bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 3231: Identification of CD245 as myosin 18A, a receptor for surfactant A: A novel pathway for activating human NK lymphocytes effector function
Authors: Giustiniani Jérôme , de Masson Adèle , Marie-Cardine Anne , Bouaziz Jean-David , Garbar Christian , Bagot Martine , Merrouche Yacine , Bensussan Armand
Published: July 2016

Natural Killer (NK) cells were identified over 40 years ago as a subset of lymphocytes able to spontaneously kill tumor cells in the absence of pre-stimulation. Present in most mammalian and avian species, NK cells play a critical role in the anti-tumor and anti-infectious immunity and in reproduction. NK cell cytotoxicity is tightly controlled by a balance between signals delivered through the engagement of activating and inhibitory receptors. Beside these receptors, costimulatory molecules co-exist at the surface of activated NK cells to potentiate NK cells functions. 4-1BB (CD137) is a costimulatory receptor expressed on T, B and NK cells whose expression is triggered by engagement of the Fc receptors on the NK cell surface, as during antibody-dependent cell cytotoxicity (ADCC). Consequently the engagement of CD137 increases cetuximab-, rituximab-, and trastuzumab-dependent NK cell cytotoxic function in different cancer models. We previously described CD245 as an unidentified structure on the surface of human peripheral blood lymphocytes that was recognized by the monoclonal antibodies DY12 and DY35. We also reported that CD245 on NK lymphocytes was associated with tyrosine phosphatase activities. We found that CD245 is the unconventional myosin 18A, which is a receptor for the surfactant protein A (SP-A). We characterized the molecular and functional properties of CD245 and identified a novel co-activation pathway that potentiates the NK cell cytotoxicity. Stimulation by specific antibodies or its physiological ligand SP-A is able to increase NK cell degranulation and lymphokine-activated killer activity towards tumor B cells and EBV-infected B cells, respectively. We also found that myosin 18A stimulation is able to induce CD137 expression at the NK cell surface and that the myosin 18A-induced NK cell cytotoxicity toward CD137L-expressing tumor cells is dependent on the CD137/CD137L interaction. Thus, CD245 could represent a novel and promising target in cancer immunotherapy.

Citation Format: Jérôme Giustiniani, Adèle de Masson, Anne Marie-Cardine, Jean-David Bouaziz, Christian Garbar, Martine Bagot, Yacine Merrouche, Armand Bensussan. Identification of CD245 as myosin 18A, a receptor for surfactant A: A novel pathway for activating human NK lymphocytes effector function. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3231.
Abstract 327: Anti-tumor effect and destabilization of R175H-mutant p53 by CB002, a p53-pathway restoring small molecule that stimulates autophagy
Authors: Hernandez Borrero Liz J. , Zhang Shengliang , Dicker David , El-Deiry Wafik
Published: July 2016

Tumor suppressor p53 is a master regulator of genotoxic and cellular stress signals, controlling cell fate by transcriptionally activating genes involved in DNA repair, cell cycle arrest, and apoptosis. p53 is mutated in over half of human cancers and this is associated with tumor development and chemotherapy resistance. TP53 gene mutations can result in the abolishment of p53 contact with DNA and disruption of p53 structural conformation. These mutations not only prevent p53 to exert its normal tumor suppressive functions but can result in gain-of-function activity, acquiring oncogenic characteristics. Therefore, altering the stability of mutant p53 protein is an attractive therapeutic strategy in cancer cells. We investigated small molecules that modulate mutant p53 stability and restore the p53-signaling pathway. We identified a small molecule, CB002, as a candidate for restoration of the p53 pathway in mutant p53-bearing cancer cells. Three colorectal cancer cell lines: SW480, DLD-1, HCT116-R175H and the RXF393 renal cancer cell line, were treated with different concentrations of CB002 at various time points. Cell lines exposed to CB002 showed an increase in apoptotic and cell death markers, such as NOXA/DR5 induction, cleaved caspases and PARP, as early as 16 hrs. CB002 decreased mutant p53 stability in structural conformation-mutant bearing cells (HCT116 R175H and RXF393). Our data suggests that CB002 stimulates an increase of p53 target genes and promotes expression of pro-apoptotic proteins. R175H p53 mutant protein expression was largely rescued by the co-treatment with MG132, a proteasomal inhibitor, implicating a role for the ubiquitin proteasome system. Furthermore, we observed significant autophagy induction upon CB002 treatment, as indicated by LC3 conversion and p62 levels. Autophagy inhibition decreased levels of cell death markers and increased the stability of the R175H-mutant p53, suggesting that autophagy might be required for CB002-induced cell death and mutant p53 turnover. Therefore, we hypothesize that CB002 is capable of degrading mutant p53 and restoring the p53 pathway through p53 family members in colorectal cancer cells. Currently we are investigating p53 degradation mechanism by CB002, the role of p53 family members in the restoration of the pathway and autophagy on mutant p53 stability. Hence, our results provide an insight on effective p53 pathway activation through the use of small molecules.

