bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract LB-345: Amplification of miR-26a-2 in human liposarcoma is correlated with poor patient survival
Authors: Lee Dhong Hyun Tony , Goff Catherine , Cutter Suzanne , Amanat Soroosh , Doan Ngan , Said Jonathan , Forscher Charles , Koeffler H. Phillip
Published: July 2012

Human liposarcoma (LPS) is one of the most common soft tissue sarcomas in adults. However, its molecular mechanism is poorly understood. For better understanding of the disease, we examined 54 human liposarcoma samples including 51 primary tumors and 3 cell lines (SW872, LP6, LP141) using Affymetrix 250K single nucleotide polymorphism (SNP) array. Allele-specific copy number (CN) analysis using anonymous references revealed that CN gain was dominant event over CN loss and loss of heterozygosity (LOH) in human LPS. Recurrent CN gain at 1q21–24 (43% of the samples), 5p13-p15 (46%), and 8q24 (41%) were identified. The most prominent CN gain was found in the 12q13-q15 region. 88% of the samples, mostly well-differentiated / de-differentiated subtype (WDLPS / DDLPS), showed various levels of CN gains centered at MDM2 gene.

In addition to MDM2 amplicon, we also identified an MDM2-independent amplicon in the 12q13-q15 region centered at miR-26a-2 gene at the same frequency (88%). MDM2 amplicon almost always accompanied miR-26a-2 amplicon. Likewise, samples without MDM2 amplicon did not have a miR-26a-2 amplicon. Quantitative reverse transcription real-time PCR (qRT-PCR) analysis showed that this CN gain of miR-26a-2 was strongly correlated with high mRNA expression of the gene in the WDLPS / DDLPS subtype. Furthermore, high mRNA expression of miR-26a-2 significantly correlated with a worse patient survival (p=0.05). Interestingly, some samples in myxoid / round-cell subtype (MRC) also showed high expression of miR-26a-2 without any prominent CN changes. High expression in the MRC subtype was also correlated with poor patient survival (p=0.0029). Western blot analysis using LPS cell lines revealed that cells with high miR-26a-2 expression showed decreased levels of RB1 and PTEN, which are two verified targets of miR-26a-2.

In conclusion, our analysis demonstrated the clinical importance of miR-26a-2 gene in human LPS. This finding may contribute to the discovery of prognostic markers as well as novel therapeutic targets for human LPS.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-345. doi:10.1158/1538-7445.AM2011-LB-345
Abstract LB-350: Tissue and serum miRNA profiling for detection of bladder, breast and prostate cancer
Authors: Porter-Gill Patricia A. , Fu Yi-Ping , Kaushiva Alpana , Price Douglas , Dahut William , Figg William , Prokunina-Olsson Ludmila
Published: July 2012

Biomarkers that can differentiate between normal and tumor state, and can be measured in easily accessible body fluids such as blood and urine, can be very important for cancer diagnostics and disease monitoring. MicroRNAs (miRNAs), short non-coding regulatory RNA molecules, are attractive as biomarkers because they are stable in different conditions and are easy to measure with quantitative PCR (qPCR) methods. In this study we aimed to identify a universal panel of miRNAs for cancer screening that can be easily tested in the serum of healthy individuals and patients with different types of cancer. First, we measured expression of ∼800 miRNAs in 40 controls and 60 patients with bladder, breast or prostate cancer using the low density TaqMan expression arrays (Applied Biosystems) and starting from 250 ul of serum. Based on these results we selected a panel of 24 miRNAs that showed best discrimination between normal and cancer samples. These miRNAs were then re-tested as a custom-designed mini-panel in serum samples of 44 healthy controls and cancer patients (31 bladder, 25 breast and 28 prostate) and in relevant normal and tumor tissue samples (42 normal bladder and 43 bladder tumors, 44 normal breast and 42 breast tumors and in 50 normal prostate and 20 prostate tumors). Only miRNAs that expressed in the same direction in serum and tissue samples and showed significant association with cancer in both sample types were used for further analysis.

The current panel consists of 16 miRNAs – 14 targets, one positive control and one negative control. Using this panel on serum samples from 44 controls, 31 bladder cancer patients, 25 breast cancer patients and 28 prostate cancer patients we performed ROC analysis and achieved complete discrimination (AUC ∼1.0) between all types of cancers and controls and good discrimination between different types of cancers (minimal AUC 0.89 for breast and bladder samples). Our results prove that miRNA detection from serum might be a promising method of cancer detection. Currently, we are performing validation studies in independent sets of samples. A combination of information on genetic susceptibility factors identified by genome-wide association studies (GWAS), other cancer-specific factors such as PSA for prostate cancer and miRNA expression profiling, might provide additional tools for early disease diagnostics and help to guide treatment options.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-350. doi:10.1158/1538-7445.AM2011-LB-350
Abstract LB-420: Intratumoral de novo steroid synthesis mediates prostate cancer resistance to androgen deprivation and CYP17a1 inhibition
Authors: Cai Changmeng , Balk Steven P.
Published: July 2012

