bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 3343: Targeting the Lin28A/B axis reverts stem cell-like phenotype and tumor-initiating properties in prostate cancer
Authors: Albino Domenico , Civenni Gianluca , Dallavalle Cecilia , Roos Martina , Jahns Hartmut , Hall Jonathan , Carbone Giuseppina M. , Catapano Carlo V.
Published: July 2016

Cancer stem cells (CSCs) represent the most tumorigenic, metastatic and therapy resistant cell subpopulation within human tumors. Current therapies target bulk tumor cells while spare the most aggressive CSC subpopulation. Understanding the mechanisms responsible for the acquisition and maintenance of the CSC phenotype will help to identify new strategies to target CSCs. In this study, we describe a link between deregulated expression of the ETS transcription factor ESE3/EHF and upregulation of Lin28A and Lin28B in prostate CSC-enriched subpopulations. Furthermore, using various cell line models and in vitro/in vivo experimental systems we demonstrate the efficacy of targeting the Lin28A/B axis for selective elimination of cancer cells with tumor-initiating and stem-like properties. Mechanistically, we found that ESE3/EHF represses transcription of Lin28A and Lin28B in normal prostate epithelial cells. Downregulation of ESE3/EHF in prostate tumors led to upregulation of Lin28A and Lin28B and consequent reduction of microRNAs (miRNAs) of the let-7 family, which exert tumor suppressor functions. These events promoted cell transformation and expansion of the prostate CSC subpopulation. Conversely, targeting Lin28A/Lin28B with small interfering RNAs (siRNAs) in transformed prostate epithelial cells and prostate cancer cell lines restored the levels of let-7 miRNAs, decreased expression of several CSC marker genes, and restrained tumor-sphere formation and self-renewal properties in vitro and tumor-initiating capability in vivo. Notably, systemic treatment with a siRNA targeting Lin28B reduced growth of prostate tumor xenografts in mice. This was associated with a significant contraction of the CSC subpopulation in tumor xenografts, as demonstrated by the reduced content of ex vivo tumor-sphere forming cells, reduced expression of CSC marker genes, and upregulation of let-7 miRNAs. Furthermore, tumor cells derived from siLin28B-treated xenografts exhibited reduced in vivo tumor-initiating and self-renewal capability, in line with a persistent loss of CSC properties. Collectively, these data establish the Lin28/let-7 axis as a critical element in malignant transformation and acquisition of tumor-initiating and stem-like properties and identify a valid therapeutic strategy to antagonize CSCs in human prostate cancer.

Citation Format: Domenico Albino, Gianluca Civenni, Cecilia Dallavalle, Martina Roos, Hartmut Jahns, Jonathan Hall, Giuseppina M. Carbone, Carlo V. Catapano. Targeting the Lin28A/B axis reverts stem cell-like phenotype and tumor-initiating properties in prostate cancer. [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 3343.
Abstract 3355: Opening up heterochromatin by histone deacetylase inhibition improves response to DNA damage in lung cancer tumor initiating cells
Authors: Lundholm Lovisa , Hååg Petra , Eriksson Mina , Brzozowska Beata , Lewensohn Rolf , Wojcik Andrzej , Viktorsson Kristina
Published: July 2016

Tumors are suggested to be highly responsive to epigenetic alterations such as histone modifications and DNA methylation. We have previously reported a resistant phenotype of sphere-forming non-small cell lung cancer (NSCLC) tumor initiating cells (TICs) with an impaired activation of DNA-damage response proteins. Here we set out to analyze chromatin compactness since a heterochromatic structure has been postulated to constitute a barrier to DNA damage and repair. We show that certain NSCLC and small cell lung cancer (SCLC) TICs have elevated levels of the heterochromatin markers heterochromatin protein 1γ (HP1γ) and trimethylated lysine 9 of histone 3 (H3K9me3). Chromatin modulators were tested and histone deacetylase inhibitors (HDACi) vorinostat, panobinostat and trichostatin A reduced the cell viability of NSCLC TICs compared to bulk cells after 72 h. We could also demonstrate that TICs are more responsive to HDAC inhibitors since the euchromatin marker acetylated lysine 8 of histone H4 (H4K8ac) was increased after vorinostat and trichostatin A in NSCLC TICs but not in bulk cells. Pretreatment with HDACi inhibitors sensitized NSCLC TICs to cisplatin and ionizing irradiation. Accordingly, pretreatment with vorinostat increased the phosphorylation of the DNA-damage response proteins ataxia telangiectasia mutated (ATM) and DNA-dependent protein kinase (DNA-PK) upon irradiation in NSCLC TICs, whereas bulk cells already had a higher level with radiation only. In conclusion, we demonstrate that lung cancer TICs display a heterochromatic structure compared to bulk cells and that NSCLC TICs have an enhanced sensitization upon DNA damage inflicted by cisplatin or radiation after HDACi pretreatment.

Citation Format: Lovisa Lundholm, Petra Hååg, Mina Eriksson, Beata Brzozowska, Rolf Lewensohn, Andrzej Wojcik, Kristina Viktorsson. Opening up heterochromatin by histone deacetylase inhibition improves response to DNA damage in lung cancer tumor initiating 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 3355.
Abstract 3373: TGF-β1 signaling mediated lymphangiogenesis in gastric cancer
Authors: Pak Kyung Ho , Cheong Jae-Ho , Park Ki Chung
Published: July 2016

Background

Recent evidence showed that Transforming growth factor (TGF)-β1 could have important role for gastric cancer progression and metastasis. However, the role of TGF- β1 for lymph node metastasis and lymphangiogenesis, the important steps of gastric cancer progression, is largely unknown. To investigate the role of TGF-β1 on lymphangiogenesis and its molecular mechanisms is the main purpose of this study.

