutant mice and gradually decreases with tumor development and decreased differentiation. However, focal expression of HOXA10 is observed in poorly differentiated tumors and is highly expressed in metastases. To determine clinical significance of HOXA10 in human prostate cancer, we examined HOXA10 expression by immunohistochemistry in matched normal and cancer specimens from prostatectomy cases. HOXA10 nuclear expression was measured according to intensity and distribution. Our analysis shows that HOXA10 is strongly expressed in benign glands and low expression is significantly correlated with Gleason grade (p<0.001), tumor differentiation (p<0.02), pathological stage (p<0.001) and PSA-failure (p<0.001). Expression of HOXA10 was also evaluated in human prostate cell lines and was strong in the benign prostatic hyperplasia BPH-1 human prostate cell line and weak to absent in the malignant human prostate cancer cell lines PC3, DU145 and LNCaP. These data show that HOXA10 is related to tumorigenesis of prostate cancer prostate cancer and warrants further investigation into the functional role of HOXA10 in tumor development.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3629. doi:1538-7445.AM2012-3629
Abstract 3639: Systemic inflammation and survival of patients with prostate cancer: Evidence from the Glasgow Inflammation Outcome Study.
Authors: Shafique Kashif , Proctor Michael , McMillan Donald , Qureshi Khaver , Leung Hing , Morrison David
Published: August 2012

Background: There is some evidence that pre-treatment systemic inflammation may be associated with survival in patients with prostate cancer; however, it is unclear whether this is independent of grade and stage of cancer. We therefore investigated the role of inflammation-based prognostic scores, the modified Glasgow Prognostic Score (mGPS) and Neutrophil Lymphocyte Ratio (NLR), and their associations with Gleason grade and socioeconomic circumstances in patients with prostate cancer. Methods: Patients from a cohort, the Glasgow Inflammation Outcome Study, who had diagnosis of prostate cancer, were included in this study. The mGPS was constructed by combining C-reactive protein and albumin while NLR by calculating the ratio of neutrophils to lymphocytes. We estimated five-year relative survival using the age, gender and deprivation specific life tables and relative excess risk of death by mGPS and NLR categories after adjusting for age, socioeconomic circumstances and Gleason grade. Results: Eight hundred and ninety seven prostate cancer patients were identified; of those 422 (47%) died during a maximum follow up of 6.2 years. Systemic inflammation appeared to have significant prognostic value. The mGPS predicted poorer 5-year overall and relative survival independent of age, socioeconomic circumstances, disease grade and NLR. Raised mGPS also had a significant association with excess risk of death (mGPS 2: Relative Excess Risk = 2.41, 95% CI 1.37-4.23) among aggressive, clinically significant prostate cancer (Gleason grades 8-10). Similarly, age-specific analyses were also carried out and raised mGPS showed significantly higher risk of death among those with age <65 and 65-74 years at diagnosis. However, a non-significant increased risk of death was also observed among those age >75 years. Conclusions: The mGPS is a strong measure of systemic inflammation, when compared to NLR. Prostate cancer patients with a raised mGPS had significantly higher risk of death for overall as well high grade disease. Inflammation-based prognostic scores predict outcome in patients with prostate cancer and should be added to their routine clinical assessment. Keywords: mGPS, NLR, prostate cancer, prognosis, Gleason grade, systemic inflammation

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3639. doi:1538-7445.AM2012-3639
Abstract 3648: Nanofluidic technologies to define biological and response profile in neoadjuvant patients with ovarian cancer
Authors: Mariani Marisa , Ferlini Cristiano , Wilmot Amanda , Shahabi Shohreh
Published: August 2012