Prostate cancer (PCa) that relapses after androgen deprivation therapy (ADT, medical or surgical castration), termed castration resistant prostate cancer (CRPC), has increased expression of enzymes that convert adrenal dehydroepiandrosterone (DHEA) and androstenedione to testosterone and dihydrotestosterone (DHT). DHEA and androstenedione are synthesized at high levels by the adrenals through the sequential actions of CYP11A1 and CYP17A1; hence CYP17A1 inhibitors such as abiraterone are effective therapies for CRPC. However, mechanisms contributing to CYP17A1 inhibitor relapse remain to be determined. We show that castration resistant VCaP PCa xenografts synthesize androgens de novo at levels that fully restore androgen receptor (AR) activity and respond to abiratrone, and that development of abiraterone resistance is associated with markedly increased intratumoral CYP17A1 expression. Consistent with these results, we find that tumor expression of CYP17A1 is markedly increased in patients after CYP17A1 inhibitor therapy. We further show that CRPC cells expressing a T877A mutant AR are not CYP17A1 dependent, and that AR activity in these cells is instead mediated by upstream CYP11A1 dependent pregnenolone/progesterone synthesis. These findings indicate that CYP17A1 inhibitor resistant tumors are still steroid dependent and may respond to dose escalation, alternative CYP17A1 inhibitors, or agents blocking other steps in steroid synthesis.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-420. doi:10.1158/1538-7445.AM2011-LB-420
Abstract LB-438: Proteomic analysis of aristolochic acid-induced nephrotoxicity in rats
Authors: Yu Li-Rong , Li Zhiguang , Gao Yuan , Chen Tao
Published: July 2012

Aristolochic acids (AA) are a family of structurally related nitrophenanthrene carboxylic acids, mainly consisting of aristolochic acid I (AAI) and aristolochic acid II (AAII), and are the active component of some herbal medicines. Use of dietary supplements and other botanical products containing AA have resulted in severe nephrotoxicity and consequent renal replacement therapy. Aristolochic acids are potent carcinogens as well, inducing urothelial cancers in humans and kidney tumors in rats. Previous studies have shown that the tumorigenicity of AA could result from AA-induced DNA adduct formation and mutation induction. To further understand the molecular mechanisms underlying AA-induced nephrotoxicity (e.g., carcinogenesis) and identify disease biomarkers, a quantitative proteomic analysis was conducted on kidneys from AA-treated rats. Animal treatment was conducted according to the approved protocol and followed the recommendations of the NCTR Institutional Animal Care and Use Committee. Six-week-old Big Blue rats were treated with AA as its sodium salt at concentrations of 0.1, 1.0, and 10.0 mg/kg body weight by gavage five times/week for 12 weeks or with 0.9% sodium chloride as the control using the same schedule. Six rats from each treatment group were sacrificed 1 day after the last treatment. The kidneys were isolated, frozen quickly in liquid nitrogen, and stored at −80 °C. Kidney tissues from the control and the highest AA dose treatment (10 mg/kg body weight) were selected for proteomic analysis. Proteins were extracted and digested into peptides. Trypsin-catalyzed 16O/18O stable isotope labeling was performed for each pair of control/treatment samples, which were then analyzed using two-dimensional liquid chromatography coupled online with tandem mass spectrometry (LC-MS/MS). Approximately 3000 proteins were quantified from each pair of samples, and more than 150 proteins were concordantly over expressed or under expressed across all the AA-treated samples. Pathway analysis indicated that significant changes include proteins involving xenobiotic metabolism, response to stimulus including DNA damage, cell proliferation and neoplasm, etc. Intriguingly, proteins indicating kidney pathological changes such as nephron degeneration were identified as well. Although further verification is needed, the quantitative proteomic study identified proteins related to potential toxicity and oncogenic pathways and proteins that could serve as urinary biomarkers of renal damage inflicted by aristolochic acid exposure.

The views presented do not necessarily reflect those of the U. S. Food and Drug Administration.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-438. doi:10.1158/1538-7445.AM2011-LB-438
Abstract LB-441: The genome wide gene-environment interaction analysis for asbestos exposure on lung cancer susceptibility
Authors: Wei Sheng , Wang Li-e , McHugh Michelle K. , Han Younghun , Amos Christopher I. , Spitz Margaret R. , Xiong Momiao , Wei Qingyi
Published: July 2012