Methods

We selected two gastric cancer cell-line models, MKN45 and KATOIII, which hold appropriate characteristics for the current study. We checked the possibility of the autocrine function of TGF-β1 for lymphangiogenesis in these gastric cancer cell-lines. We investigated the changes of TGF-β1 signaling molecules and VEGF-C expression in responding to TGF-β1 and its inhibitor. To examine the binding of Smad3 to the promoter region of VEGF-C, we performed electrophoretic mobility shift assay (EMSA). Both Smad-dependent and Smad-independent pathways were also examined to elucidate which pathways were involved in lymphangiogenesis. Finally, tube forming assay was performed to validate phenotypical effect of TGF-β1 on lymphangiogenesis.

Results

Two gastric cancer cell-line models, MKN45 and KATOIII, showed autocrine regulation of TGF-β1. TGF-β1 signaling was transduced to VEGF-C, mediated by Smad3. Smad3 was bound to the promoter of VEGF-C which was confirmed with EMSA. Based on EMSA results, KATOIII showed stronger reaction between Smad3 and VEGF-C promoter than MKN45 did. In MKN45, TGF-β1 also transduced its signal to VEGF-C through PI3k-Akt pathway, one of the Smad-independent pathway. Lymphatic endothelial cells cultured in the condition media of MKN45 and KATOIII underwent tubule structure formation. The growth of HLEC was accelerated with TGF-β1 mixed conditioned media, while failed to induce tubular structure in the presence of TGF-β1 inhibitor. The expression level of secreted VEGF-C was as same in responding to TGF-β1 and its inhibitor as the lymphatic tube forming results in gastric cancer cells.

Conclusion

TGF-β1 could promote lymphangiogenesis through VEGF-C expression in gastric

cancer cell line models. TGF-β1 signaling could be transduced through either

Smad-mediated or non- Smad-mediated depending on gastric cancer cell-line

characteristics.

Citation Format: Kyung Ho Pak, Jae-Ho Cheong, Ki Chung Park. TGF-β1 signaling mediated lymphangiogenesis in gastric cancer. [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 3373.
Abstract 3384: IGFBP5-derived peptide as a novel angiogenesis inhibitor for treatment of ovarian cancer
Authors: Lee Jeong-Won , Hwang Jae Ryoung , Cho Young-Jae , Lee Yoo-Young , Choi Chel Hun , Bae Duk-Soo , Kim Byoung-Gie
Published: July 2016

Insulin-like growth factor-binding protein 5 (IGFBP5) plays a role in cell growth, differentiation, and apoptosis. We found that IGFBP5 was markedly downregulated in ovarian cancer tissue, and that its overexpression in cancer cells induced cell death. In this study, we undertook to evaluate the functional significance of each region of IGFBP5 as a tumor suppressor of ovarian cancer. We found that the C-terminal region of IGFBP5 inhibited tumor growth in a 2774 cell xenograft mouse model, and that expression of VEGF, IL-6, and TNF-α were inhibited in 2774 cells stably expressing the C-terminus of IGFBP5. In order to evaluate its effects on tumor suppression, a peptide derived from the C-terminus of IGFBP5 (BP5-C) was synthesized. As a control, a peptide mutated in the IGF-binding site of BP5-C (BP5-Cmut), as well as peptides derived from the IGFBP2 C-terminus and heparin-binding site were also synthesized. Of these peptides, BP5-C and BP5-Cmut inhibited VEGF expression and NF-kB activity. Furthermore, BP5-C inhibited angiogenesis in an in vitro and an ex vivo system, consisting of HUVEC tube formation and rat aortic ring blood vessel sprouting, respectively. The in vivo effect of BP5-C on tumor growth was studied using i.p. injection of ovarian cancer 2774 cells into mice, as well as with a patient-derived xenograft mouse model. BP5-C peptide significantly inhibited tumor growth, angiogenesis, and VEGF expression in both xenograft models. These results suggest that the C-terminus of IGFBP5 exerts an anti-cancer activity by inhibiting angiogenesis via downregulation of VEGF in an IGF-independent manner, and may be considered as a novel angiogenesis inhibitor for the treatment of ovarian cancer.

Citation Format: Jeong-Won Lee, Jae Ryoung Hwang, Young-Jae Cho, Yoo-Young Lee, Chel Hun Choi, Duk-Soo Bae, Byoung-Gie Kim. IGFBP5-derived peptide as a novel angiogenesis inhibitor for treatment of ovarian cancer. [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 3384.
Abstract 3390: CTHRC1 promotes angiogenesis by recruiting Tie2-expressing monocytes to pancreatic tumors
Authors: Jo Seongyea , Lee Jaemin , song. jinhoi
Published: July 2016