Objectives: Neoadjuvant chemotherapy is used in the treatment of advanced ovarian cancer. In this study, we determined the impact of chemotherapy on gene and microRNA (miRNA), expression in ovarian cancer specimens using nanofluidic technology. We performed the validation of this technique by using RNA extraction from archival formalin-fixed paraffin-embedded tissue. Molecular pathways involved in prediction of the outcome in neoadjuvant patients were analyzed. Methods: Seventy-eight patients with advanced ovarian cancer who were treated with primary surgical debulking versus neoadjuvant chemotherapy (15/78) were investigated. All patients were treated with Paclitaxel and Carboplatin. A chip 48.48 served to analyze a panel of 96 potential predictors of the outcome and response to chemotherapy. All the samples were normalized for multiple housekeeping genes and as consistent reference the ovarian cancer cell line A2780 was used. When needed for the analysis each factor was then categorized as high and low expression using the mean value as cutoff. Overall survival was analyzed using the methods of Kaplan and Meier and comparisons between groups by log-rank and Wilcoxon test. Results: We assessed the impact of neoadjuvant chemotherapy on the selected genes and microRNAs. Among the cell growth and proliferation genes MKI67, PLK1, PBK were reduced. Deactivation of the TUBB3 survival pathway, which was reduced while its negative regulator GNAI1 was increased. ERBB2 resulted downregulated in the neoadjuvant setting, while HGF and PTEN were increased. MicroRNAs expression broadly increased, with the only exception of miR-20a and miR-141. Patients exhibiting high levels of COL11A1 and PLK1 were poor performers, while the opposite occurred for GLI1. At the micro-RNA level the best predictors were miR-193a-5p, miR-375 and miR-20a. The poor performers (miR-193a-5p, miR-375) were featured by high levels of the micro-RNA while the opposite was evident for miR-20a. Conclusions: Use of the nanofluidic technology provides deeper insight into the specific roles of clinically relevant major molecular networks. Chemotherapy induced modification of genes and microRNA expression can be used as a model to develop future prognostic biomarkers and therapeutic modalities. Moreover, our findings suggest that neoadjuvant patients with ovarian cancer may benefit from biologic agent targeting HGF treatment.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3648. doi:1538-7445.AM2012-3648
Abstract 3649: Expression of CXCR5 and its natural ligand CXCL13 in ovarian cancer
Authors: Singh Rajesh , Grizzle William E. , Singh Shailesh , Lillard James W.
Published: August 2012

Ovarian carcinoma (OvCa) is the most lethal gynecological malignancy among women and its poor prognosis is mainly due to metastasis. Chemokines and their corresponding receptors play an important role in metastasis and organ specific homing of cancer cells including OvCa. CXCL13 is a homeostatic chemokine for lymphocyte- and prostate cancer cell-homing and -positioning within secondary lymphoid tissues. This important chemokine acts through its only known receptor, CXCR5. In this study, we provide the first evidence that in OvCa CXCR5 and CXCL13 are highly elevated in OvCa cell lines and clinical samples. Flow cytometry analysis of OvCa cell lines (OVCAR-3 and SK-OV-3) show significantly higher expression of CXCR5 in comparison to normal adult ovarian epithelial cells. To determine the clinical significance of CXCR5 expressed by OvCa cell lines, ovarian cancer tissue microarrays were stained for CXCR5 and CXCL13. Aperio ScanScope scanning system was used to quantify the immuno-histochemical staining of CXCR5 and CXCL13. Our results show significantly higher expression of CXCR5 and CXCL13 (p < 0.001) in cancerous tissue than compared to non-neoplastic ovarian tissue. Among cancerous tissues, CXCR5 and CXCL13 expression was highest in serous adenocarcinoma followed by serous papillary cystadenoma, endometrioid adenocarcinoma, mucinous adenocarcinoma, cystadenoma, mucinous boderline adenocarcinoma, clear cell carcinoma, granulosa cell tumor, dysgerminoma, transitional cell carcinoma, brenner tumor, yolk sac tumor, adenocarcinoma and fibroma. These data demonstrate biological and clinical significance of CXCR5 and CXCL13 as an OvCa biomarker.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3649. doi:1538-7445.AM2012-3649
Abstract 3654: Prognostic role of androgen receptor in bladder cancer
Authors: Hartmann Arndt , Bertz Simone , Keck Bastian , Dyrskjot Lars , Orntoft Torben , Wullich Bernd , Hake Roland , Eidt Sebastian , Wirtz Ralph
Published: August 2012