Citation Format: Liz J. Hernandez Borrero, Shengliang Zhang, David Dicker, Wafik El-Deiry. Anti-tumor effect and destabilization of R175H-mutant p53 by CB002, a p53-pathway restoring small molecule that stimulates autophagy. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 327.
Abstract 3294: Treponema denticola, a periodontal pathogen, promotes stemness and migration in oral squamous cell carcinoma
Authors: Kamarajan Pachiyappan , Ateia Islam , Shin Jae M. , Fenno J Christopher , Kapila Yvonne L.
Published: July 2016

Periodontitis is a chronic infectious disease characterized by inflammation and destruction of periodontal tissues including the periodontal ligament fibers and alveolar bone. Recent epidemiological studies have revealed a significant association between periodontitis and oral cancer. While the precise mechanisms that mediate these associations are not well understood, periodontal pathogens, including Treponema denticola (T. denticola), which are believed to initiate the destructive inflammatory responses and dysbiosis or dysregulation of tissue homeostasis that characterize periodontal disease may contribute to oral cancer. However, knowledge about T. denticola's contribution to oral cancer is limited. Previously, we showed that nisin ZP, a bacteriocin and commonly used food preservative, reduced tumorigenesis in vivo and long term treatment with nisin ZP extended survival. In a separate study, we further showed that nisin ZP exhibits antimicrobial and antibiofilm effects, limiting T. denticola viability. The antimicrobial doses of nisin ZP are two orders of magnitude lower than the antitumor doses. The present study investigated the impact of T. denticola on the stemness, migration, and tumorigenesis of oral squamous cell carcinoma (OSCC), and nisin's potential modulatory effects on these processes. To investigate the role of T. denticola on OSCC tumorigenesis, OSCC cells were treated with T. denticola and with or without nisin ZP then assayed for stemness (orasphere) and migration. Treatment with T. denticola enhanced OSCC orasphere formation and migration without affecting cell viability or inducing apoptosis. Addition of nisin ZP inhibited these T. denticola-mediated processes. These data indicate that the periodontal pathogen T. denticola promotes stemness and migration of OSCC cells, and thereby may contribute to oral cancer tumorigenesis.

Citation Format: Pachiyappan Kamarajan, Islam Ateia, Jae M. Shin, J Christopher Fenno, Yvonne L. Kapila. Treponema denticola, a periodontal pathogen, promotes stemness and migration in oral squamous cell carcinoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3294.
Abstract 3296: Breast mammographic density and the fecal microbiota
Authors: Jones Gieira S. , Feigelson Heather S. , Ravel Jacques , Goedert James J.
Published: July 2016

The microbial population (microbiota) of the distal human gut has multiple functions that modulate cancer risk including digestion of nutrients, deconjugation and enterohepatic circulation of hormones and other bile acids, and regulation of immunity and inflammation. We have previously reported that postmenopausal breast cancer cases, compared to controls, have lower fecal microbiota alpha diversity, independent of age, body mass index, and estrogen levels, and that the cases’ microbiota is compositionally altered. For deeper understanding of these associations with breast cancer, we compared microbiota metrics to a strong cancer risk factor, breast density, among 48 cancer-free, postmenopausal controls in the Breast and Colon Health study (86% non-Hispanic White, mean age 62 years). In routine screening mammograms, they had the following Breast Imaging Reporting and Data System (BI-RADS, 5th ed.) composition: a) almost entirely fatty (N = 4); b) scattered areas of fibroglandular density (N = 14); c) heterogeneously dense (N = 26); and d) extremely dense (N = 4).

As shown in the Table, simple linear regression across these four ordered BI-RADS categories revealed that there was no significant association with fecal microbiota alpha diversity (PD_tree β -0.08, P = 0.56). Breast density in these women also was not associated with microbiota beta diversity (composition) by MiRKAT analysis of un-weighted and weighted UniFrac metrics (P = 0.25 and 0.08, respectively).

We conclude that breast density is unlikely to mediate the association of the gut microbiota with breast cancer in postmenopausal women. Fecal alpha diversity by mammographic density categoryBI-RADS DensityNo.Mean (SD) PD_Whole_TreeAlmost Entirely Fatty436.06 (4.22)Scattered Fibroglandular1438.18 (8.25)Heterogeneously Dense2637.19 (4.88)Extremely Dense438.33 (7.99)

Citation Format: Gieira S. Jones, Heather S. Feigelson, Jacques Ravel, James J. Goedert. Breast mammographic density and the fecal microbiota. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3296.
Abstract 3356: Characterization and enrichment of head and neck cancer stem cells suggests differences between HPV+ and HPV- subtypes of HNSCC cells
Authors: Chatterjee Anirban , Nickel Kwangok , Kimple Randall J.
Published: July 2016

Head and neck squamous cell carcinomas (HNSCC) are the sixth most prevalent type of malignancy worldwide. Despite recent advances in multidisciplinary treatments, the overall survival and quality of life of patients with advanced HNSCC have not improved considerably over the past decade. Recent reports have demonstrated that tumors contain a small subpopulation of cells called cancer stem-like cells (CSCs), which are responsible for tumor maintenance and metastasis. CSCs have the ability to self-renew and are responsible for tumorigenesis, progression, metastasis, and relapse after treatment. Recent studies demonstrate that even established HNSCC cell lines contain a definite sub-population of CSC providing us with the opportunity to discerning their roles in progression, treatment, and relapse of the disease.

In vitro Sphere Forming Assays (using ultra-low attachment plate and serum free media) were employed as the key method of CSC enrichment. qPCR analyses, aldehyde dehydrogenase (ALDH) activity, Side Population Phenotype assay (SPP) were used to confirm the results of the primary analyses. To confirm an in vivo CSC phenotype, xenograft tumor formation, through subcutaneous injection in immunocompromised mice was done.

