bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1407: A transgenic mouse model for the Hedgehog pathway effector GLI1 induced mammary gland tumors.
Authors: Norum Jens H. , Andersson Agneta , Kasper Maria , Sørlie Therese , Toftgård Rune 
Published: August 2014

Abstract
Increased expression of the Hedgehog (Hh) signaling pathway effector GLI1 in breast cancer patients has been shown to correlate inversely with disease free and overall survival. Activation of the Hh signaling pathway is known to promote proliferation of breast cancer cells and stimulate mammosphere formation. In addition, the Hh signaling pathway has been reported activated in CD44 positive breast cancer stem cells. Despite the evidence supporting a role for Hh signaling in breast cancer development and maintenance, the model systems to study the Hh pathway in breast carcinogenesis are limited.
We used a transgenic mouse model to show that GLI1 expression in the mammary gland cause tumor formation. The GLI1 induced primary tumors showed different histological characteristics, suggesting that the GLI1 expression influenced the tumor initiating cells. The GLI1 induced primary tumors were orthotopically transplanted on NOD/SCID mice and we have established serial transplantable tumor lines. The different histological characteristics of the individual primary tumors have been maintained for &gt;10 serial transplantations in NOD/SCID mice. The stem cell marker CD44 is expressed in the mouse mammary gland ducts. The CD44 positive cell population is increased in the GLI1 induced tumors. The G protein coupled receptor (GPCR) like protein Lgr5 has been suggested as a stem cell marker in several tissues, including mammary gland. We show that cells in the basal layer of the adult mammary gland ducts express Lgr5. The Lgr5 positive cell population is increased in the GLI1 induced tumors, suggesting a basal like characteristic of these tumors.
Taken together, our data show that expression of GLI1 in the mammary gland result in formation of mammary gland tumors with heterogeneous histological characteristics. The cell populations identified by the stem cell markers CD44 or Lgr5 are increased in the GLI1 induced tumors compared with the normal mammary gland. Furthermore, we have established serial transplantable GLI1 induced mammary gland tumor lines. These serial transplantable tumor lines are novel tools to address the role of GLI1 expression in breast carcinogenesis.
Citation Format: Jens H. Norum, Agneta Andersson, Maria Kasper, Therese Sørlie, Rune Toftgård. A transgenic mouse model for the Hedgehog pathway effector GLI1 induced mammary gland tumors. [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 1407. doi:10.1158/1538-7445.AM2013-1407
Abstract 1428: Bone marrow adipocyte-derived CXCL1 and CXCL2 in prostate tumor progression in bone.
Authors: Hardaway Aimalie L. , Herroon Mackenzie M. , Rajagurubandara Erandi N. , Podgorski Izabela 
Published: August 2014