Aims: Hormone receptors are the prototype predictive marker in breast and prostate cancer. Hormone receptor positive cancers have a better prognosis, increased tropism to metastasize into the bones and respond to endocrine treatment options. The prognostic value of hormone receptor in urothelial carcinoma of the bladder (UCB) is less established. This may in part result from technical limitations of immunhistochemical detection methods. Interestingly, female gender has recently been identified as strong adverse factor in advanced UCB (May et al., 2011). By analyzing whole genome expression data from non-muscle invasive bladder cancer patients, we have evaluated the potential of top candidate genes (ESR1, PGR, AR, CYP19, HER2, RACGAP1) commonly used to stratify breast cancer patients to predict bladder cancer progression. In view of the gender specific effects, we have focused on the prognostic role of androgen receptor expression on tumor invasion, disease progression and survival. Methods: Affymetrix microarray data from 41 non-metastatic bladder cancer patients undergoing curative surgery were analyzed. Prognostic value of androgen receptor mRNA expression was analyzed by unsupervised Cluster analysis, partitioning tests, Mann Whitney tests and Kaplan Meier estimates of cancer specific survival. Results: Cluster analysis in the microarray date of the superficial UCB cohort identified a hormone receptor positive subtype and a proliferation dominated subtype of equal size. Androgen receptor expression was negatively associated with cancer specific death (r=−0,42; p=0,005), while proliferation correlated with increased risk of cancer specific death (r=0,46; p=0,003). In addition, low androgen receptor expression was associated with higher tumor stage (pTa vs pT1-4; p=0,017). In Kaplan Meier analysis, the cancer specific survival was significantly better in tumors exhibiting high androgen receptor levels (80% vs. 20 %; p<0,0001). Discussion: Resembling to some extent the situation in other cancer types, hormone receptors are prognostic factors in early stage bladder cancer. These results may also explain the recently described gender specific effects in bladder cancer. Moreover, these results raise the possibility, that UCB patients may be stratified according to their androgen receptor status in view of prognosis and putative endocrine therapy options.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3654. doi:1538-7445.AM2012-3654
Abstract 3655: Stem cell-associated gene Lin-28B genotype and phenotype in epithelial ovarian cancer and their associations with disease survival outcomes
Authors: Lu Lingeng , Katsaros Dionyssios , Risch Harvey , Yu Herbert
Published: August 2012

Several single nucleotide polymorphisms (SNPs) in lin-28B, a gene encoding RNA binding protein that represses miRNA let-7 maturation and acts as an oncogene, were found in the genome-wide association studies (GWAS), to be associated with the risk of ovarian cancer and cancer-related risk factors such as age at menarche, body mass index (BMI) and height. However, whether these SNPs are functionally important and can serve as prognostic markers in ovarian cancer remain unknown. The purposes of this study were to investigate the genotype-phenotype relationship in lin-28B and their associations with patient survivals in epithelial ovarian cancer. To achieve these purposes, we analyzed five lin-28B SNPs using Taqman® assays and lin-28B expression using SYBR green-based qPCR in tumor samples collected from 211 patients diagnosed with primary epithelial ovarian cancer. Wilcoxon rank sum test was performed to analyze cis-regulatory eQTL; Kaplan-Meir survival curves and Cox proportional hazards regression models were used to assess the associations of lin-28B SNPs and expression with the risks of relapse and death. The results showed that three SNPs (rs314276, rs314277 and rs7759938) were associated with lin-28B mRNA levels. Using mfold, rs314276 and rs314277 were predicted to affect the secondary structures of lin-28B mRNA. SNP rs7759938 is located at the 500 bp downstream of the region with H3K4Me1 (an enhancer marker) enrichment restricted to stem cells. However, these SNPs were not significantly associated with clinical and pathological parameters including disease stage, tumor grade, histological types, residual tumor size, and debulking results. No SNPs alone were related to patient survivals. Among patients initially responding to chemotherapy, those with high lin-28B expression had higher risks of death (hazard ratio (HR)=3.27, 95% CI: 1.63-6.56), and relapse (HR=2.53, 95% CI: 1.41-4.54) than those with low one. After adjustment for patient age at surgery, disease stage, tumor grade, histological types and residual tumor size, the associations were still statistically significant. These findings suggest that 3 of the GWAS-hit SNPs in lin-28B may affect gene expression, but these SNPs are not associated with ovarian cancer survival. The results also indicate that lin-28B may affect the outcome of chemotherapy.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3655. doi:1538-7445.AM2012-3655
Abstract 3658: The association of mitochondrial DNA content with bladder cancer risk and outcome
Authors: Ye Yuanqing , Dinney Colin P. , Kamat Ashish M. , Wu Xifeng
Published: August 2012