CTHRC1 (collagen triple helix repeat-containing 1), a protein secreted during the tissue repair process, is highly expressed in several malignant tumors, including pancreatic cancer. We recently showed that CTHRC1 plays an important role in the progression and metastasis of pancreatic cancer. Although CTHRC1 secretion affects tumor cells, how it promotes tumorigenesis in the context of the microenvironment is largely unknown. Here, we demonstrate a novel role of CTHRC1 as a potent endothelial activator, promoting angiogenesis by recruiting bone marrow-derived cells into the tumor microenvironment during tumorigenesis. Recombinant CTHRC1 (rCTHRC1) enhanced endothelial cell (EC) proliferation, migration and capillary-like tube formation, consistent with observed increases in neovascularization in vivo. Moreover, rCTHRC1 induced upregulation of angiopoietin-2 (Ang-2), a Tie2 receptor ligand, through ERK-dependent activation of AP-1 in ECs, resulting in recruitment of Tie2-expressing monocytes (TEMs) to CTHRC1-overexpressing tumor tissues. Treatment with a CTHRC1-neutralizing antibody abrogated Ang-2 expression in ECs in vitro. Moreover, CTHRC1-neutralizing antibody treatment in a xenograft mouse model reduced tumor burden and infiltration of TEMs in tumor tissues, indicating that blocking the CTHRC1/Ang-2/TEM axis during angiogenesis inhibits tumorigenesis. Collectively, our findings support the conclusion that CTHRC1 induction of the Ang-2/Tie2 axis mediates the recruitment of TEMs, which are important for tumorigenesis and can be targeted to achieve effective antitumor responses in pancreatic cancers.

Citation Format: Seongyea Jo, Jaemin Lee, jinhoi song. CTHRC1 promotes angiogenesis by recruiting Tie2-expressing monocytes to pancreatic tumors. [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 3390.
Abstract 3392: Lung cancer cell derived extracellular vesicles carrying DNAs, RNAs and proteins that may trigger oncogenic signals and promote angiogenesis
Authors: Lin Chien-Chung , Huang Wei-Lun , Su Wu-Chou
Published: July 2016

Extracellular vesicles (EVs) secreted from tumor cells have been implicated in modulating the tumor microenvironment changes. In this study, we demonstrated that EVs secreted by lung cancer cell are loaded with several cargos, such as DNA, RNA, cytokines, and growth factors. After the EVs had been taken up by recipient cells, the cargos might activate oncogenic pathways. We firstly isolated EVs from cell-free medium of lung cancer cells lines (AS2, PC9) and malignant pleural effusion (MPE) from patients with lung cancer. Isolated EVs were confirmed by the morphology and size in transmission electron microscopy (TEM) and the presentation of specific EV markers (Alix, CD63, and Tsg101). We found that several RNA species with enrichment of small RNAs and mutated EGFR DNA in the EVs of PC9 cells. After labeling with the green fluorescent dye Cellvue, the uptake of EVs by AS2 cells was imaged by the fluorescent microscopy. With these data, we further investigated the role of EVs in regulating the tumor microenvironment. We found the content of IL-6 in EVs, secreted from AS2 and CL1-5 cells, increased gradually after changing culture medium. And after uptake of EVs by recipient cells the cargos induced higher phsophorylation of Stat3 and AKT compared to the treatment with serum-free medium. Previously, we have shown that IL-6/Stat3/tissue factor (TF)/VEGF pathway enhances lung cancer angiogenesis, metastasis and the generation of MPE. In the current study, we demonstrated that EVs from lung cancer cells and in the MPE contain high level of VEGF and TF. And treatment with the EVs, containing high VEGF and TF, induced more prominent extravasation than cell free medium did in Miles assays. In conclusion, we successfully isolated EVs not only from culture supernatants but also from MPE of lung cancer patients. The EVs contain many biologically active molecules that may modulate behaviors of cancer cells and cells in tumor microenvironment.

Citation Format: Chien-Chung Lin, Wei-Lun Huang, Wu-Chou Su. Lung cancer cell derived extracellular vesicles carrying DNAs, RNAs and proteins that may trigger oncogenic signals and promote angiogenesis. [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 3392.
Abstract 3403: Amphiregulin promotes vascular endothelial growth factor-dependent angiogenesis in human chondrosarcoma cells
Authors: Huang Yu-Wen , Tsai Hsiao-Chi , Tang Chih-Hsin
Published: July 2016

Chondrosarcoma is the second most common sarcoma in bone malignancy and is characterized by a high metastatic potential. Angiogenesis has been considered an important role in the cancer metastasis. Therefore, a better understanding of angiogenic and metastatic pathways are needed. Amphiregulin (AR) has been implicated in tumor metastasis and angiogenesis. However, the relationship of amphiregulin with vascular endothelial growth factor A (VEGF-A) expression and angiogenesis in human chondrosarcoma cells is mostly unknown. In this study, we found that the expression of amphiregulin and VEGF-A were correlated with tumor stage and were significantly higher than that in the normal cartilage. VEGF-A expression increased which depend on time and dose dependent of amphiregulin. Exogenous amphiregulin with chondrosarcoma cells promoted VEGF-A expression and subsequently increased migration, proliferation and tube formation in endothelial progenitor cells (EPCs) and human umbilical vein endothelial cells (HUVECs). We also found that amphiregulin increased VEGF-A expression and angiogenesis through focal adhesion kinase (FAK), Src and protein kinase C (PKC) signaling pathway. Knockdown of amphiregulin decreased VEGF-A expression in chondrosarcoma cells. The angiogenesis effects in Matrigel plug nude mice model in vivo was also abolished in amphiregulin-knockdown cells. Taken together, these results indicate that amphiregulin occurs through FAK, Src, and PKC pathway, resulting in the activation of VEGF-A expression and contributing to the angiogenesis of human chondrosarcoma cells.