Abstract
Prostate cancer (PCa) is the second most common cause of death from cancer in men. Bone is a primary site for tumor metastasis and obese and overweight men have a three-fold higher risk of progression to metastatic disease compared to normal-weight men receiving the same treatment. Recent epidemiological evidence suggests that obesity is an independent prognostic contributor to the development of distant metastases and death from PCa. Obesity leads to adipocyte accumulation within the bone marrow, which stimulates infiltration of inflammatory cells, particularly macrophages, and promotes inflammation. Many of the inflammatory cytokines released by both adipocytes and macrophages are involved in increased tumor growth, neovascularization, and cell survival. CXCL1 and CXCL2 are two such chemokines that have been implicated in prostate, breast, and ovarian tumorigenesis. Therefore, we hypothesized that obesity-induced bone marrow adiposity and inflammation would alter prostate tumor behavior in the bone via CXCL1- and CXCL2-dependent mechanisms. Histological evaluations confirmed that mice fed high fat diet (HFD) had increased adipocyte accumulation within the bone. PC3-DsRed cells intratibially injected into HFD mice progressed strikingly faster and grew much larger than those injected into mice on normal (LFD) diet. RT PCR analyses revealed an induction of several inflammatory genes, including CXCL1 and CXCL2, in the marrow of obese mice, and these levels were further increased in tumor-bearing tibiae of HFD hosts. In vitro short-term exposure of tumor cells to media conditioned by primary bone marrow derived adipocytes (Adipo CM) led to increased growth and invasiveness. This effect was further potentiated by chronic exposure to Adipo CM. CXCL1 and CXCL2 expression and secretion increased in co-culture of tumor cells with bone marrow macrophages in the presence of adipocyte-derived factors. Studies are currently underway to determine the role of obesity-induced marrow CXCL1 and CXCL2 in osteoclastogenesis and bone resorption. We are also investigating additional inflammatory mediators that sustain the upregulation of CXC1 and CXCL2 in the tumor microenvironment. Collectively, the results of our studies demonstrate that adipocyte-induced upregulation of CXCL1 and CXCL2 may play a critical role in promoting prostate tumor aggressiveness and survival in the bone metastatic niche.
Citation Format: Aimalie L. Hardaway, Mackenzie M. Herroon, Erandi N. Rajagurubandara, Izabela Podgorski. Bone marrow adipocyte-derived CXCL1 and CXCL2 in prostate tumor progression in bone. [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 1428. doi:10.1158/1538-7445.AM2013-1428
Abstract 1431: Upregulation of CXCR2 and its ligands in KRAS oncogene-induced initiation of pancreatic cancer.
Authors: Purohit Abhilasha , Varney Michelle , Rachagani Satya , Ouellete Michelle , Batra Surinder K. , Singh Rakesh K. 
Published: August 2014

Abstract
Pancreatic cancer (PC) is considered the fourth leading cause of cancer-related deaths in the United States. The high mortality-to-incidence ratio for the disease can be attributed to late clinical presentation. Thus, the detection of early markers of this disease remains a major challenge in the field of PC research. Somatic mutations in oncogene KRAS are the most common and earliest events during development of PC, suggesting their crucial role in tumor initiation; however, the precise functional molecular mechanism of action remains poorly understood. CXCR2, a CXC chemokine receptor, and its ligands have also been found to be important in regulating angiogenesis and metastasis. Their enhanced expression is observed as early as the precursor lesions of PC. The objective of this study was to investigate the role of CXCR2 signaling in the KRAS(G12D)-induced PC development. To validate that mutant KRAS(G12D) is essential for this increased secretome, studies were performed using two cell line models having both exogenous and endogenous expression of mutant KRAS(G12D): Htert-HPNE-E6-E7-st/KRAS(G12D), which is an immortalized pancreatic duct-derived cell line having exogenous expression of mutant KRAS (G12D), and CD18/HPAF KRAS (G12D) -scram/Sh, which is a tumor-derived cell line. The endogenous expression of mutant KRAS (G12D) was silenced by stable expression of Sh-RNA specific to the KRAS(G12D) allele. Real time PCR, ELISA and western blot analysis of these cells revealed that mutant KRAS (G12D) regulates the expression of CXCR2 and its ligands at both transcription and protein levels. We observed an enhanced expression of the CXCR2 and its ligands in Htert-HPNE-E6-E7-st-KRAS(G12D) cells. Interestingly, stable knock-down of KRAS in CD18/HPAF-shKRAS(G12D) cells upregulated CXCR2 expression, but inhibited the expression of its ligands. In addition, immunohistochemical analysis of PC lesions from Pdx-cre-LSL-KRAS (G12D) mice showed a higher expression of both receptor and its ligands as the lesions progress to advanced stages. Taken together, these results suggest that KRAS effector pathways are essential for modulating the expression of CXCR2 and its ligand, which, in turn, can mediate cellular- responses in PC growth and progression.
Citation Format: Abhilasha Purohit, Michelle Varney, Satya Rachagani, Michelle Ouellete, Surinder K. Batra, Rakesh K. Singh. Upregulation of CXCR2 and its ligands in KRAS oncogene-induced initiation of pancreatic cancer. [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 1431. doi:10.1158/1538-7445.AM2013-1431
Abstract 1439: Periostin expression is altered by TGF and hypoxia during breast cancer progression.
Authors: Coleman Michelle , Lance Amanda , Ricci Krista , Secrest Adam , Dréau Didier 
Published: August 2014