Mitochondrion plays essential role in energy production and apoptosis process from the initiation to regulation of apoptosis. Many studies have showed the association of dys-regulated mitochondrial DNA (mtDNA) with the development and progression of cancer, aging and longevity, and neurodegenerative diseases. In this study, we will test the hypothesis that variation in mtDNA content (also called mtDNA copy number) may be associated with individual's bladder cancer risk and clinical outcome in a case-control study of 1026 bladder cancer patients and 980 healthy-controls. We will also assess the association of mtDNA content with progression/recurrence in non-muscle invasive bladder cancer (NMIBC) patients and overall survival in muscle invasive and metastatic bladder cancer (MIMBC) patients. Quantitative real-time polymerase chain reaction in peripheral blood lymphocytes was used to measure mtDNA content. We observed significantly lower mtDNA content in bladder cancer patients (mean = 1.05, SD = 0.36) than controls (mean = 1.11, SD = 0.39) with P value < 0.001. When we categorized the mtDNA content using the quartile distribution in controls, Lower mtDNA content (less than 1st quantile) was associated with 1.69-fold increased risk of bladder cancer (95% confidence interval [CI] = 1.17 to 1.68), compared to those who have higher mtDNA content (greater than 4th quartile). In patients with MIMBC, we also observed the significant association of lower mtDNA content with poor survival. After categorizing the mtDNA content using quartile distribution in patients who were alive, there is a significantly increased risk of death for patients with lower mtDNA content (hazard ratio = 1.75, 95% CI = 1.11 to 2.77). There is also a significantly reduced median survival time (44.5 months vs 25.4 months, log-rank P = 0.004). However, there is no significant association of mtDNA content with progression/recurrence in NMIBC patients. In conclusion, low mtDNA content is associated with significantly increased risk of bladder cancer risk and poor survival. The resulted from our study will contribute to personalized risk prediction and may also become potential molecular targets for prevention.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3658. doi:1538-7445.AM2012-3658
Abstract 3663: A gene signature for predicting outcome in patients with basal-like breast cancer
Authors: Hallett Robin M. , Dvorkin-Gheva Anna , Bane Anita , Hassell John A.
Published: August 2012