Citation Format: Yu-Wen Huang, Hsiao-Chi Tsai, Chih-Hsin Tang. Amphiregulin promotes vascular endothelial growth factor-dependent angiogenesis in human chondrosarcoma 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 3403.
Abstract 3405: The analysis of TRPV6 expression in lymphoid tumours
Authors: DiPasquale Ashley M. , Rahmeh Tarek , Andrew Lauren , Agar Jane , Miller Kim , Finniss Matthew , Murugesan Alli , Reiman Anthony
Published: July 2016

Introduction:

TRPV6 is a calcium channel that is found overexpressed in various malignancies and is correlated with the prognosis of patients with prostate cancer. TRPV6 targeted anticancer therapies are in development. We are interested in the potential of TRPV6 as a potential biomarker and therapeutic target in lymphoma. This retrospective study examines the expression levels of TRPV6 in various lymphoid tumour types, and correlates expression levels with grade, prognostic scores, and survival rates.

Methods:

A clinical-pathological database was constructed using the health records and lymphoid tumor samples of patients diagnosed with diffuse large B-cell lymphoma (DLBCL), Follicular lymphoma (FL), small lymphocytic lymphoma/chronic lymphocytic leukemia (SLL/CLL), and Hodgkin's lymphoma (HL). Immunohistochemical studies were performed on lymphoid tumor samples to analyze the level of TRPV6 expression. Tumor samples were graded on a 3-point scale. A score of +3 indicated dense staining with high expression levels, and a score of +1 indicated minimal staining with low expression levels. TRPV6 expression levels were correlated with prognostic scores (IPI, FLIPI) and survival rates using Chi-squared, Mantel-Cox, and Kaplan-Meier survival curves. Descriptive statistics were used to describe patient demographics.

Results:

We found high TRPV6 expression levels in DLBCL and HL tumor samples with > 40% of samples scoring +3. We found low TRPV6 expression levels in FL and SLL/CLL with > 40% of samples scoring +1. We found no significant correlation between the level of TRPV6 expression and prognostic scores or survival rates in any of the lymphoma subtypes studied. In follicular lymphoma tumor samples, it was noted on observation that the large tumor cells generally stained +3 while the small tumor cells generally stained +1.

Conclusion:

This retrospective study showed DLBCL and HL tumors have high levels of TRPV6 expression. It also showed that TRPV6 is found highly expressed in the large transformed cells (centroblasts) in follicular lymphoma. These results demonstrate a need to further assess the role of TRPV6 in the aggressiveness of follicular lymphoma, as well as the prognosis and survival in DLBCL and HL with a larger sample size. Further studies of the potential of TRPV6 as a therapeutic target in lymphoma will focus on DLBCL, high grade/transformed FL, and HL.

Citation Format: Ashley M. DiPasquale, Tarek Rahmeh, Lauren Andrew, Jane Agar, Kim Miller, Matthew Finniss, Alli Murugesan, Anthony Reiman. The analysis of TRPV6 expression in lymphoid tumours. [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 3405.
Abstract 3412: Prognostic significance of plasma ghrelin in patients with gastric cancer
Authors: Soleyman-Jahi Saeed , Zendehdel Kazem , Abdirad Afshin , Fallah Amir Afraz , Ghasemi Sevil , Sadeghi Fatemeh
Published: July 2016

Background: Different prognosis observed for patients of the same clinical stage in gastric cancer, emphasizes the fact that new biological prognostic factors are needed to complement clinical staging. We aimed to investigate the prognostic significance of plasma ghrelin in gastric cancer patients.

Methods: In this prospective study, we included 83 gastric cancer patients from Cancer institute of Tehran, Iran. All the patients were candidates for gastrectomy with or without preoperative neoadjuvant chemotherapy (PNC). The patients were followed for three years. Demographic, clinical and para clinical data were registered. Using an ELISA based assay plasma levels of total and active ghrelin were assessed prior to and one week after the operation. Univariate and multivariate COX analyses were used to investigate the independent predictors of patients overall survival.

Results: The mean (±SD) age of the patients was 60.3±13.6. Sixty-five (78.3%) patients were male. Majority of the patients had gastric adenocarcinoma (95.2%). Thirty-seven (44.6%) patients had TNM stage II or I. Poorly differentiated grade was detected in 29 (34.9%) of the patients. Forty-eight (57.8%) patients received PNC before the operation. Mean (±SD) survival was 529 ± 373 days. Mean level of the plasma total ghrelin was 269.8±268.7 and 108.7±91.2 (pg/ml) before and after the operation, respectively (P<0.001). Mean level of the plasma active ghrelin was 68.0 ± 63.8 and 44.0± 29.6 (pg/ml) before and after the operation, respectively (P<0.001). Patients in the upper half or highest quartile of postoperative total ghrelin had better survival compared to the corresponding subgroups (Log rank test P = 0.02 and P<0.001, respectively). Multivariate COX model revealed that late TNM stage (HR = 2.93, 95% CI: 1.37-6.27), no PNC (HR = 2.18, 95% CI: 1.08-4.37), history of significant weight-loss (HR = 2.32, 95% CI: 1.04-5.00) and lower quartile (≤38 pg/ml) of postoperative plasma total ghrelin (HR = 3.74, 95% CI: 1.45-9.63) predicted poor survival of patients. The level of other ghrelins did not show independent prediction of survival.

Conclusion: Our findings showed that low level of plasma total ghrelin after the gastrectomy could independently predict poor survival in gastric cancer patients. This emphasizes both prognostic and therapeutic significance of this biomarker in gastric cancer.