Asbestos exposure is a known risk factor for lung cancer. Although recent genome wide association studies (GWAS) have identified a few novel loci for lung cancer risk, little is known about genome wide gene-environment interactions and lung cancer risk. To determine genetic variations involved in the interactions of gene-asbestos exposure on lung cancer risk, we conducted genome wide gene-environment interaction analyses at levels of single nucleotide polymorphisms (SNPs), genes and pathways, using the Texas lung cancer GWAS dataset. This dataset included 307,870 SNPs from 1,154 lung cancer cases and 1,137 cancer-free controls. The initial SNP-level p values for interactions between genetic variants and self-reported asbestos exposure were estimated by unconditional logistic regression models adjusted for age, sex, smoking status and pack-years. The p value for the most significant SNP rs12706823 was 1.37 × 10–4 and did not reach the genome-wide statistical significance. Using a versatile gene-based test approach to estimate the interactions at the gene level, we found the top significant gene was RNF121and was located on 11q13.4 (p value = 4 × 10–4). Interestingly, most of the genes with top significant p values were located in 11q13. When we used an improved gene set enrichment analysis approach (i-GSEA), however, we found a total of 249 pathways containing 16,079 genes, of which the Fas signaling pathway was the most significant pathway, significantly involved in the interactions between genetic variations and self-reported asbestos exposure (nominal p value < 0.001; false discovery rate (FDR) < 0.05). We believe our analysis is the first to comprehensively describe the genome wide gene-asbestos exposure interaction on lung cancer risk at the levels of SNPs, genes and pathways. Our findings suggested that the current designed GWAS may have a limited power to detect gene-environment interactions at the SNP or gene levels, but the pathway-based approach may be more powerful in performing genome wide gene-environment analyses. (This study was supported by NIH grants R01 ES 11740, R01CA 131274, R01CA055769, R01CA127219, R01CA121197 and P30CA016672)

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-441. doi:10.1158/1538-7445.AM2011-LB-441
Abstract LB-449: The relationship between CHRNA5 gene polymorphism and the strength of nicotine addiction in lung cancer, COPD and healthy smokers
Authors: Wojas-Krawczyk Kamila , Krawczyk Pawel A. , Biernacka Beata , Kucharczyk Tomasz , Mlak Radosław , Kowalski Dariusz M. , Andrzejuk Jolanta , Milanowski Janusz
Published: July 2012

Introduction. A rare variant of chromosomal region 15q25.1, marked by rs16969968 (substitution 1354G>A or D398N in CHRNA5 gene), was found to be associated with increased lung cancer risk and nicotine dependence appearance. We attempted to confirm the relationship between polymorphism of gene for nicotine acetylocholine receptor A subunit 5 (CHRNA5) and stage of nicotine dependence measured by the result of Fagerström test and cotinine level in serum in lung cancer, COPD and healthy smokers.

Methods. Polymorphism of CHRNA5 gene was analised using PCR-RFLP method in the group of 97 lung cancer patients, 99 COPD patients and 98 healthy volunteers. The Fagerström Test for Nicotine Dependence was used as a standard instrument for assessing the intensity of this physical addiction. Cotinine serum level was measured using ELISA method.

Results. In all analyzed subjects, the frequency of AA, AG and GG genotypes were 11%, 47% and 42%, respectively. The polymorphism of CHRNA5 gene does not have a significant influence on the elevated risk of lung cancer and COPD. The presence of GG genotype decreased the risk of strength of nicotine addiction (HR=0.238, 95%CI:[0.066–0.857], p<0.05). We observed that allele A was presented more frequently in the subjects with high level of nicotine dependence and in the subjects with early (<25 years) onset of addiction (p<0.05). Moreover, cotinine serum level significantly correlated with results of Fagerström test (p<0.001). The carriers of allele A expressed significantly higher level of serum cotinine when compared with the carriers of GG genotype (p=0.05).

Conclusion. In the presented abstract we report for the first time the relationship between the polymorphism of CHRNA5 gene and the strength of nicotine addiction.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-449. doi:10.1158/1538-7445.AM2011-LB-449
Abstract LB-61: Trends in Kidney Cancer.
Authors: Bitkower Jay
Published: July 2012

Kidney cancer_one of only four cancer types that have experienced greater than a 2 percent increase in incidence per year_has not had a significant decline in the mortality rate. According to the National Cancer Institute, kidney cancer incidence has been steadily increasing for the last 65 years. Meanwhile, although Federal funding for the disease has increased, it still lags behind the major cancers, especially when analysed with respect to research dollars per mortality.

A group of kidney cancer survivors and caregivers formed the organization Action to Cure Kidney Cancer (ACKC) out of concerns about the inadequate government and private funding for kidney cancer research. ACKC's primary mission is to advocate specifically for kidney cancer research, and through our advocacy efforts, ACKC has reached out to thousands of kidney cancer survivors throughout the country. With their support, ACKC has met with members of Congress and local political leaders, has mounted letter writing campaigns, conducted briefings on kidney cancer for both the U.S. Senate and House health aides, and initiated a request by the House Labor, Health and Human Services and Education (LHHSE) sub-committee asking the National Cancer Institute to develop a strategic plan to combat kidney cancer. A another major focus of ACKC's efforts is to convince the U.S. Congress to appropriate kidney cancer research money for the Congressionally Directed Medical Research Programs (CDMRP) at the Department of Defense.