In vitro sphere forming assay followed by subsequent passaging of the sphere enriched cells (SECs) have successfully demonstrated the existence and enrichment of a CSC sub-population in HNSCC cell lines. Findings suggest a differential existence of CSCs related to the HPV status of the cell. ALDH assay and SPP assay confirmed the results of sphere formation. qPCR analyses of the SECs have confirmed enrichment in several stemness marker genes (Oct-4, Sox2, Nanog, Bmi-1, cMyc, KLF4, Beta catenin etc.), also following the identical differential pattern. Various EMT markers genes (Vimentin, Fibronectin, E-cadherin, N-cadherin, Snail, Slug, Twist, ZO-1 etc.) were also assessed, portraying a significant level of expression in CSC populations. SECs subcutaneously injected in immunocompromised mice formed tumors with as few as 50 cells.

We have demonstrated that a definite subpopulation of CSCs exists in HNSCC cell lines. Significant differences were seen between the HPV+ and HPV- subtypes. Analyses of EMT marker genes and other molecular pathways in CSC confirm the differences between HPV+ and HPV- cells too following the similar pattern. In vivo tumor xenograft formation establishes the heightened tumorigenicity of CSCs/SECs.

Citation Format: Anirban Chatterjee, Kwangok Nickel, Randall J. Kimple. Characterization and enrichment of head and neck cancer stem cells suggests differences between HPV+ and HPV- subtypes of HNSCC cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3356.
Abstract 3389: Androgen deprivation therapy potentiates the efficacy of vascular targeted photodynamic therapy of prostate cancer xenografts
Authors: Kim Kwanghee , Watson Philip A. , Jebiwott Sylvia , Somma Alexander J. , La Rosa Stephen P. , Mehta Dipti , Murray Katie S. , Lilja Hans , Ulmert David , Scherz Avigdor , Coleman Jonathan
Published: July 2016

Focal therapies for prostate cancer offer the possibility of less side effects than more aggressive interventions for organ-confined tumors. Vascular targeted photodynamic therapy (VTP) is being investigated in phase II and phase III clinical trials, and relies upon rapid, free radical-mediated destruction of tumor vasculature following photoactivation of a systemic prodrug. In a phase II trial, >80% of patients did not have detectable cancer in prostate biopsies taken 6 months after VTP treatment. Although these early results are encouraging, VTP efficacy could potentially be improved upon by combining with other therapies. Using the LNCaP-AR prostate cancer model system, we employed microarrays and Gene Set Enrichment Analysis (GSEA) to identify potential druggable pathways active in tumors exposed to VTP. Three to six hours post-VTP, androgen responsive gene sets were enriched, suggesting that the androgen receptor (AR) may be a viable target in combination with VTP. We tested this hypothesis in mice bearing LNCaP-AR xenograft tumors by using the AR pathway inhibitors degarelix (to achieve pharmacological castration) or enzalutamide (AR antagonist), alone or in combination with VTP. Degarelix was administered as a single 0.5-1 mg dose 3 days prior to initiation of VTP, while enzalutamide was given daily for two weeks total both before and after VTP. Serum measurements of prostate specific antigen (PSA) were used as a readout of AR activity. Compared to either AR pathway inhibitor or VTP used alone, degarelix or enzalutamide in combination with VTP significantly inhibited tumor growth. A sharp decline in serum PSA confirmed AR inhibition. Combined degarelix plus VTP treated tumors displayed intense TUNEL staining 7 days post-treatment, supporting an increased apoptotic frequency underlying the effect on tumor inhibition. In prostate cancer treated with VTP, compensatory acute upregulation of pro-survival AR signaling may occur. These findings may warrant investigation of combination with androgen deprivation therapy in future clinical trials utilizing VTP for prostate cancer.

Citation Format: Kwanghee Kim, Philip A. Watson, Sylvia Jebiwott, Alexander J. Somma, Stephen P. La Rosa, Dipti Mehta, Katie S. Murray, Hans Lilja, David Ulmert, Avigdor Scherz, Jonathan Coleman. Androgen deprivation therapy potentiates the efficacy of vascular targeted photodynamic therapy of prostate cancer xenografts. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3389.
Abstract 3401: Impact of VEGF and VEGFR polymorphisms on neuroendocrine tumors of the gastro-entero-pancreatic system (GEPNETs) outcome
Authors: Berardi Rossana , Torniai Mariangela , Pagliaretta Silvia , Rinaldi Silvia , Morgese Francesca , Partelli Stefano , Caramanti Miriam , Onofri Azzurra , Polenta Vanessa , Pasquini Sonia , Falconi Massimo , Cascinu Stefano
Published: July 2016

Introduction: Gastro-entero-pancreatic neuroendocrine tumors (GEP-NETs) are uncommon neoplasms including a wide range of anatomical, clinical, histological and molecular malignant entities. Improving our understanding of the molecular biology of GEP-NETs represents a key challenge in the treatment of these rare tumors. Therefore we aimed to analyze genotypes of VEGF-A, VEGFR2 and Flt4 in GEP-NETs and their potential correlation with the risk of these tumors and/or with the outcome.

