bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4759: HOXB7 functions as a co-activator of estrogen receptor in the development of tamoxifen resistance.
Authors: Jin Kideok , Teo Wei Wen , Yoshida Takahiro , Park Sunju , Sukumar Saraswati 
Published: August 2014

Abstract
Background: Multiple factors including long term treatment with tamoxifen are involved in the development of selective estrogen receptor modulator (SERM)-resistance in ERα positive breast cancer. Increased expression of HER family members can also directly alter cellular responses to tamoxifen, but the mechanism underlying the increased expression of the HERs is not clear. In this report we show that HOXB7 is an upstream regulator of HER2 and ER expression.
Results: Overexpression of HOXB7 results in upregulation of HER2 and ERα target genes, while knockdown of HOXB7 with siRNA in tamoxifen-resistant cell lines causes decrease of HER2 and ERα target genes expression and loss of tamoxifen resistance. To mediate upregulation of HER2 and ER-target genes occurring in tamoxifen resistance, the HOXB7-ERα complex recruits ERα coactivators and promotes HER2- and ER-target genes transcriptional activity through direct binding to the HER2 enhancer and regulatory regions of ER target genes. However, depletion of HOXB7 negatively affects the binding affinity of its cofactors to the HER2 enhancer element and ER-binding sites. Also, it is likely that miR196a controls HOXB7 expression; reducing miR196a levels in tamoxifen-resistant cells causes an increase of HOXB7 expression. Overexpression of miR196a sensitizes MCF-7 tamoxifen resistant cells to tamoxifen through downregulation of HER2 and ER-target genes while inhibition of miR196a by anti-miR196a inhibitors increases tamoxifen resistance through the upregulation of HER and ER target genes in MCF-7 cells. Further, miRNA 196a is regulated by c-MYC which undergoes stabilization through the EGFR-HER2 signaling pathway. Depletion of c-MYC by MYC shRNA enhances tamoxifen sensitivity by increasing the level of miR196a transcripts. Also, by c-MYC ChIP assay, we found that c-MYC inhibits miR196a expression through direct binding to its promoter region.
Conclusions: Overexpression of HOXB7 is a key event in the initiation and maintenance of tamoxifen resistance. These studies suggest that HOXB7 acts as a key regulator orchestrating two major groups of target molecules, ERα and HER2, in the oncogene hierarchy. Blocking MYC expression or reexpression of miR196a in TAM-R cells may provide novel strategies for reversing SERM-resistance. Therefore, we have provided additional evidence that supports the thesis that functional antagonism of HOXB7 has the potential to circumvent tamoxifen resistance.
Citation Format: Kideok Jin, Wei Wen Teo, Takahiro Yoshida, Sunju Park, Saraswati Sukumar. HOXB7 functions as a co-activator of estrogen receptor in the development of tamoxifen resistance. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4759. doi:10.1158/1538-7445.AM2013-4759
Abstract 4761: Glial cell derived neurotrophic factor (GDNF)-RET signaling as a target in aromatase inhibitor resistant ER-positive breast cancers.
Authors: Morandi Andrea , Martin Lesley-Ann , Gao Qiong , Mackay Alan , Robertson David , Zvelebil Marketa , Dowsett Mitch , Plaza-Menacho Ivan , Isacke Clare M. 
Published: August 2014

Abstract
The majority of breast cancers are estrogen receptor (ER)-positive and depend on estrogen for growth and survival. Blockade of estrogen biosynthesis by aromatase inhibitors (AIs) is the first-line endocrine therapy for post-menopausal women with ER-positive breast cancers. Despite providing substantial improvements in patient outcome, resistance to such therapy remains a major clinical challenge. We previously showed that GDNF-RET signaling plays an important role in ER-positive breast tumors and in the response to tamoxifen treatment. Resistance to this therapy is often associated with estrogen-independent activation of ER mediated by cell surface growth factor receptors, such as RET. Here, a multidisciplinary strategy was used to address the impact of GDNF-RET signaling in the response to AI treatment. First, using 2D and 3D in vitro approaches we show that GDNF-mediated RET signaling is enhanced in a model of AI resistance. Further, GDNF-RET signaling promotes the survival of AI-resistant cells and increases resistance in AI-sensitive cells, effects that are selectively reverted by a potent RET kinase inhibitor.