Basal-like breast cancer is a molecular subtype of breast cancer generally thought to have a universally poor prognosis. Subsequent studies examining the long-term outcome in thousands of patients with basal-like breast cancer have shown that these patients can be separated into two clinically distinct groups: those likely to experience a systemic recurrence and succumb to their disease within the first 5 years and those expected to show excellent long term survival. The ability to distinguish between these two sub-groups (good and poor prognosis) of basal-like breast cancer patients at the time of initial diagnosis would permit tailoring more aggressive therapeutic regimens to those patients with an inherently poorer prognosis and conversely to avoid such therapy in patients with a more indolent course. We aimed to identify a gene signature that could predict the clinical outcome of basal-like breast cancer patients. To this end we mined publicly available human breast tumor gene expression profiling data and identified patients with basal-like breast cancer. We divided these patients into training and validation sets to identify and confirm the accuracy of a prognostic signature. We identified 137 basal-like breast tumors among 995 breast tumor gene expression profiles. We used 85 of these samples as a training group and identified an optimal 14-gene signature, which accurately identified patients that experienced poor and good long-term survival. We confirmed the accuracy of our gene signature on a 49 patient independent validation set. Importantly, we also confirmed the capacity of our signature to predict outcome in a chemotherapy naïve 27 patient sub-set of the 49 patients validation set.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3663. doi:1538-7445.AM2012-3663
Abstract 367: Imaging and diagnostic potentials of a novel cancer targeting peptide on bladder cancer in vitro and in vivo
Authors: Trehan Siddharth , Lin Tzu-yin , Liu Ruiwu , Zhang Hong-Yong , Pan Chong-Xian
Published: August 2012

Background: We have previously identified a cyclic peptide PLZ4 through screening of “one bead one compound”(OBOC), that specifically binds to bladder urothelial carcinoma cells. The main objective of this study is: 1) to optimize the binding and diagnostic potential of PLZ4 on cancer cells in urine, 2) to determine the imaging potential in xenograft mouse model. Methods: PLZ4 peptide was conjugated to the fluorescent dye Alexa 488 to determine the binding affinity toward several human and canine clinical biopsy smears and paraffin-fixed bladder tumor sections. It was also tested for in vitro diagnostic efficiency with human and dog bladder cancer cell lines treated with urine for 2 and 4 hours. To determine the in vivo targeting and imaging efficacy, PLZ4 was labeled with 64Cu through the chelator DOTA or near-infrared dye DiD loaded in nanocarriers. Mice carrying subcutaneous human or dog bladder cancer xenografts generated from cell lines or clinical specimens were used for in vivo imaging. Results: Our results indicated that PLZ4-Alexa 488 bound to primary bladder cancer obtained from dog and human patients and had higher affinity in paraffin-fixed bladder tumor sections compared to H232A lung cancer xenograft tissue sections. PLZ4 also retained its affinity toward both human and dog bladder cancer cells in the presence of urine for 2 and 4 hours. Positron emission tomography (PET) imaging displayed the accumulation of PLZ4-DOTA-64Cu conjugate at human xenograft bladder cancer sites, while liver and kidney were also found to have high uptake. DiD-loaded nanomicelles decorated with PLZ4 showed a better homing property than non-targeting nanomicelles in both human and canine xenograft bladder cancers. Conclusion: PLZ4 has high imaging, diagnostic and therapeutic potential both in vitro and in vivo. It can possibly be developed for targeted delivery of radionuclides or chemotherapeutic nanoformulations in the management of bladder cancer.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 367. doi:1538-7445.AM2012-367
Abstract 368: Development of a highly potent and non-invasive optical imaging agent for glioblastoma
Authors: Liu Ruiwu , Xiao Wenwu , Bononi Fernanda C. , Sanchez Eduardo , Liu Yanlei , Mazloom Anisha , Tseng Harry , Lam Kit S.
Published: August 2012