Citation Format: Saeed Soleyman-Jahi, Kazem Zendehdel, Afshin Abdirad, Amir Afraz Fallah, Sevil Ghasemi, Fatemeh Sadeghi. Prognostic significance of plasma ghrelin in patients with gastric cancer. [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 3412.
Abstract 3414: Ethnic disparities in breast cancer survival in Sarawak, Malaysia
Authors: Sung Hyuna , Devi C.R. Beena , Guida Jennifer , Tang Tieng Swee , Anderson William F. , Yang Xiaohong R.
Published: July 2016

Introduction: There are three distinct South-East Asian ethnic groups in Sarawak, Malaysia (Chinese, Malay, and natives) whose breast cancer incidence rates and the distribution of tumor subtypes were reported to be significantly different. It remains unclear whether survival varies among breast cancer cases in these ethnic groups. We aimed to evaluate the relationship between survival and ethnicity when taking into account tumor characteristics.

Methods: We analyzed incident breast cancer cases who were enrolled and treated in Sarawak General Hospital, Malaysia, between 1992 and 2014. The association of ethnicity with survival (relapse-free survival and overall survival) was evaluated using multivariate Cox-proportional hazard model. Subgroup analysis was conducted for each tumor subtype defined by hormone receptor (HR+, ER+ or PR+; HR-, ER- and PR-) and HER2 status (HR+/HER2-, HR+/HER2+, HR-/HER2-, and HR-/HER2+).

Results: Among 2,758 eligible cases (median follow-up years, 2.90 years), there were 636 deceased and 423 relapsed cases. While there was no significant difference in disease recurrence, overall survival varied significantly by ethnicity. Compared with Chinese women, Malay women had a higher proportion of mortality (HR = 1.50; 95% CI = 1.14-1.96; P = 0.0037). This disparity remained significant only among cases with HR+ tumors (HR = 1.91; 95% CI = 1.17-3.11; P = 0.0091 among HR+/HER2-; HR = 2.74; 95% CI = 1.30-5.77; P = 0.0079 among HR+/HER2+). There was no difference in survival between Chinese and native women overall or stratified by subtype.

Conclusions: Our results showed that Malay women experienced worse survival compared to Chinese women particularly among cases with HR+ tumors. Future studies are needed to clarify the underlying factors for this association in order to develop intervention strategies to reduce disparity.

Citation Format: Hyuna Sung, C.R. Beena Devi, Jennifer Guida, Tieng Swee Tang, William F. Anderson, Xiaohong R. Yang. Ethnic disparities in breast cancer survival in Sarawak, Malaysia. [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 3414.
Abstract 3440: Time and regional incidence trends of human papillomavirus-associated oropharyngeal cancer in Ontario, Canada
Authors: Shi Wei , Hall Stephen F. , Rey-McIntyre Katrina , Griffiths Rebecca , Xu Wei , Su Jie , Bruce Jeff , Huang Shaohui , O’Sullivan Brian , Yip Kenneth W , Liu Fei-Fei
Published: July 2016

Background: Despite the increasing incidence of human papillomavirus (HPV)-associated oropharyngeal cancer (OPC) in the Western World, there are little data describing the change in HPV incidence within Ontario, Canada. We therefore assessed HPV-positivity in a retrospective study of 612 OPC patient samples.

Methods: Diagnostic formalin-fixed and paraffin embedded OPC patient samples belonging to two cohorts were retrieved from institutions across Ontario, Canada over two time periods: 1998-1999 (n = 245) and 2003-2004 (n = 367). In all samples, HPV status was assessed initially using p16 immunohistochemistry (IHC). For p16 negative and equivocal staining samples, HPV in situ hybridization (ISH; using an HPV subtype 16/18 probe) was performed as the final indicator for HPV positivity. HPV-positivity rate was then compared over time and geographic region.

Results: Overall, p16-positivity was observed in 52.3% (320 of 612) of the OPC patients. For the p16-negative (n = 246) and p16-equivocal (n = 46) samples, 25.3% (n = 74) were positive by HPV16/18 ISH. The HPV infection incidence for the 1998-1999 cohort was 54.3% (133 of 245 samples; 95% CI: 53.9(47.4-60.2)). The HPV infection incidence increased significantly in the 2003-2004 cohort to 71.1% (261 of 367 samples; 95% CI: 71.4(66.5-76.0)) (p<0.0001). When divided based on geographical region, HPV incidence also increased significantly over time (Northern Ontario by 49%, p = 0.04; Eastern Ontario by 23%, p = 0.009; Southern Ontario by 17%, p = 0.009; Central Ontario by 12%, p = 0.05). There were no significant differences between urban and rural areas over the two cohort periods (urban p = 0.8; rural, p = 0.6).

Conclusions: HPV-associated OPC increased in incidence in Ontario, Canada, over a 6-year period from 1998 to 2004, which appeared to be applicable across the entire province, regardless of urban or rural regions. A composite HPV detection method using p16 in combination with HPV ISH identified an additional 25% of HPV-positive OPC cases.