Methods: The genomic DNA of 28 consecutive patients with GEP-NETs treated at our Institution was extracted from paraffinembedded tissue. We selected polymorphisms in the following genes: VEGF-A (rs2010963G>C, rs699947A>C), VEGFR-2 (rs2305948C>T, rs1870377T>A) and VEGFR-3 (rs307826T>C, rs307821C>A). Gene polymorphisms were determined by Real-Time PCR using TaqMan assays.

Results: Median age was 58 (range 33-78) and M/F ratio was 1/1. Twenty-one out of the 28 patients had NETs of the pancreas. The allele frequency of VEGFR2 rs2305948C and of VEGFA rs2010963G showed a trend of lower frequency than in general population (82% vs. 92% and 60.3% vs. 68.8%, respectively, p<0.001). The following factors significantly correlated with a poorer overall survival (p<0.05): VEGFA rs699947C, VEGFA rs2010963A, VEGFR-2 rs1870377T/A, VEGFR-2 rs2305948C/T, VEGFR-3 rs307821C and VEGFR-3 rs307826T.

Conclusion: Our results suggest, for the first time, that inherited abnormalities in VEGF pathway influence the risk and aggressiveness of GEP-NETs. Within March 2016 final data about all the enrolled 64 patients will be also available. These results should be validated prospectively in order to optimize the diagnosis and treatment of these patients.

Citation Format: Rossana Berardi, Mariangela Torniai, Silvia Pagliaretta, Silvia Rinaldi, Francesca Morgese, Stefano Partelli, Miriam Caramanti, Azzurra Onofri, Vanessa Polenta, Sonia Pasquini, Massimo Falconi, Stefano Cascinu. Impact of VEGF and VEGFR polymorphisms on neuroendocrine tumors of the gastro-entero-pancreatic system (GEPNETs) outcome. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3401.
Abstract 3410: Downregulation of let 7a 5p predicts lymph node metastasis and prognosis in colorectal cancer: implications for chemotherapy
Authors: Cheng Ya-Wen , Liu Tsang-Pai , Wei Po-Li , Lee Huei
Published: July 2016

Background. Colorectal cancer guidelines recommend adjuvant chemotherapy is based on the number of lymph nodes metastasis. Let-7a-5p is a microRNA which could inhibits migration, invasion and epithelial-mesenchymal transition by targeting HMGA2. The aim of this study was to investigate the role of let-7a-5p in clinical impact of colorectal cancer (CRC).

Methods. One hundred ninety-two CRC patients were enrolled. The expression of let-7a-5p and HMGA2 in serums and tumor tissues were analyzed by real-time PCR and immunohistochemistry. Univariate (Kaplan-Meier) analysis was used to analyze primary outcomes included 5-year overall survival and tumor recurrence.

Results. The expression of let-7a-5p in tumor tissues was significantly negative correlated with tumor size, stage, and lymph node metastasis in CRC patients (p = 0.024 for tumor size, p = <0.0001 for stage, and p<0.0001 for lymph node metastasis). There was a negative correlation between levels of let-7a-5p and the HMGA2 gene (p <0.0001), especially in CRC patients with wildtype APC gene. Patients with let-7a-5p low / HMGA2 high had poorer overall survival (OS) and disease-free survival (DFS) rates than those with let-7a-5p high / HMGA2 high, let-7a-5p high / HMGA2 low, and let-7a-5p low /HMGA2 low groups. In addition, the expression levels of let-7a-5p in PBMCs were positive correlated with in tumor tissues of CRC patients.

Conclusion. We suggest that down-regulation of let-7a-5p in PBMCs and tumor tissues patients could be used to predicts lymph node metastasis and prognosis impact on chemotherapy of colorectal cancer

Citation Format: Ya-Wen Cheng, Tsang-Pai Liu, Po-Li Wei, Huei Lee. Downregulation of let 7a 5p predicts lymph node metastasis and prognosis in colorectal cancer: implications for chemotherapy. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3410.
Abstract 342: BGB-283, a slow-off inhibitor of RAF dimers, differentiates from vemurafenib in MAPK signaling inhibition
Authors: Liu Ye , Yuan Xi , Tang Zhiyu , Wang Lai , Luo Lusong , Wei Min
Published: July 2016

Dysregulations of the mitogen-activated protein kinase (MAPK) signaling through abnormal expression or activating mutations of key signaling molecules, including RAS and RAF, have been identified in a wide range of cancers. Targeting these signaling molecules in the pathway represents a promising strategy to target dysregulated MAPK signaling. BGB-283 is a novel pan-RAF inhibitor and currently under clinical development to treat BRAF and KRAS/NRAS mutated tumors. In this study, we show that BGB-283 inhibits WT B-RAF dimer much more potently than vemurafenib at millimolar ATP concentration that is representative of the cellular ATP level, although BGB-283 and vemurafenib display similar inhibitory activity at the Km ATP concentration. BGB-283 has very slow off-rate and the dissociation half-life (t1/2) on WT B-RAF enzyme is well above 24 hrs. In comparison, vemurafenib has much faster off rates with t1/2 in the range of minutes. The crystal structure of BGB-283/B-RAF protein complex shows the benzimidazole and trifluoro group of BGB-283 binds significantly deeper into pocket formed by α-C helix and activation loop than vemurafenib. BGB-283 exhibits time-dependent inhibition both in biochemical assay and in B-RAF or K-RAS mutated cells. BGB-283 potently inhibits the p-ERK signaling in splicing isoform p61B-RAF(V600E) cells which were reported to be resistant to vemurafenib through a dimer mechanism. In vivo, BGB-283 significantly suppressed the tumor growth in A375-p61B-RAF(V600E) melanoma xenograft model. In addition, BGB-283 inhibits vemurafenib induced p-ERK activation and selumetinib induced p-MEK feedback activation in K-RAS mutated cancer cells. In both cases, activation is reported to be mediated by RAF dimers. Taken together, we propose that BGB-283 is a novel, slow-off RAF dimer inhibitor that targets the MAPK signaling differently from the first generation BRAF inhibitor vemurafenib. This feature of BGB-283 may help to address the drug resistance issues in BRAF mutated tumors and further expand its utility as mono- or combination therapy into RAS mutated patient populations.