Second, we generated a proliferation-independent GDNF-response gene set, identified from gene expression profiling in ER-positive breast cancer cells, and demonstrated this to be an independent prognostic marker of poor patient outcome and, importantly, to be predictive of poor response to AI treatment and development of resistance. Finally, the relevance of these findings was validated by demonstrating increased RET protein expression levels in an independent cohort of AI resistant patient samples. Together these preclinical and clinical models identify GDNF-RET signaling as a key determinant of response and resistance to AIs in ER-positive breast cancers. As a consequence, RET inhibition may be of use in the clinical setting either in combination with an AI to prevent and delay the onset of resistance, or to prolong the efficacy of the AI in the recurrent and/or metastatic setting.
Citation Format: Andrea Morandi, Lesley-Ann Martin, Qiong Gao, Alan Mackay, David Robertson, Marketa Zvelebil, Mitch Dowsett, Ivan Plaza-Menacho, Clare M. Isacke. Glial cell derived neurotrophic factor (GDNF)-RET signaling as a target in aromatase inhibitor resistant ER-positive breast cancers. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4761. doi:10.1158/1538-7445.AM2013-4761
Abstract 4766: Follicle stimulating hormone (FSH) inhibits apoptosis in ovarian cancer cell through regulating OCT4 stem cell signal pathway.
Authors: Zhang Zhenbo , Zhu Yaping , Xu Xianming , Xi Xiaowei , Bast Robert C. , Yu Yinhua , Feng Youji 
Published: August 2014

Abstract
Ovarian cancer is the most lethal malignancy of the female reproductive system with an overall mortality rate of greater than 70%. Our group has demonstrated that Follicle stimulating hormone (FSH) stimulates the proliferation and invasion of ovarian cancer cells, inhibits apoptosis, and facilitates neovascularization by increasing expression of vascular endothelial growth factor (VEGF). OCT4, a stem cell marker, is overexpressed in several types of human cancer and can induce resistance to chemotherapy and inhibition of apoptosis. We have found that FSH stimulates the expression of OCT4 mRNA and protein in a time- and dose-dependent manner. Subcellular analysis by immunofluorescent staining confirmed that FSH stimulation increased OCT4 protein expression in both the cytoplasm and nucleus of ovarian cancer cells. Re-expression of OCT4 in ovarian cancer cells reversed the inhibition of apoptosis induced by FSH, whereas siRNA-mediated knockdown of OCT4 resulted in a significantly rate of apoptosis. Depletion of OCT4 resulted in reduction of p-AKT and survivin, and also blocked FSH-induced upregulation of p-AKT and survivin. Moreover, FSH stimulation induced the expansion of CD44+CD117+ cells with a stem cell-like phenotype. Interestingly, re-expression of OCT4 enhanced the expression of Notch, Sox2, and Nanog, molecules that play critical roles in cancer stem cell proliferation and differentiation. FSH upregulated the expression of Notch, Sox2 and Nanog and these effects were abolished by knocking down OCT4, suggesting that several cancer stem cell pathways are involved in FSH regulation. We have also examined OCT4 expression in surgical specimens of ovarian cancer. Immunohistostaining revealed that OCT4 expression was increased in ovarian carcinoma compared with benign cystadenomas and borderline tumors, and OCT4 expression was significantly correlated with histological grade. Staining for OCT4 was increased in serous cystadenocarcinoma, when compared with clear cell carcinoma. In summary, the OCT4 cancer stem cell signaling pathway may mediate FSH-induced inhibition of apoptosis and could provide a target for treatment of ovarian cancer.
Citation Format: Zhenbo Zhang, Yaping Zhu, Xianming Xu, Xiaowei Xi, Robert C. Bast, Yinhua Yu, Youji Feng. Follicle stimulating hormone (FSH) inhibits apoptosis in ovarian cancer cell through regulating OCT4 stem cell signal pathway. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4766. doi:10.1158/1538-7445.AM2013-4766
Abstract 4789: Human papillomavirus genotyping in urine samples of women with squamous intraepithelial lesions of cervix.
Authors: Viscarra Tamara , Andana Alejandra , Brebi Priscilla , Menzel Doris , Ili Carmen G. , Silva Ramon , Roa Juan C. , Sanchez Raul 
Published: August 2014

Abstract
Human papillomavirus (HPV) is the most frequent microorganism sexually transmitted and is the causal agent of cervical carcinoma were it could be found in 99.7% of cases. The detection of HPV en women with or without lesions of cervix is generally performed in biopsies and cytobrush, which are invasive samples; therefore many patients do not attend to health care to get HPV test. The aim of this study was to develop a technique capable of detect and genotype HPV in urine samples of women with squamous intraepithelial lesions of cervix.