In addition to the organization's efforts at the federal level, ACKC raises funds in order to grant awards to researchers developing innovative studies in the field of kidney cancer. ACKC has enabled grants supporting the work to develop an early screening test for kidney cancer based on methylated genes, to investigate the effects of the activation of a human endogenous retrovirus in the pathogenesis of kidney cancer, and to develop a therapy using a cytotoxic agent that destroys cancer cells based on the principle of synthetic lethality, to name a few.

ACKC communicates with its constituency via its website www.ackc.org, Facebook (actiontocurekidneycancer), listservs like ACOR (Association of On-line Cancer Resources), and personal emails. Mr. Bitkower's poster will describe his organization's efforts and accomplishments in increasing research funding for this deadly disease.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-61. doi:10.1158/1538-7445.AM2011-LB-61
Abstract LB-63: From the Golf Course to Education: Outreach & Support for Prostate Cancer
Authors: Brown Egbert
Published: July 2012

Central Ohio Men Against Prostate Cancer provides access to education, outreach and support for diagnosed or at-risk prostate cancer patients, their families, and friends. There is extensive medical information available online and through healthcare providers. The organization's goal is to help people connect with resources that can help them become more aware of prostate cancer, better informed about treatment options, and lead men to seek early screening for prostate cancer.

Prostate cancer is the second leading cause of deaths in African American men. It was estimated that 3,690 deaths from prostate cancer would occur in African American men in 2009. African American men have the highest mortality rate for prostate cancer of any racial or ethnic group in the U.S. An estimated 27,130 cases of prostate cancer were expected to occur among African American men in 2009, accounting for 34 percent of all cancers diagnosed in African American men. Between 2001–2005, the average annual prostate cancer incidence rate was 59 percent higher in African American men than in white men.

Numerous studies have shown that education and support have an impact on the decision of individuals to be screened for prostate cancer, resulting in early detection and diagnosis.

The Central Ohio Men Against Prostate Cancer organization was founded in 2004 by a group of African American gentlemen who were golfing buddies. Since its inception, the group has raised awareness of prostate cancer among all men living in Central Ohio through education, outreach and fundraising. An annual golf tournament has donated funds to the Columbus Cancer Clinic to help cover costs of digital rectal examinations and prostate specific antigen tests for underserved men. The advocacy efforts of the group have extended to participation in national initiatives for prostate cancer, including memberships in the US Too National Prostate Cancer Education and Support Team, memberships in the National Association of Prostate Cancer Advocates, and service as an ad- hoc member of the U. S. Army Research and Materials Command Prostate Cancer Research Program.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-63. doi:10.1158/1538-7445.AM2011-LB-63
Abstract LB-78: A New Paradigm: the Inflammatory Breast Cancer Research Foundation BioBank
Authors: McWilliams Carol
Published: July 2012

The Inflammatory Breast Cancer Research Foundation is a non-profit 501(c) (3) incorporated in 1994, whose mission is to assist scientists and researchers in indentifying the definitive causes of inflammatory breast cancer, and in finding more effective treatments for this highly aggressive form of breast cancer. The organization aims to support research in order to reach an unambiguous definition of inflammatory breast cancer (IBC) and assure that all cases of IBC will be correctly diagnosed, possible sub-types more easily identified, and better treatment outcomes as a result. Research has been hampered by the lack of an easily accessible, well-documented IBC cohort, and IBC cell lines are limited. However, the Inflammatory Breast Cancer Research Foundation has established a BioBank and Clinical Database. The BioBank contains non-tumor DNA, blocks and slides from diagnostic pathology, and medical records describing clinical and pathologic findings at diagnosis providing an invaluable resource. A unique characteristic of this BioBank is the inclusion of specimens and records from deceased patients who had rapid disease progression and resistance to treatment. This data provides valuable comparison for future study.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-78. doi:10.1158/1538-7445.AM2011-LB-78
Abstract LB-80: Building Bridges for Pancreatic Cancer Research
Authors: Peckenpaugh Jason
Published: July 2012

Almost 40 years after President Nixon signed into law the National Cancer Act, the survival rate for pancreatic cancer has not substantially improved. Today, 75 percent of patients diagnosed with pancreatic cancer die within one year of diagnosis, and 94 percent of pancreatic cancer patients will die within five years of diagnosis.

Although pancreatic cancer is the fourth leading cause of cancer death in the U.S., causing 36,800 deaths in 2010, only two percent of the National Cancer Institute's budget is spent on researching the disease ($89.4 million in 2009). Early detection tools for pancreatic cancer do not exist, and thus, patients are typically diagnosed after the disease has metastasized and surgery is no longer a possibility.