Citation Format: Ye Liu, Xi Yuan, Zhiyu Tang, Lai Wang, Lusong Luo, Min Wei. BGB-283, a slow-off inhibitor of RAF dimers, differentiates from vemurafenib in MAPK signaling inhibition. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 342.
Abstract 3426: Recurrent breast cancer risk and physical activity
Authors: Lehman Teresa A. , Modali Ramakrishna V. , Ratnasinghe Luke D.
Published: July 2016

Introduction: Physical activity reduces the risk of breast cancer. However, the potential role of physical activity in recurrence of breast cancer is not well established. The aim of our study is to examine the association between physical activity and risk of recurrent breast cancer. Methods: Data was obtained from the Global Epidemiological Study (GES). The GES is an IRB approved multinational biorepository and database to assess cancer and other disease risk factors and biomarkers. In-person interviews of all subjects provided demographics, family-history and other disease related information including age, BMI, diet and physical activity. For statistical analyses, t-tests were used for continuous variables and chi-square tests for categorical variables. The association between recurrent breast cancer and physical activity was assessed using logistic regression in univariate and multivariate analyses. Results: From a total of 2435 breast cancer subjects 215 had recurrent breast cancer. The average age of subjects without recurrence was 55.62 years and those with breast cancer recurrence was 58.35 years. In univariate analysis, subjects in the highest tertile of physical activity were 39% less likely to have recurrent breast cancer compared to those who reported no physical activity [Odds Ratio: 0.61, 95% Confidence Interval: 0.40-0.93]. In multivariate analysis, subjects in the highest tertile of physical activity were 45% less likely to have recurrent breast cancer compared to those who reported no physical activity [Odds Ratio: 0.55, 95% Confidence Interval: 0.34-0.89] after adjusting for age, BMI and cancer-stage. A statistically significant dose-response for physical-activity and reduced risk of recurrent breast cancer was observed with a P-value for trend of 0.05. Conclusion: Our study suggests that physical activity reduces the risk of recurrence of breast cancer. Further studies with larger sample size are needed to confirm our findings.

Citation Format: Teresa A. Lehman, Ramakrishna V. Modali, Luke D. Ratnasinghe. Recurrent breast cancer risk and physical activity. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3426.
Abstract 3448: ERG-negative index tumor status combined with obesity predict prostate cancer progression in Caucasian American prostate cancer patients
Authors: Cullen Jennifer , Young Denise , Chen Yongmei , Degon Michael S. , Baptiste Wagner , Farrell James S. , Sedarsky Jason S. , Kuo Huai-Ching , Kagan Jacob , Srivastava Sudhir , Rosner Inger L. , Petrovics Gyorgy , Dobi Albert , McLeod David G. , Srivastava Shiv , Sesterhenn Isabell A.
Published: July 2016

Introduction: and Objectives: A significantly lower prevalence of ERG oncoprotein has been reported for African American (AA) compared to Caucasian American (CA) prostate cancer (PCa) patients. This difference has been observed when examining prostate cancer (PCa) index tumors as well as for comparisons of non-index tumor foci. To evaluate the potential of ERG status in predicting disease progression, this study examined a large cohort of AA and CA PCa patients within a racially diverse, equal access, military health care center.

Methods: Representative sections of whole mounted prostatectomy specimens from AA (n = 373) and CA (n = 684) patients were evaluated for ERG oncoprotein status by immunohistochemistry. Demographic, clinical, and pathologic patient features, including body mass index, were compared across ERG status (positive vs. negative). Time to event regression analysis was used to model ERG status as a putative predictor of biochemical recurrence (BCR) and distant metastasis.

Results: A significantly lower prevalence of ERG positivity was noted in both index and non-index tumors of AA patients as compared to CA patients. Among CA patients only, ERG-negative index tumors were associated with greater odds of developing BCR and metastasis. Similarly, among CA patients only, having an ERG negative index tumor and being obese at time of prostatectomy was strongly associated with developing biochemical recurrence and metastasis.

Conclusions: These provocative data warrant further investigation of the combined roles between race, obesity, and ERG status on PCa progression. Despite a robust sample size of AA men, the absence of statistically significant associations between ERG and obesity status on disease progression among AA patients could be attributed to insufficient statistical power.

Source of Funding: This research was supported by the National Cancer Institute R01CA162383 grant to SS, by the Center for Prostate Disease Research and by the EDRN/NCI ACN12011-001 to GP, AD, IAS, DGM and SS.