Using the “one-bead one-compound” (OBOC) combinatorial library approach, we have previously identified a peptide ligand LXY1, cyclic c-d-G-L-G-Hyp-N-c, that targets the α3β1 integrin of U87MG glioblastoma cells. Very recently, we have further optimized LXY1 using the OBOC focused library approach, and subsequently traditional medicinal chemistry. Three focused OBOC peptide libraries have been designed by fixing the motif c-d-G_G_ _c, randomizing the other positions with a large number of D- and other unnatural amino acids, and extending with 1-2 random amino acids at the N-terminus and/or C-terminus of LXY1. The bead libraries have been screened against U87MG cells using an on-bead cell binding assay. Three out of the twelve positive ligands have an additional L-amino acid at the C-terminus of LXY1. However, none of the positive beads has an extension of additional residues at the N-terminus. A series of new ligands has been designed based on the screening results, and extensive structure-activity relationship (SAR) studies have been performed. Several ligands have shown more potent in vitro binding to U87MG cells, and better in vivo tumor uptake than LXY1. Among them, LXY30 [cyclic c-d-G-Phe(3,5-diF)-G-Hyp-N-c-R] is the most promising ligand. Optical imaging of LXY30, using LXY30-biotin/streptavidin-Cy5.5 conjugate, in both subcutaneous and orthotopic U87MG glioblastoma mouse models, will be presented. LXY30 could be used as an efficient vehicle for the delivery of imaging probes and therapeutic agents against glioblastoma and other tumors with a high expression of the α3β1 integrin.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 368. doi:1538-7445.AM2012-368
Abstract 3684: Targeting Aurora kinase in peripheral T-cell non-Hodgkin's lymphomas
Authors: Mahadevan Daruka , Qi Wenqing , Liu Xiaobing , Cooke Laurence S. , Agarwal Amit , Persky Daniel O. , Miller Thomas P.
Published: August 2012

Aurora kinases (A and B) are oncogenic serine/threonine (S/T) kinases that play central roles in the mitotic phase of the eukaryotic cell cycle. Over-expression of Auroras during dysregulated cell cycling and their aberrant activation over-rides mitotic and spindle check points leading to anueploidy in many human cancers make Auroras attractive therapeutic targets. Gene expression profiling in mantle cell lymphoma [MCL] have shown the Auroras are over-expressed and is a poor prognostic marker within the ‘proliferative’ signature. PTCL (NOS) are a heterogeneous group of rare non-Hodgkin's lymphomas (NHL) derived from activated CD4+ or CD8+ T cells. PTCL and anaplastic large cell lymphoma (ALCL) both of T-cell phenotype and ALK negative have an aggressive clinical course with an inferior event free and overall survival relative to B-cell NHL counterparts. The biological explanation for the difference is unknown. Patients with PTCL have a poor prognosis due to a very aggressive disease course coupled to a lack of effective therapies. Therefore, the development of novel and effective treatments based on biologically validated targets is urgently needed for this disease. We hypothesized and investigated that (1). Auroras are over-expressed in human PTCL-NOS, (2). Aurora ATP-site small molecule inhibitor (SMI) is effective in inhibiting cell proliferation and promoting apoptosis in cell culture and (3). Aurora SMI will be safe and effective in treating patients with relapsed aggressive T-cell NHL in early phase clinical trials. In this study, we demonstrate that both aurora A and B are highly over-expressed in PTCL patients and cell lines. MLN8237 (alisertib), an ATP-site small molecule inhibitor of Aurora A had potent activity in inhibiting phosphorylation of Aurora A and histone H3 in PTCL cell lines. Cells treated with MLN8237 exhibited endoreduplication confirming the mechanism of action of an Aurora inhibitor. Also, treatment of PTCL cell lines with MLN8237 induced apoptosis in a dose and time dependent manner (flow cytometry and PARP-cleavage) and inhibited cell proliferation with an IC50 < 0.1µM. Preliminary data from a phase II clinical trial using single-agent MLN8237 in patients with relapsed refractory aggressive NHL has demonstrated notable activity with 4 confirmed responses in 6 evaluable PTCL patients. Cytokine profiling on day 1 (pre-treatment) and day 8 (post-treatment) showed a profile consistent with aurora A activity. Together the data suggest inhibition of Auroras offers a promising treatment strategy for patients with aggressive T-cell NHL [Funded by the Lymphoma SPORE, P50 CAB0805501A1].

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3684. doi:1538-7445.AM2012-3684