For this study, 87 urine samples from patients with normal epithelia of cervix (25), low grade squamous intraepithelial lesion (LSIL) (24), high grade squamous intraepithelial lesion (HSIL) (38) were collected from women who attended to gynecological care in a public health center in Temuco, Chile. DNA extraction was performed with a manual method. For protein precipitation, Phenol-Chloroform and ammonium acetate were used. DNA precipitation was performed with absolute ethanol. HPV detection and genotyping was performed with the kit HPV Typing (patent pending) which is capable of detect 18 more frequent HPV types and beta globin gen as control of DNA integrity.
20% of urines from normal epithelia women were positive for HPV. Three genotypes were found in normal samples: HPV52, HPV42 and HPV53. LSIL there was a 92% of HPV positivity and the most frequent genotypes were HPV16 and HPV18. In HSIL, 95% of urine sample were positive for HPV. HPV16, HPV18 and HPV31 were the most frequent genotypes in HSIL. Genotypes found in urine samples were similar to world reports.
Using the DNA extraction described before and HPV easy typing kit it is possible to detect and genotype HPV in urine samples. These results suggest that is possible a HPV primary screening test in non-invasive sample, complementing PAP smear in order to determinate which women have a higher risk of developing preneoplastic and neoplastics lesions.
Grant Support: Proyect CORFO N° 09CN14-5960 (CEGIN). CI is recipient of grants from FONDECYT Postdoctoral Proyect N° 3130630. PB is recipient of grants from FONDECYT Postdoctoral Proyect N° 3120141.
Citation Format: Tamara Viscarra, Alejandra Andana, Priscilla Brebi, Doris Menzel, Carmen G. Ili, Ramon Silva, Juan C. Roa, Raul Sanchez. Human papillomavirus genotyping in urine samples of women with squamous intraepithelial lesions of cervix. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4789. doi:10.1158/1538-7445.AM2013-4789
Abstract 4792: Analysis of the relationship between experimentally induced rodent forestomach hyperplasia and tumorigenesis.
Authors: Fritz Jason M. , Gwinn Maureen R. 
Published: August 2014

Abstract
Hyperplasia is an increase in cell number resulting from physiological processes such as irritation, or pathological processes like carcinogenesis. The difficulty in differentiating reactive versus preneoplastic (or dedicated) hyperplasia has been the subject of debate in the literature, especially in regard to prediction of human health risks following chronic chemical exposure. Squamous hyperplasia and neoplasia are frequently detected in the rodent forestomach (FS) following chronic oral administration of chemicals evaluated in rodent cancer bioassays. Molecular level mechanistic details related to FS hyperplasia progression are not available for a wide range of chemicals, despite the increasing need for this level of mechanistic understanding to support evaluations for human health risk. In order to facilitate further discussion on the use of rodent FS lesions in the estimation of cancer and noncancer reference values, a comparison of chemical hyperplasia versus tumor induction was performed. FS lesion classification and incidence data were obtained from rat and mouse gavage bioassays on over 50 chemicals from National Toxicology Program (NTP) 2-year bioassays that reported dose-related increases in FS hyperplastic or neoplastic lesions in one or more rodent sex/strain combinations tested. Chemical effects were tabulated and sorted by strain, sex, genotoxicity assay results and irritation effects, and the relationship between FS hyperplasia and FS tumor (e.g., squamous cell papilloma or carcinoma) induction was analyzed using grouped animal data. When considering chemicals with positive results in genotoxicity assays, FS tumors positively correlated with FS hyperplasia incidence in both rats and mice. Increased incidence of FS hyperplasia was not correlated with FS tumors in animals exposed to chemicals that were negative for genotoxicity and irritation. The potential results of this analysis may be useful in the evaluation of chemicals with limited chronic bioassay data by informing predictions of long-term tumor formation based on chemical properties observable during short-term animal or in vitro studies (e.g., genotoxicity, irritation).
The views expressed in this abstract are those of the authors and do not necessarily represent the views or policies of the U.S. Environmental Protection Agency.