Citation Format: Jennifer Cullen, Denise Young, Yongmei Chen, Michael S. Degon, Wagner Baptiste, James S. Farrell, Jason S. Sedarsky, Huai-Ching Kuo, Jacob Kagan, Sudhir Srivastava, Inger L. Rosner, Gyorgy Petrovics, Albert Dobi, David G. McLeod, Shiv Srivastava, Isabell A. Sesterhenn. ERG-negative index tumor status combined with obesity predict prostate cancer progression in Caucasian American prostate cancer patients. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3448.
Abstract 3460: Breast and ovarian cancer prevention: is it time for population screening for BRCA mutations
Authors: Campbell Ian G. , Thompson Ella , Mitchell Gillian , Trainer Alison , Young Mary-Anne , James Paul
Published: July 2016

Germline mutations in BRCA1 and BRCA2 confer high lifetime risk of breast and ovarian cancer but importantly these risks are not irreversible. Identification of asymptomatic carriers could significantly reduce the incidence of these diseases. The traditional model of familial breast and ovarian cancer practice involves ascertaining high-risk individuals based on family history. In general, the family is first identified because one member develops cancer and because of high-risk indicators, is referred to a Familial Cancer Centre. However, more than 50% of women who carry a BRCA1/2 mutation may not have a family history of cancer in a close relative. Momentum toward genetic screening of the asymptomatic population is growing but there remain some significant unknowns. For example it is unclear what is the true frequency of actionable mutations in the general western population and the extent to which the public would accept such screening, particularly for those individuals identified with an actionable mutation in the absence of an overt family history. As a first step toward population based BRCA gene screening, we are sequencing the entire coding region of 18 known and proposed HBOC genes in 4,000 cancer-free Australian women recruited from the lifepool study (www.lifepool.org), which is a cohort of women attending the Australian population, based mammographic screening program. To date, data from 1,997 women has identified 17 with actionable mutations in BRCA1 (4 mutations), BRCA2 (9 mutations) or PALB2 (4 mutations). All 17 women subsequently accepted an invitation to attend a Familial Cancer Centre and then proceeded to formal clinical genetic testing. In addition 4 women had pathogenic mutations in BRIP1. Our unique pilot data directly demonstrates a population carrier frequency of ∼1% for pathogenic mutations in these recognized high risk breast and/or ovarian cancer genes and that such testing is well accepted by the screened population.

Citation Format: Ian G. Campbell, Ella Thompson, Gillian Mitchell, Alison Trainer, Mary-Anne Young, Paul James. Breast and ovarian cancer prevention: is it time for population screening for BRCA mutations. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3460.
Abstract 3471: Perceived role of family for Hispanic/Latino lung cancer patients: A qualitative study
Authors: Motta-Moss Ana , Alago William , Lin Lorna , Akhuetie Jane
Published: July 2016

Healthcare decisions are not made by the patients alone, but rather the result of collaborative efforts between healthcare professionals and, more importantly, family members who become significant because of the various roles they perform throughout the process. The purpose of this study was to examine the role of family in the care of Hispanic/Latinos patients with lung cancer. Inconsistent expectations of the role of family affect how patients view family support throughout the diagnosis and treatment process. Therefore, it is important to examine what patients perceive to be an appropriate role for family members that assist in their healthcare. Twenty-four patients self-identified as Hispanic/Latino and treated at Memorial Sloan Kettering Cancer Center (MSKCC) for lung cancer stage I-IV participated in semi-structured face-to-face interviews. The four major themes of the role of family identified in this study include: general support, navigation of healthcare system, communications, and lack of family support. It is important to understand that family roles change as the patients’ needs change over the course of the disease. Nonetheless, identifying the various forms of support provided by family is essential to understanding the benefits of family presence in the diagnosis and treatment of lung cancer, particularly among Latinos.

Citation Format: Ana Motta-Moss, William Alago, Lorna Lin, Jane Akhuetie. Perceived role of family for Hispanic/Latino lung cancer patients: A qualitative study. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3471.
Abstract 3483: ESR1 gene expression and expression ratio of ESR1 to ESR2 are associated with worse prognosis in papillary thyroid carcinoma
Authors: Yi Jin Wook , Song Ra-Yeong , Yu Hyeong Won , Lee Joon-Hyop , Kwon Hyungju , Chai Young Jun , Choi June Young , Kim Su-jin , Lee Kyu-Eun
Published: July 2016

Introduction

Expression of estrogen receptor (ER) and progesterone receptor (PR) in breast cancer have been widely studied and used as prognostic markers or therapeutic targets in breast cancer patients. However, clinical and pathologic roles of these hormone receptor genes have not been clearly established in thyroid cancer.

Materials and methods

To evaluate the relationship between sex hormone receptor gene expressions and clinicopathologic variables, we analyzed ESR1, ESR2, ESR ratio (ESR1/ESR2) and PGR mRNA expression data from The Cancer Genome Atlas (TCGA) RNA sequencing experiment in papillary thyroid carcinoma (PTC). To validate results from TCGA analysis, we additionally analyzed a public microarray data (GSE 54598) from the gene expression omnibus (GEO) database.