Jason Peckenpaugh became an independent advocate for pancreatic cancer patients and research after seeing his father, Jon, bravely battle pancreatic cancer for 18 months until his passing in October 2009. Mr. Peckenpaugh's fight illustrates the statistics above, including his seven month quest to simply discover his diagnosis.

The focus of his advocacy work is communicating scientific information with caregivers, patients, and the public, while sharing the perspective of patients and caregivers with oncologists and researchers. He is participating in the AACR Scientist<–>Survivor Program to improve my knowledge of cancer science and research so that he may become a patient advocate on GI cancer grant committees and/or research control boards. Despite the poor prognosis for patients with pancreatic cancer, this is a promising time for pancreatic cancer research, in part due to grants from the Stand Up 2 Cancer organization, advances in molecular profiling of tumors, and recent research showing the progression of pancreatic cancer. Pancreatic cancer needs a patient advocate at the table wherever gastrointestinal cancers and other cancers are being discussed. Patient advocates serve on grant review boards of the Food and Drug Administration, the Gastrointestinal Specialized Program of Research Excellence (GI SPORE), and other government research consortia.

Mr. Peckenpaugh is a volunteer with the Pancreatic Cancer Action Network (PanCAN) and a volunteer fundraiser for the Lustgarten Foundation and Johns Hopkins University's pancreatic cancer research program. He has raised more than $14,000 for pancreatic cancer research since 2008.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-80. doi:10.1158/1538-7445.AM2011-LB-80
Abstract LB-82: Basal Cell Carcinoma Nevus Syndrome: Networking for Good
Authors: Burr Kristi Schmitt
Published: July 2012

Basal Cell Carcinoma Nevus Syndrome (BCCNS) Life Support Network set out on its journey in 2000 and have since provided support to over 1200 families, stimulated new drug development, and connected with diverse medical specialties – including dermatology, plastic surgery, genetics, cardiology, radiology, oral surgery and dentistry – to increase medical professionals' awareness of the needs of the BCCNS patient community.

The organization's success means a better future for everyone vulnerable to this potentially disabling and life-threatening disease. While BCCNS affects a small portion of the American public (1 in 19,000 or about 16,500 American adults and children annually), the disease comes with significant cost and burdens. As there is no cure and few effective treatments, people suffering with this disease face a lifetime challenge in managing the disease. The numerous skin cancers and jaw cysts_the most common symptoms of the disease_generally require numerous surgeries throughout one's life. In addition, patients' experiences are afflicted by brain tumors, cognitive delays, physical disabilities including auditory, vision and speech impairments. Early diagnosis is important in order for children with BCCNS to survive life-threatening brain tumors and to overcome potential future disability. The financial burden for all patients is significant.

A major hurdle in coping with BCCNS is finding a doctor knowledgeable about the disorder. Securing a prompt diagnosis and appropriate treatment is complicated by the fact that the disease affects so many different parts of the body, thereby crossing over diverse medical specialties. Working with inadequate knowledge, caregivers may use inappropriate therapies which can cause deformities and increased morbidity and mortality. Common treatments, such as radiation and x-rays, can result in the formation of thousands of basal cell carcinomas (BCCs or skin cancers), which are particularly perilous for undiagnosed children exhibiting brain tumors.

To minimize the occurrence of death, widespread networking and education is essential. This is the cornerstone of the organization as it is only through communicating directly with individuals that advocates are made aware of new practices and current concerns. BCCNS is able to connect members with medical professionals in their region, or offer advice on preventative screenings, and serve as a knowledgeable resource. As the only national organization in the United States serving BCCNS patients, the organization has extensive experience in providing educational support to patients and doctors, national credibility and recognition among patients and stakeholders, and well-established communication links with many medical specialties.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-82. doi:10.1158/1538-7445.AM2011-LB-82
Abstract LB-85: Advocacy in Indian Country
Authors: Whitewolf Celeste
Published: July 2012

Native People's Circle of Hope (NPCOH) aims to help cancer survivors, their family members and caregivers understand they are not alone. Advocating for quality health care for native people is NPCOH's primary goal. NPCOH projects include the Medicine Bag Project, which gifts newly diagnosed cancer survivors items they may need during treatment; the Native Hope Project, which promotes wearing yellow (the color of hope) in traditional regalia to show solidarity with cancer survivors; the Roots of Strength Annual Conference; the Speaker's Bureau; and the educational training session titled, “How to Start Your Own Cancer Support Group.” Local chapters are the basis of community support and advocacy. NPCOH's AACR poster features the activities of the local chapters and provides examples of their personalized projects.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-85. doi:10.1158/1538-7445.AM2011-LB-85
Abstract LB-9: Intersection of Notch and ERBB signalling in melanoma
Authors: Bedogni Barbara
Published: July 2012

Malignant melanoma is an aggressive malignancy of the melanocytes. The incidence rates for melanoma are steadily increasing and melanoma has now become the most common form of cancer among young adults between the ages of 25 and 29 years old. Because melanomas are highly resistant to the majority of therapies, the survival rate for patients with metastatic disease is less than 15%. There is a clear need for novel more effective therapies.