Citation Format: Wei Shi, Stephen F. Hall, Katrina Rey-McIntyre, Rebecca Griffiths, Wei Xu, Jie Su, Jeff Bruce, Shaohui Huang, Brian O’Sullivan, Kenneth W Yip, Fei-Fei Liu. Time and regional incidence trends of human papillomavirus-associated oropharyngeal cancer in Ontario, Canada. [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 3440.
Abstract 3457: Social support as emotional adjustment determinant of breast cancer patients after surgery in selected hospitals in Nigeria
Authors: Oyewusi Christiana Oluseun , Oyewusi Samuel Oyebode
Published: July 2016

Breast cancer is the most common invasive cancer and a leading cause of premature mortality for females worldwide. It accounts for 16% of all female cancers; 18.2% of all cancer deaths globally are from breast cancer. Social support plays a major role in modifying negative effect of this disease on affected individuals. It is an important psychosocial resource for coping with stressful life events. This study was carried out to examine social support as determinant of emotional adjustment of breast cancer patients after surgery in selected hospitals in Ibadan, Nigeria.

This cross-sectional descriptive survey utilized a quantitative approach. A sample of two hundred and eighteen patients was randomly selected from hospitals in Ibadan. The respondents were reassured of confidentiality of the data. The instrument used basically was self-structured questionnaire. Data were collected, coded and analyzed using Pearson correlation coefficient.

The respondents’ ages were between 21- 51 years; 87.2% were females, majority of them (81.6%) were Christians, more than half (62.4%) were married, about one third (31.2%) had higher qualifications, 55.0% were civil servants and 74.3% were living with other family members. Result findings show that instrumental support had significant effect on emotional adjustment of the breast cancer patients after surgery. Family and friends helping the patients had a positive effect on their emotional adjustment. Therefore, it was revealed that instrumental support had a positive effect on emotional adjustment of the patients (r.cal = .217, r. critical = .195, P < 0.05). Also, emotional support had a significant effect on emotional adjustment of the patients after surgery. Having family members and friends to talk to and help with personal problems was helpful to emotional adjustment. Thus it was evident that emotional support had a positive effect on emotional adjustment (r. cal = .250, r. critical = .195, P < 0.05)

The patients admitted that they had friends and family members who helped them and were a source of comfort to them. This helped them to show a better psychological and emotional adjustment to breast cancer than those who did not have support. It is recommended that adequate attention be given to financial, material and emotional needs of the breast cancer patient.

Keywords: Social support, determinant, emotional adjustment, breast cancer patients.

Citation Format: Christiana Oluseun Oyewusi, Samuel Oyebode Oyewusi. Social support as emotional adjustment determinant of breast cancer patients after surgery in selected hospitals in Nigeria. [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 3457.
Abstract 3467: Moderate-intensity exercise to reduce radiation therapy-related fatigue in black breast cancer patients: A feasibility trial
Authors: Dash Chiranjeev , Mills Mary , Watkins Vivian , Randolph-Jackson Pamela , Isaacs Claudine , Makambi Kepher , Adams-Campbell Lucile L.
Published: July 2016

Background: Fatigue is an important side-effect of radiation therapy (RT) for treatment of early stage breast cancer. Evidence on the efficacy of physical activity (PA) interventions in reducing fatigue among Black cancer patients undergoing RT is lacking. In a randomized controlled trial we tested the efficacy of a structured PA intervention, coinciding with the start of RT, in reducing cancer-related fatigue among Black patients undergoing RT for breast cancer.

Methods: We randomly assigned 30 Black, sedentary, RT-naïve, non-pregnant patients diagnosed with stage 0-IIIA breast cancer who had completed adjuvant or neo-adjuvant chemotherapy and were scheduled for RT to the PA intervention (n = 15) and control groups (n = 15). PA intervention was an 8-week structured, moderate-intensity aerobic exercise regimen (75 minutes/week) using PEDLARS (portable stationary cycle ergometers) concurrent with RT. Fatigue was measured by using the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) survey, a 13-item scale whose score ranges from 0 to 52 with a higher score denoting lower fatigue. We used ANCOVA to compare fatigue levels between the groups at T8 weeks after adjusting for baseline (T0) fatigue levels. We also compared change in fatigue scores (T8 weeks - T0) using 2-sample t-tests. All tests were double-sided with alpha = 0.05.

Results: 27 women completed baseline and follow-up assessments. After adjusting for baseline fatigue scores, intervention group participants reported lower fatigue at T8 weeks than the control group (42.53 vs. 37.12; P = 0.17). Intervention group participants improved their fatigue scores at T8 weeks compared to T0 (mean change +1.3) but the control group did not (mean change -1.91; P = 0.42).

Conclusion: Although statistically not significant, moderate-intensity exercise regimen among Black breast cancer patients undergoing RT was associated with lower RT-associated fatigue. This trial demonstrated the feasibility and acceptability of conducting a randomized clinical trial of a moderate-intensity exercise program among women initiating RT for breast cancer.

Citation Format: Chiranjeev Dash, Mary Mills, Vivian Watkins, Pamela Randolph-Jackson, Claudine Isaacs, Kepher Makambi, Lucile L. Adams-Campbell. Moderate-intensity exercise to reduce radiation therapy-related fatigue in black breast cancer patients: A feasibility trial. [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 3467.
Abstract 3474: Prevalence of BRCA1 and BRCA2 small mutation and large genomic rearrangements in breast cancer patients visiting a genetic counseling clinic
Authors: Sohn Ji Yeon , Park Boyoung , Yoon Kyong-Ah , Park Soo Jin , Lee Moo Hyun , Cho Eun Hae , Lee Keun Seok , Lim Myong Cheol , Kong Sun-Young , Lee Eun Sook
Published: July 2016

BACKGROUND: This study was conducted to investigate mutation prevalence of the BRCA1 and BRCA2 genes in breast cancer patients, including both small mutations and large genomic rearrangements (LGRs) following the patients in the process of genetic counseling.