Results

In TCGA data analysis, ESR1, ESR ratio and PGR expression were significantly higher in PTC tissue than in normal thyroid tissue (Mean value of normal versus tumor were 264.045 vs 659.427 in ESR1, 19.064 vs 92,017 in ESR ratio and 58.514 vs 119.792 in PGR, respectively). In female patients, ESR1 and ESR ratio was negatively correlated with advanced age (t-value was -2.257 and -2.949 in linear regression analysis). Expression of ESR1 and ESR ratio were higher in classic type PTC, presentation of lymphovascular invasion and BRAF V600E mutation. Higher expression group of ESR1 and ESR ratio showed worse overall survival in female PTC patients (Hazard ratio was 6.348 in ESR1 and 4.031 in ESR ratio, respectively). In microarray analysis, ESR1 and ESR ratio expressions were higher in tumor than normal, classic than follicular variant and BRAF V600E than wild type.

Conclusion

Expression of ESR1 and ESR ratio were associated with aggressive prognostic factors and worse overall survival in female PTC patients. These results suggest that higher expression of ESR1 and ESR ratio can be used as prognostic markers to predict survival in female patients.

Citation Format: Jin Wook Yi, Ra-Yeong Song, Hyeong Won Yu, Joon-Hyop Lee, Hyungju Kwon, Young Jun Chai, June Young Choi, Su-jin Kim, Kyu-Eun Lee. ESR1 gene expression and expression ratio of ESR1 to ESR2 are associated with worse prognosis in papillary thyroid carcinoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3483.
Abstract 3501: Puma/pBcl-2 axis influences sensitivity of cancer cells to multiple stimuli
Authors: Liu Yubo
Published: July 2016

Bcl-2 is a central regulator of cell survival that is overexpressed in the majority of cancers cells.Previous reports indicated that Bcl-2 phosphorylation (S70) may provide a switch by which cellscan regulate the pro-survival functions of Bcl-2. But there is still controversy over the function of phosphorylatedBcl-2 (pBcl-2).In the presentstudy, Puma/pBcl-2 axis was found to play a key role in regulating the sensitivity of cancer cells to multiple stimuli.Based on immunoprecipitation, weobserved that the pro-apoptoticBH3-only protein Puma which was induced by paclitaxel competitively bound pBcl-2 (S70) and displaced Bim and Bax from pBcl-2(S70) in Hela and HL60 cells.Further study showed thatdepletion of Puma (siRNA), but not other BH3 only proteins, significantlydecreased paclitaxel-induced apoptosis.Bim/pBcl-2 and Bax/pBcl-2 complexeswere largely maintained when Pumawas reduced. These data indicated that the phosphorylation of Bcl-2(S70) enhancedits anti-apoptotic function and the induction of Puma could neutralize this effect. Similarly,the induced Puma was also responsible for Bim and Bax displacement from pBcl-2 (S70) when Hela and HL60 cellswere treated with DNA damage agents(cisplatin and etoposide).However, Pumacannot displace Bax or Bim when pBcl-2 (S70) was redundant in the cells expressedphospho-mimetic S70E-Bcl-2. It demonstrated that DNA damage induced apoptosis could be inhibit by pBcl-2 (S70) and the induction of Puma could antagonize pBcl-2 (S70). In a cell free system, mitochondria from Hela and HL60 cells which expressing the S70E-Bcl-2 wereincubated with different BH3 peptides. Cytochrome c release couldbe induced by a low concentration of Puma-BH3 peptide, but a higher concentrationwas necessary during Bimengagement.By contrast, Bad-BH3 and Noxa-BH3cannot initiate the release of cytochrome c.In conclusion, multiple stimuli activates the mitochondrial apoptoticpathway in cancer cells, in which Puma/pBcl-2(S70) axisplay a key role in a novel mechanism involving the displacement of Bim and Bax from pBcl-2 (S70)by Puma. In contrast with the debatable function of Bcl-2 phosphorylation (S70), this study provided evidence that the phosphorylation of Bcl-2 at S70 enhanced cell survivalin multiplestimuli triggered apoptosis.

Citation Format: Yubo Liu. Puma/pBcl-2 axis influences sensitivity of cancer cells to multiple stimuli. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3501.
Abstract 3535: Induction of MAPK- and ROS-dependent autophagic cell death in gastric carcinoma by combination of bortezomib and romidepsin
Authors: Chiang Alan K. , Yeung Pauline L. , Hui Kwai Fung
Published: July 2016

Proteasome inhibitors and histone deacetylase (HDAC) inhibitors can synergistically induce apoptotic cell death in certain cancer cell types but their combinatorial effect on the induction of autophagy remains unknown. Here, we investigated the combinatorial effects of a proteasome inhibitor, bortezomib, and an HDAC inhibitor, romidepsin, on the induction of apoptotic and autophagic cell death in gastric carcinoma (GC) cells. Isobologram analysis showed that low nanomolar concentrations of bortezomib/romidepsin could synergistically induce killing of GC cells. The synergistic killing was due to the summative effect of caspase-dependent intrinsic apoptosis and caspase-independent autophagy. The autophagic cell death was dependent on the activation of MAPK family members (ERK1/2 and JNK), and generation of reactive oxygen species (ROS), but was independent of Epstein-Barr virus infection. In vivo, bortezomib/romidepsin also significantly induced apoptosis and autophagy in GC xenografts in nude mice. This is the first report demonstrating the potent effect of combination of HDAC and proteasome inhibitors on the induction of MAPK- and ROS-dependent autophagy in addition to caspase-dependent apoptosis in a cancer type.