Identification of the signaling pathways that are altered in melanoma provides opportunities for the development of novel targeted therapies. The Notch pathway is an evolutionary conserved signaling cascade that has an essential role in embryonic development but is inappropriately active in various types of cancers. Studies from our group and others have shown that hyper activation of Notch1 is an early event in melanocyte transformation and modulates both growth and metastasis in melanoma.

We have found a new interaction between Notch1 and neuregulin1 (NRG1) signaling that plays a role in melanoma. Neuregulin1 is the ligand for ERBB3, a member of the Epidermal Growth Factor family of receptors that are involved in the genesis and progression of a number of cancers. Notch1 binds to the NRG1 promoter thereby modulating NRG1 expression and consequently the activation of the ERBB3 pathway. Inhibition of either NRG1 or ERBB3 activity in melanoma cells lead to cell growth inhibition and tumor growth delay similar to Notch1 inhibition. Mechanistically, these effects are dependent on the accumulation of p27 following either NRG1 or Notch1 down regulation. In addition, we find that NRG1/ERBB3 signaling influences Notch1 activation likely through the modulation of the Notch ligands Jaggged-1 (JAG-1) and Delta like 3 (Dll3), thus providing a feed forward regulatory loop linking the two pathways.

Taken together, our findings underline a new, previously undescribed interaction between Notch1 and NRG1/ERBB3 in melanoma. Our goal is to investigate the mechanisms by which these two oncogenic signaling pathways intersect to promote a highly aggressive disease phenotype and to provide experimental evidence that the targeting of Notch and ERBB signaling is a tractable and effective approach to treat forms of melanoma that may be resistant to current available therapies.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-9. doi:10.1158/1538-7445.AM2011-LB-9
Abstract LB-99: Bif-1 promotes EGFR endocytic degradation and contributes to suppression of metastatic potential in breast and colon cancers
Authors: Runkle Kristin B. , Takahashi Yoshinori , Wang Hong-Gang
Published: July 2012

Bif-1, a member of the endophilin B protein family, is involved in apoptosis and autophagy induction and in regulating membrane dynamics of organelles such as the Golgi and mitochondria. While endophilin A family members are involved in the formation and fission of endocytic vesicles at the plasma membrane, recent data suggest a role for Bif-1 in promoting epidermal growth factor receptor (EGFR) endocytic degradation. Increased EGFR expression is seen in a variety of tumors including breast and colorectal cancers and has been correlated with disease progression, poor survival, poor response to therapy, and resistance to cytotoxic agents. Activation of EGFR promotes cell growth, differentiation, survival, and migration through MAPK, PI3K, STAT, and Src signaling pathways; whereas signal termination and receptor down-regulation occur primarily through clathrin-mediated endocytosis and lysosomal degradation. However, the mechanism through which Bif-1 regulates EGFR endocytic trafficking and degradation has not been thoroughly investigated. Here we report that suppression of Bif-1 expression in breast and colon cancer cells delays EGFR degradation. While Bif-1 depletion does not disrupt EGFR internalization or trafficking to the vicinity of LAMP-1 positive late endosomes/lysosomes, endosome maturation and endosome/lysosome fusion seem to be suppressed in cells lacking Bif-1. Moreover, knockdown of Bif-1 enhances breast cancer cell migration and invasion. These findings, together with previous data showing that loss of Bif-1 promotes tumorigenesis in mice and that decreased expression of Bif-1 is seen in many types of human cancers including breast and colorectal cancers, further suggest that Bif-1 functions as a tumor suppressor. In addition to its roles in apoptosis and autophagy induction, this study supports a new role for Bif-1 in regulating the late stages of EGFR lysosomal degradation and identifies Bif-1 as a suppressor of metastatic potential in breast cancer.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-99. doi:10.1158/1538-7445.AM2011-LB-99
Abstract PL02-01: A systems biology approach to integrative cancer genomics
Authors: Califano Andrea
Published: July 2012

The recent onslaught of molecular data across multiple human malignancies is producing an unprecedented repertoire of genetic and epigenetic alterations contributing to tumorigenesis and progression. Yet, the direct impact of this knowledge on tumor treatment and prevention is still largely unproven. Loss of tumor suppressor function is difficult to target pharmacologically and, with a handful of exceptions, alterations providing potential drug targets are relatively infrequent in cancer patients and are thus unlikely to support clinical development.