Citation Format: Jason M. Fritz, Maureen R. Gwinn. Analysis of the relationship between experimentally induced rodent forestomach hyperplasia and tumorigenesis. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4792. doi:10.1158/1538-7445.AM2013-4792
Abstract 4794: An undesired effect of chemotherapy: gemcitabine promotes pancreatic cancer cell invasiveness through upregulation of CXCR4.
Authors: Arora Sumit , Bhardwaj Arun , Singh Seema , Srivastava Sanjeev K. , McClellan Steven , Grizzle William E. , Owen Laurie B. , Singh Ajay P. 
Published: August 2014

Abstract
Pancreatic cancer (PC) remains a therapeutic challenge with a rising incidence and unabated mortality. Gemcitabine (GEM), the current standard of care drug, is largely ineffective due to chemoresistance, thus underscoring the need for a refined understanding of the molecular mechanisms that drive drug-resistant nature of this malignancy. Recently, we have shown that CXCL12/CXCR4 signaling axis is involved in conferring chemoresistance to PC cells. Here, we explored the effect of GEM on this resistance mechanism and its functional consequences. Our data demonstrated that GEM upregulated CXCR4 expression in two PC cell lines (MiaPaCa and Colo357) in a dose- and time- dependent manner. GEM-induced CXCR4 expression was dependent on generation of reactive oxygen species (ROS) as it was abrogated upon pre-treatment of PC cells with radical scavenger N-acetyl-L-cysteine (NAC). CXCR4 upregulation by GEM correlated with time-dependent accumulation of p65/NF-κB and HIF-1α in the nucleus. An enhanced binding of p65/NF-κB and HIF-1α to the CXCR4 promoter was observed in chromatin immunoprecipitation assay in GEM-treated PC cells, while their silencing by RNA interference suppressed GEM-induced CXCR4 expression. ROS induction upon GEM treatment preceded the nuclear accumulation of p65/NF-κB and HIF-1α and suppression of ROS diminished these effects. Effect of ROS on p65/NF-κB and HIF-1α was mediated through activation of ERK1/2 and Akt and their pharmacological inhibition also suppressed GEM-induced CXCR4 upregulation. Lastly, our data demonstrated that GEM-treated PC cells were more motile and exhibited significantly greater invasiveness against a CXCL12 gradient. Altogether, these findings reinforces the role of CXCL12/CXCR4 signaling in GEM resistance and point toward an undesired effect of chemotherapy that is potentiation of invasion and spread of resistant tumor cells.
Citation Format: Sumit Arora, Arun Bhardwaj, Seema Singh, Sanjeev K. Srivastava, Steven McClellan, William E. Grizzle, Laurie B. Owen, Ajay P. Singh. An undesired effect of chemotherapy: gemcitabine promotes pancreatic cancer cell invasiveness through upregulation of CXCR4. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4794. doi:10.1158/1538-7445.AM2013-4794
Abstract 4801: Bronchoalveolar lavage fluid (BALF) from subchronic exposure to butylated-hydroxytoluene (BHT) inhibits gap junctional communication in a toll-like receptor 4-dependent manner.
Authors: Hill Thomas , Alexander Carla-Maria , Bauer Alison K. 
Published: August 2014

Abstract
Subchronic dosing of BHT in mice is a well-known model used to discretely study the tumor promotion stage of lung adenocarcinoma. Using this model, we have previously shown that functional toll-like receptor 4 (TLR4) is protective against inflammatory sequelae and primary tumor formation in the mouse lung. Gap junctional intercellular communication (GJIC) has been shown to regulate the signal transduction pathways of cells, and inhibition of this communication by toxicant exposure has been linked to dysregulation and eventual carcinogenic endpoints. As part of our research on the protective nature of TLR4 during tumor promotion, we utilized the BHT subchronic model (4 weekly i.p. doses of BHT) to examine the early effects on BALF in both BALB/c (BALB; Tlr4 sufficient) and C.C3H-Tlr4Lps-d mice (BALBLps-d-d; Tlr4 mutant). Analysis of the BALF 24 hours after the final dose for protein content and cytology was indicative of an inflammatory profile in all mice treated with BHT. Magnitude of response to BHT was highest in the BALBLps-d mice; the BALB appeared resistant. In an effort to further characterize the response of the pulmonary epithelium, the BALF samples were used to treat cultured C10 cells, a murine immortalized line derived from BALB/c alveolar type II cells, which are a precursor cell type for adenocarcinoma. Using the scrape-load dye transfer assay, a well-defined method to measure GJIC, we demonstrated marked inhibition of cellular communication after a 4 hour exposure to cell-free BALF that is both treatment and strain dependent. The direction and magnitude of effect is in parallel with that of the direct analysis of the BALF, i.e. we observed more inhibition in BALF from BALBLps-d compared to BALB mice. In addition, quantitative PCR (QPCR) analysis of C10 cells exposed to cell-free BALF for 24 hours indicates alterations in the transcription patterns in genes of innate immunity that are also treatment and strain dependent. These novel findings suggest endocrine signaling from the inflammatory milieu are complicit in the inhibition of GJIC during the promotion phase of carcinogenesis. Furthermore, these data establish a link between active gap junctions, tumor promotion, and the protective nature of TLR4 in an ex vivo model which will facilitate a mechanistic examination of these protective effects at the molecular level. Funded by ACS RSG-10-162-01-LIB (AKB).