METHODS: A total of 358 breast cancer patients who visited genetic counseling clinic and screened for BRCA1/2 mutation at the National Cancer Center were included. Among the non-carriers by direct sequencing, a subset of patients who were agreed on participation of the research were screened for the presence of LGRs using a multiple ligation-dependent probe amplification (MLPA) assay. Clinico-pathologic characteristics of cancer were evaluated thorough medical record review and characteristics for those who found BRCA mutation through MLPA were described.

RESULTS: 53 (14.8%) mutation carriers were identified. The frequency of BRCA small mutations in specific subgroups was as follows: 18.0% of patients with a family history, 12.8% of early-onset breast cancer, and 20.6% of bilateral breast cancer patients. MLPA identified BRCA1 LGRs in 3 (1.5%) out of 204 patients with BRCA1 and BRCA2 small mutation-negative results. Those with LGRs showed higher probabilities of BRCA mutation carriers estimated by risk assessment models and receptor negatives of tumor immunohistochemistry.

CONCLUSIONS: The prevalence of BRCA1/2 mutation prevalence in breast cancer patients with family history or personal risk factors were comparable to previous Korean studies. MLPA to screen for mutations in the BRCA1 gene could be recommended for breast cancer patients negative for small mutations. To specify proper targets of MLPA, probabilities of carrying BRCA1/2 mutation and tumor receptor status could be considered.

Citation Format: Ji Yeon Sohn, Boyoung Park, Kyong-Ah Yoon, Soo Jin Park, Moo Hyun Lee, Eun Hae Cho, Keun Seok Lee, Myong Cheol Lim, Sun-Young Kong, Eun Sook Lee. Prevalence of BRCA1 and BRCA2 small mutation and large genomic rearrangements in breast cancer patients visiting a genetic counseling clinic. [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 3474.
Abstract 3481: Kisspeptin regulates the invasiveness of endometrial cancer cells through FAK/ Src signaling-dependent activation of matrix metalloproteinase (MMP)-2
Authors: Wu Hsien-Ming , Liang Yung-Yu , Chiu Wei-Jung , Wang Hsin-Shih , Huang Hong-Yuan , Lai Chyong-Huey , Soong Yung-Kuei
Published: July 2016

Introduction:

More than 25% of patients diagnosed with endometrial carcinoma have an invasive primary cancer accompanied by metastasis. The kisspeptin has an important role in reproduction. In mammals, kisspeptin may regulate tumor progression of endometrial cancer. FAK and Src signaling have been considered important components of tumor progression. MMPs are largely implicated in promoting angiogenesis and tumor metastasis. In the present study, we examined the action of kisspeptin-promoted motility of endometrial cancer cells and the mechanisms of the action in endometrial cancer.

Materials and methods:

Endometrial cancer cell line Ishikawa and ECC-1 were derived from an endometrial adenocarcinoma. Kisspeptin agonist and antagonist were synthetic peptides. Cell motility was estimated by invasion and migration assay. The activities of MMP-2 was assessed by gelatin zymography. Immunoblot analysis was done to study the expression of kisspeptin receptor and the effects of kisspeptin in the activation of FAK,Src and MMP-2. Human FAK siRNA and Src siRNA were used to knock down the expression of FAK and Src to evaluate the effects of FAK and Src. MMP-2 inhibitor (OA-Hy) was pretreated for 30 min to evaluate the effects of MMP-2 in cell motility.

Results:

The kisspeptin regulated cell motility in a dose-dependent manner. Kisspeptin activated the phosphorylation of FAK and Src signaling and the phosphorylation was abolished by FAK siRNA and Src siRNA. Kisspeptin-regulated cell motility was suppressed in cells pretreated with FAK siRNA and Src siRNA. Moreover, FAK siRNA and Src siRNA abolished kisspeptin-induced activation of MMP-2. Inhibition of MMP-2 with 10μM OA-Hy suppressed cell motility in response to kisspeptin.

Conclusion:

Our study shows that the kisspeptin regulated the cell motility of endometrial cancer cells through the kisspeptin receptor, and the phosphorylation of FAK and Src-dependent activation of MMP-2. Our findings represent a new concept regarding the mechanisms of kisspeptin-regulated cell motility in endometrial cancer cells, suggesting the possibility of kisspeptin analogues as a potential therapeutic intervention for the treatment of human endometrial cancer.

Citation Format: Hsien-Ming Wu, Yung-Yu Liang, Wei-Jung Chiu, Hsin-Shih Wang, Hong-Yuan Huang, Chyong-Huey Lai, Yung-Kuei Soong. Kisspeptin regulates the invasiveness of endometrial cancer cells through FAK/ Src signaling-dependent activation of matrix metalloproteinase (MMP)-2. [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 3481.
Abstract 3497: Metformin enhances TRAIL-induced apoptosis by Mcl-1 degradation via Mule in colorectal cancer cells
Authors: Park Seong Hye , Lee Dae-Hee , Kim Jung Lim , Lee Sun Il , Kim Bo Ram , Na Yoo Jin , Lee Suk Young , Kim Hong-Jun , Joung Sung Yup , Kang Sanghee , Oh Sang Cheul
Published: July 2016

Recent studies have reported that metformin is an anti-diabetic drug, and is the potential a promising anti-cancer agent. The purpose of this study is to evaluate whether metformin effectively sensitize human colorectal cancer (CRC) cells to tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL)-induced apoptosis. Metformin alone did not induce apoptosis, but significantly potentiated TRAIL-induced apoptosis in CRC cells. CRC cells treated with metformin and TRAIL activated the intrinsic and extrinsic pathways of caspase activation. To elucidate the underlying mechanism, we found that metformin significantly reduced the protein levels of Mcl-1 (Myeloid cell leukemia 1) in CRC cells, and overexpression of Mcl-1 attenuated the cell death by metformin alone, or in combination with TRAIL. Further experiments revealed that metformin did not affect the mRNA level, but proteasomal degradation and protein stability of Mcl-1. The metformin-induced degradation of Mcl-1 required the E3 ligase Mule, which is responsible for the polyubiquitination of Mcl-1. Taken together, our study is the first report indicating that metformin enhances TRAIL-induced apoptosis through the degradation of Mcl-1 by the proteasome machinery.