By reconstructing and interrogating the regulatory logic of the cancer cell, which is responsible for integrating multiple aberrant signals in vivo, systems biology is starting to elucidate broad addiction mechanisms, both oncogene and non-oncogene based that are exquisitely specific to the cancer subtype. In this presentation, we will discuss recent result in the discovery of synergistic, non-oncogene addiction mechanisms in high-grade glioma, of the upstream genetic alterations causally related to their functional activation, and of candidate targets for combination therapy. This approach has been generalized to a number of additional tumor subtypes and provides a novel framework for cancer target discovery and development in patient-centric fashion.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr PL02-01. doi:10.1158/1538-7445.AM2011-PL02-01
Abstract PL03-03: The clinical significance of intratumor diversity in breast cancer
Authors: Polyak Kornelia
Published: July 2012

Intratumor diversity for hereditary traits is the driver of tumor evolution, including disease progression and therapeutic resistance. To investigate the role of intratumor genetic and phenotypic heterogeneity in breast tumor progression and in therapeutic responses, we performed immunoFISH (iFISH) analyses of distant metastases from the same patient and breast tumor biopsies before and after treatment. iFISH allows for the combined analysis of phenotypic markers (e.g., such as CD24 and CD44) and chromosomal copy number gains at the single-cell level. In each tumor we evaluated four distinct tumor cell populations (CD44+/CD24-, CD44-/CD24+, CD44+/CD24+, and CD44-/CD24- cells) for chromosomal gain at 8q24 and other commonly gained chromosomal regions. iFISH data was evaluated using ecological and evolutionary models. We found high degree of genetic heterogeneity within and between the four different cell subpopulations in some tumors, in some patients the distant metastases were highly divergent, and the degree of intratumor diversity was altered by treatment and was associated with clinical characteristics. Our findings demonstrate the power of analyzing tumors as ecosystems and indicate that numerical measures of intratumor diversity can be used as clinically useful biomarkers predicting the risk of progression and therapeutic resistance.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr PL03-03. doi:10.1158/1538-7445.AM2011-PL03-03
Abstract SY01-01: Harnessing genetic dependencies in cancer therapy
Authors: Ashworth Alan
Published: July 2012

Many tumors harbor defects in their ability to maintain genomic integrity. This contributes to the mutational burden and likely fosters pathogenesis. We have been exploring therapeutic strategies to exploit these defects. We have used a synthetic lethal approach to target the defect in DNA repair by homologous recombination in tumors with a BRCA1 or BRCA2 mutation. This strategy using PARP inhibitors is showing considerable promise in the clinic. Here, I will describe the approach as well recent work defining determinants of sensitivity and resistance to PARP inhibitors. The application of the synthetic lethal approach to other cancer types will also be discussed. In addition, we have been using high- and medium-throughput RNAi screens to uncover new therapeutic targets for cancer as well as biomarkers of patients who might respond to specific treatments. In particular I will discuss the integration of genomic, gene expression, and RNAi data to generate functional maps of cancer cell lines.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr SY01-01. doi:10.1158/1538-7445.AM2011-SY01-01
Abstract SY02-01: Pericellular proteolysis and the regulation of the 3-D cancer invasion program
Authors: Weiss Stephen J.
Published: July 2012

To initiate prometastatic programs, carcinoma cells must transmigrate multiple extracellular matrix barriers, including the subtending basement membrane and the underlying interstitial matrix before gaining access to vascular and/or lymphatic beds. Subsequently, the cells extravasate and embed themselves in distant tissues where they must reactivate proliferation programs (Ann Rev Cell Dev Biol 25:567, 2009). Current evidence suggests that proinvasive carcinoma cells engage a reversible epithelial-mesenchymal cell-like transition (EMT) that falls under the regulation of a growing number of transcription factors, including Snail1 or Snail2. In response to multiple stimuli, ranging from growth factors and hypoxia to inflammatory cytokines and loss-of-function p53 mutations, EMT-inducing transcription factors promote the mobilization of a complex mix of proteinases that propagate the proteolytic remodeling of the extracellular matrix in a fashion that supports tissue-invasive activity (PNAS 106:20318, 2009; J Cell Biol 185:11, 2009; Genes & Dev 20:2673, 2006). While the identity of proteases mobilized by invading cells to traverse matrix barriers remains controversial, increasing evidence supports a critical role for a subclass of membrane-anchored matrix metalloproteinases, termed the membrane-type MMPs (MT-MMPs). In an exocyst-regulated fashion, MT-MMP family members decorate the leading edge of migrating cancer and stromal cells alike in order to drive invasion through extracellular matrix barriers. Importantly, MT-MMP function is not restricted to invasion alone as membrane-anchored proteases play additional roles in regulating cell proliferation, survival and differentiation (Cell 114:33, 2003; Cell 125:577, 2006; Genes & Dev 22:1231, 2008; Blood 115:221, 2010). While the range of cellular activities that fall under the MT-MMP umbrella is, in some ways, perplexing, new evidence suggests that MT-MMP-dependent pericellular proteolysis indirectly controls nuclear architecture and function in a 3-D extracellular matrix-specific fashion. Understanding the interplay between EMT-inducing transcription factors, the activation of tissue-remodeling cell programs, and the impact of pericellular proteolysis on gene regulation and function should provide new insights into the control of neoplastic cell trafficking and metastatic activities.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr SY02-01. doi:10.1158/1538-7445.AM2011-SY02-01
Abstract SY05-01: Biological and clinical activities of FDA-approved drugs that antagonize Hh signaling
Authors: Kim James , Tang Jean Y.
Published: July 2012