This project is funded by CRCG (#104003676) grant of KFH, CRCG (#104002845) and Epstein-Barr virus research (# 200004525) grants of AKSC.

Citation Format: Alan K. Chiang, Pauline L. Yeung, Kwai Fung Hui. Induction of MAPK- and ROS-dependent autophagic cell death in gastric carcinoma by combination of bortezomib and romidepsin. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3535.
Abstract 3543: Alternating electric fields (TTFields) induce autophagy in human cancer cell lines
Authors: Porat Yaara , Shteingauz Anna , Giladi Moshe , Schneiderman Rosa S. , Voloshin Tali , Munster Mijal , Blat Roni , Kirson Eilon D. , Weinberg Uri , Palti Yoram
Published: July 2016

Tumor treating fields (TTFields) are an established anti-neoplastic treatment modality in patients with glioblastoma. TTFields are delivered via noninvasive application of low-intensity, intermediate-frequency, alternating electric fields to the region of the tumor. Previous studies have shown that TTFields lead to increased granularity in treated cells. Granular or vesicular structures can indicate the formation of autophagosomes which are key structures in autophagy. Autophagy has been shown to regulate cell survival and proliferation under stress conditions and, in certain cases, influence cellular response to cytotoxic drugs. The goal of this study was to evaluate the possible effect of TTFields on the induction of autophapgy in treated cells.

Different cancerous cell lines were treated with TTFields using the inovitro system. Cellular granularity was evaluated using flow cytometry. Autophagy was monitored by quantifying Lipidated Microtubule Associated Protein Light Chain 3 (LC3-II, a consensus marker for autophagosomes) levels using immunoblotting and immunofluorescence microscopy. Transmission Electron Microscopy (TEM) was used to visualize autophagosome-like structures.

Flow cytometry analysis demonstrated that TTFields application leads to a significant increase in cellular granularity in all tested cell lines (up to 40%, P<0.05). Significant elevation in LC3-II levels was observed in treated U-87 MG cells using immunoblotting analysis (37%, P = 0.01). Evidence of increased autophagy following TTFields application was also detected using fluorescence microscopy, where punctate distribution of LC3-II was observed. TEM micrographs demonstrated the presence of autophagy typical, autophagosome-like structures in TTFields treated cells.

TTFields are known to exert anti-mitotic effects by disrupting highly dipolar structures which play critical roles in mitosis. Our results suggest that in addition, TTFields can also induce cellular autophagy. Future studies are warranted to examine to what extent TTFields-elicited- autophagy may affect treatment outcomes, and to investigate the therapeutic implications of combining TTFields with autophagy inhibitors.

Citation Format: Yaara Porat, Anna Shteingauz, Moshe Giladi, Rosa S. Schneiderman, Tali Voloshin, Mijal Munster, Roni Blat, Eilon D. Kirson, Uri Weinberg, Yoram Palti. Alternating electric fields (TTFields) induce autophagy in human cancer cell lines. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3543.
Abstract 3545: Gallotannin induces senescence and autophagy leading to cell death via SIRT1 inhibition and AMPK activation in hepatocellular carcinoma cells
Authors: Kwon Hee Young , Kim Sung-hoon
Published: July 2016

Hepatocellular carcinoma (HCC) is one of the most fatal malignancies with high mortality rate worldwide. In the present study, the underlying antitumor mechanism of gallotannin, a hydrolysable tannic acid, was elucidated in HepG2 and SKHep1 HCC cells. Gallotannin suppressed growth and colony formation and also induced senescence via upregulation of p21, G0 / G1 arrest and higher senescence-associated β-galactosidase (SA-β-gal) activity within 24 h culture in HepG2 and SKHep1 cells. Of note, gallotannin also induced autophagy by increasing the number of protein-cytosol-associated protein light chain 3 (LC3) punctae, LC3B-II conversion and SQSTM1/p62, autophagic vacuoles (AVOs) by transmission electron microscopy (TEM) and decreasing the of Beclin1 in HepG2 and SKHep1 cells. A tandem fluorescent-tagged LC3 reporter plasmid (GFP-mRFP-LC3) transfection revealed that gallotannin increased the number of yellow colored LC3 punctae through the co-localization of GFP and mRFP punctae and yellow colored LC3 punctae were increased by CQ or NH4Cl with accumulation of autophagosomes, LC3B-II and SQSTM1/p62 in HepG2 and SKHep1 cells. Additionally, gallotannin attenuated the of sirtuin1 (SIRT1) and mTOR and activated the phosphorylation of 5′-AMP activated protein kinase (AMPK) in two HCC cells. Furthermore, AMPK activator AICAR significantly enhanced SA-β-gal activity and antiproliferation induced by gallotannin, while AMPK inhibitor compound C did not in two HCC cells. Of note, gallotannin time dependently activated caspase 8 / 3 and time/concentration dependently increased sub G1 portion along with weak cleavages of PARP in two HCC cells. Collectively, gallotannin induces senescence and inhibits late autophagy flux, finally leading to apoptotic cell death in HepG2 and SKHep1 cells via inhibition of SIRT1 and activation of p-AMPK as a potent antitumor agent for HCC treatment.

Citation Format: Hee Young Kwon, Sung-hoon Kim. Gallotannin induces senescence and autophagy leading to cell death via SIRT1 inhibition and AMPK activation in hepatocellular carcinoma cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3545.