Citation Format: Seong Hye Park, Dae-Hee Lee, Jung Lim Kim, Sun Il Lee, Bo Ram Kim, Yoo Jin Na, Suk Young Lee, Hong-Jun Kim, Sung Yup Joung, Sanghee Kang, Sang Cheul Oh. Metformin enhances TRAIL-induced apoptosis by Mcl-1 degradation via Mule in colorectal cancer 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 3497.
Abstract 3509: Knockdown of RNF2 induces apoptosis by regulating MDM2 and p53 stability
Authors: Wen Weihong , Peng Cong , Kim Myoung Ok , Jeong Chul Ho , Zhu Feng , Yao Ke , Zykova Tatyana , Ma Wei-Ya , Carper Andria , Langfald Alyssa , Bode Ann M. , Dong Zigang
Published: July 2016

RNF2, also known as Ring1B/Ring2, is a component of the polycomb repression complex 1 (PRC1). RNF2 is highly expressed in many tumors, suggesting that it might have an oncogenic function, but the mechanism is unknown. Here we show that knockdown of RNF2 significantly inhibits both cell proliferation and colony formation in soft agar, and induces apoptosis of cancer cells. Knockdown of RNF2 in HCT116 p53+/+ cells resulted in significantly more apoptosis than was observed in RNF2 knockdown HCT116 p53−/− cells, indicating that RNF2 knockdown-induced apoptosis is partially dependent on p53. Various p53-targeted genes were increased in RNF2 knockdown cells. Further studies revealed that in RNF2 knockdown cells, the p53 protein level was increased, the half-life of p53 was prolonged and p53 ubiquitination was decreased. In contrast, cells overexpressing RNF2 showed a decreased p53 protein level, a shorter p53 half-life and increased p53 ubiquitination. Importantly, we found that RNF2 directly binds with both p53 and MDM2 and promotes MDM2-mediated p53 ubiquitination. RNF2 over-expression could also increase the half-life of MDM2 and inhibit its ubiquitination. The regulation on p53 and MDM2 stability by RNF2 was observed during the etoposide-induced DNA damage response. These results provide a possible mechanism explaining the oncogenic function of RNF2, and because RNF2 is important for cancer cell survival and proliferation, it might be an ideal target for cancer therapy or prevention.

Keywords: RNF2, p53, apoptosis

Citation Format: Weihong Wen, Cong Peng, Myoung Ok Kim, Chul Ho Jeong, Feng Zhu, Ke Yao, Tatyana Zykova, Wei-Ya Ma, Andria Carper, Alyssa Langfald, Ann M. Bode, Zigang Dong. Knockdown of RNF2 induces apoptosis by regulating MDM2 and p53 stability. [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 3509.
Abstract 3512: Cyclopamine enhances TRAIL-induced apoptosis by induction of DR5 via ER stress in gastric cancer cells
Authors: Na Yoo Jin , Lee Dae-Hee , Kim Jung Lim , Kim Bo Ram , Park Seong Hye , Min Byung-Wook , Lee Sun Il , Kang SangHee , Joung Sung Yup , Lee Suk Young , Kim Hong-Jun , Oh Sang Cheul
Published: July 2016

Activation of sonic hedgehog (Shh) signaling has been involved in progression of various cancers. Cyclopamine uses as effective treatment for cancers in which hedgehog signaling is overexpressed. In this study, we elucidated that cyclopamine sensitizes to tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL)-induced apoptosis in gastric cancer cells. Single treatment with cyclopamine or TRAIL could not induce significant cytotoxicity in gastric cancer cells. However, combination treatment of TRAIL with cyclopamine effectively led to caspase dependent apoptosis. We found that cyclopamine increased ER (Endoplasmic Reticulum) stress level in gastric cancer cells, and using ER stress inhibitor attenuated the cell death by cyclopamine. As further underlying mechanism, induction of ER stress by cyclopamine caused upregulation of JNK (c-Jun N-terminal kinases) protein, and then accumulation of p53 protein. We conducted experiment using p53 wild-type and p53-mutated gastric cancer cells, and this of particular importance since p53 wild-type gastric cancer cells had more significant efficacy than p53-mutated cells by cyclopamine. Accumulation of p53 increased DR5 protein. Taken together, we showed that cyclopamine sensitizes to TRAIL-induced apoptosis in gastric cancer cells.

Citation Format: Yoo Jin Na, Dae-Hee Lee, Jung Lim Kim, Bo Ram Kim, Seong Hye Park, Byung-Wook Min, Sun Il Lee, SangHee Kang, Sung Yup Joung, Suk Young Lee, Hong-Jun Kim, Sang Cheul Oh. Cyclopamine enhances TRAIL-induced apoptosis by induction of DR5 via ER stress in gastric cancer 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 3512.