The inappropriate activity of the Hedeghog (Hh) signaling pathway noted in a variety of tumor types has prompted efforts to develop small molecule antagonists of Hh pathway signaling. The use of FDA-approved drugs as Hh pathway antagonists may avoid some of the expense and delay associated with de novo development of Hh pathway antagonists. We have identified two FDA-approved drugs, itraconazole and arsenic trioxide, as potent inhibitors of the Hh pathway in vitro and in vivo at the level of Smoothened (Smo) and Gli, respectively. In addition, both itraconazole and arsenic trioxide have inhibitory activity against a mutant Smoothened resistant to GDC-0449, a potent Smo antagonist. These preclinical studies have led to a pilot clinical trial (ID: NCT01108094) using itraconazole for patients with basal cell carcinoma, a skin tumor that is driven by the Hh pathway. We have treated 13 subjects with 200mg of itraconazole twice daily and found -32% (95% CI: -19 to -42%) reduction in tumor diameter in 1 month. These studies suggest that FDA-approved drugs show promise as Hh pathway antagonists for the treatment of Hh-dependent cancers and warrant further study.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr SY05-01. doi:10.1158/1538-7445.AM2011-SY05-01
Abstract SY05-02: Hedgehog/wnt feedback supports regenerative proliferation of epithelial stem cells in bladder
Authors: Beachy Philip A.
Published: July 2012

Epithelial integrity in metazoan organs is maintained through the regulated proliferation and differentiation of organ-specific stem and progenitor cells. Although the epithelia of organs such as the intestine regenerate constantly and thus remain continuously proliferative, other organs, such as the mammalian urinary bladder, shift from near-quiescence to a highly proliferative state in response to epithelial injury caused by bacterial infection or chemical agents. The cellular and molecular mechanisms underlying this injury-induced mode of regenerative response are poorly defined. Here we show that proliferation within the bladder is regulated by signal feedback between basal cells of the urothelium and the stromal cells that underlie them. We demonstrate that these basal cells include stem cells capable of regenerating all cell types within the urothelium, and are marked by expression of the secreted protein signal, Sonic hedgehog (Shh). Upon injury, Shh expression in these basal cells increases and elicits increased stromal expression of Wnt protein signals, which in turn stimulate the proliferation of both urothelial and stromal cells. The heightened activity of this signal feedback circuit and the associated increase in cell proliferation appear to be required for restoration of urothelial function and, in the case of bacterial injury, may help clear and prevent further spread of infection. Our findings provide a model for injury-induced epithelial regeneration in endodermal organs, and may provide a basis for understanding the roles of signaling pathways in cancer growth and metastasis.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr SY05-02. doi:10.1158/1538-7445.AM2011-SY05-02
Abstract SY07-02: Polarity proteins in morphogenesis and metastasis
Authors: McCaffrey Luke Martin , Montalbano JoAnne , Macara Ian G.
Published: July 2012

Loss of epithelial organization is a hallmark of carcinomas, but whether polarity regulates tumor growth and metastasis is poorly understood. A conserved set of polarity proteins, called PAR proteins, drives cell polarization in many contexts, and in Drosophila these proteins can function as tumor suppressors. However, to date, only Par4 (LKB1) has been implicated in human cancers. To determine whether other polarity proteins might have tumor suppressor functions in mammals, we have used lentiviruses to deliver oncogenes and shRNAs to primary murine mammary cells, which are then implanted into the cleared fat pads of isogenic host mice. Using this system, we silenced expression of the PAR3 polarity protein in the context of oncogenic Notch (NICD) or Ras. Depletion of Par3 dramatically reduced tumor latency in both models, producing tumors that were highly invasive and metastatic. Notably, the NICD/shPAR3 tumors retained epithelial character, with no evidence of epithelial-mesenchymal transition in either the primary tumors or the lung metastases. We have identified an unexpected signaling pathway that drives invasion in these tumors. Importantly, PAR3 protein expression is significantly reduced in ∼50% of human breast cancers, as compared to matched normal tissue. Together, these data provide a link between cell polarity, tissue organization, and metastasis.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr SY07-02. doi:10.1158/1538-7445.AM2011-SY07-02