Citation Format: Thomas Hill, Carla-Maria Alexander, Alison K. Bauer. Bronchoalveolar lavage fluid (BALF) from subchronic exposure to butylated-hydroxytoluene (BHT) inhibits gap junctional communication in a toll-like receptor 4-dependent manner. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4801. doi:10.1158/1538-7445.AM2013-4801
Abstract 4818: Type 2 diabetes mellitus and colorectal neoplasia risk in Puerto Rican Hispanics: A case-control study.
Authors: Diaz-Algorri Yaritza , Gonzalez Dilka , Lozada Maria E. , Lopez-Diaz Sofia Margarita , Hernandez Jessica , Pedrosa Carmen , Toro Doris , Criuz-Correa Marcia R. 
Published: August 2014

Abstract
Introduction: Epidemiological studies have provided inconclusive evidence regarding the potential link between type 2 diabetes mellitus (DM) and colorectal cancer (CRC).The association between type 2 DM and colorectal neoplasia (colorectal cancer and/or adenomas) has not been well studied in Hispanics, an ethnic minority at high risk for type 2 DM.The specific aim of the study was to evaluate the association between type 2 DM and colorectal neoplasia (CRN) in Puerto Rican Hispanic adults enrolled in the studies Epidemiology of Loss of Imprinting in Colorectal Cancer, Familial Colorectal Cancer Registry and the Type 2 diabetes mellitus and colorectal neoplasia risk in Hispanics: A case-control study at the VA Caribbean Healthcare System. Methods: The case-control study included patients with incident CRN and controls with negative colonoscopy and without previous history of CRC or adenomas diagnosed from January 1, 2005 to December 31, 2009. Diagnosis of type 2 DM was established by previous medical diagnosis and/or anti-diabetic medications use. Unconditional logistic regression was employed to estimate the odds ratio (OR) between type 2 DM and CRN using STATA 10.0. Results: A total of 501 participants (mean age 60.3 ± 12.6 yrs., 57.9% males), prevalence of type 2 DM was 24.8%. 323 patients with CRN and 178 controls were evaluated. In the cases, the prevalence of colorectal adenomas was 25.7% (83/323) and the prevalence of colorectal cancer was 74.3% (240/323). Cases and controls did not differ by gender (p=0.19), median age (p=0.91), family history of CRC (p=0.76) and first degree of family history of DM (p=0.49). Cases had lower education (p&lt;0.001) and reported lower use of NSAIDS (p=0.054) and physical activity (p=0.005) compared to the controls. There were no statistical significant associations between DM and CRN (OR=1.21; 95% CI: 0.79-1.87), DM and CRC (OR=1.20; 95% CI: 0.76-1.90) or DM and colorectal adenomas (OR=1.24; 95% CI: 0.68-2.27). Conclusions: We did not observe a statistical significant association between type 2 DM and CRN. Nonetheless, a tendency towards an increase risk of colorectal neoplasia was observed among type 2 DM patients. Possible explanation for our lack of association may be related to high prevalence of type 2 DM in cases and controls.
Citation Format: Yaritza Diaz-Algorri, Dilka Gonzalez, Maria E. Lozada, Sofia Margarita Lopez-Diaz, Jessica Hernandez, Carmen Pedrosa, Doris Toro, Marcia R. Criuz-Correa. Type 2 diabetes mellitus and colorectal neoplasia risk in Puerto Rican Hispanics: A case-control study. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4818. doi:10.1158/1538-7445.AM2013-4818