Abstract
The extracellular matrix (ECM) contributes to the generation of normal breast tissue, and variations in the composition of the ECM have been shown to directly influence the formation and organization of acinus-like and duct-like structures. Specific ECM proteins are also important in the progression of several human cancers, and in particular upregulation of the ECM protein periostin has been linked to poor outcomes in breast cancer. Here we investigated the expression of periostin in biopsy specimens collected from breast cancer patients, as well as determined the differential effects of TGFß and hypoxia on the expression of periostin mRNA and protein in human breast cancer cells. Immunohistological analyses of the breast cancer biopsy specimens indicate that breast cancer tissues expressed different levels of periostin regardless of the stage of the disease and that the expression of periostin tended to decrease as breast cancer progressed. Multiple splice variants of periostin mRNA were expressed by breast cancer cells as determined by RT-PCR. Furthermore, treatments with either TGFß or hypoxia led to significantly different expression of periostin mRNA isoforms and of total level of periostin protein (p&lt;0.05) by breast tumor cells. These observations support the role of periostin in breast cancer progression and suggest a role for specific periostin isoforms in response to changes in the microenvironment including tissue hypoxia and TGFß paracrine signaling from mesenchymal and immune cells.
[This works is supported by grants from the Department of Defense Era of Hope research program (BC044778) and the National Science Foundation EFRI program (CBE0736007)]
Citation Format: Michelle Coleman, Amanda Lance, Krista Ricci, Adam Secrest, Didier Dréau. Periostin expression is altered by TGF and hypoxia during breast cancer progression. [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 1439. doi:10.1158/1538-7445.AM2013-1439
Abstract 145: Finding correlations between CtBP expression and breast cancer risk factors.
Authors: Obadina Mofiyinfoluwa A. 
Published: August 2014

Abstract
In women, breast cancer is ranked second in cancer deaths; almost 40,000 deaths are expected and over 225,000 new cases are expected. Research has shown that breast cancer prevalence and mortality are influenced by various factors including race and lifestyle. Studies have indicated racial disparity whereby young women of African descent have higher breast cancer mortality rate and this could be partly explained by higher occurrence of more aggressive breast cancer forms that exhibit characteristics of epigenetically re-programmed reactivation of embryonic processes that promote tumor invasion, spread and resistance to chemotherapy. These are features common to certain breast cancer subtypes including basal-like and triple negative breast cancers, which occur more frequently in younger African American women. We are focusing on epigenetic factors that explain this disparity as this understanding will help provide population-based approach to detecting and treating breast cancer.
C-terminal Binding Protein (CtBP) is a family of epigenetic regulators that undergoes dimerization which is stimulated and stabilized by NADH, a product of metabolism. CtBP has been shown to induce epithelial-to-mesenchymal transition (EMT), an embryonic program that increases tumor invasion and metastasis; we therefore hypothesize that CtBP likely plays a role in tumor progression. Research from our lab has shown an elevated level of CtBP present in the nuclei of more clinically aggressive breast cancer subtypes..
To find the correlation between CtBP expression and other patient factors such as race, age, BMI and hormone receptor status we have begun to screen several breast cancer patient cohorts obtained from larger minority serving medical centers around the country. Our preliminary findings reveal that elevated levels of CtBP expression in patient tumor samples shows a statistically significant correlation with shortened median survival. Moreover, random sampling of a small population of these cohorts suggests that the correlation between CtBP and poor clinical outcome is greater in women of African heritage compared to European descent. How epithelial features and stromal attributes of the tissue microenvironment contribute to this correlation is currently under investigation.
Citation Format: Mofiyinfoluwa A. Obadina. Finding correlations between CtBP expression and breast cancer risk factors. [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 145. doi:10.1158/1538-7445.AM2013-145
Abstract 1455: In vivo circulating tumor cells in blood, lymph and cerebrospinal fluid: dynamic cross-correlations and amplification for cancer diagnosis.
Authors: Galanzha Ekaterina I. 
Published: August 2014

Abstract
We introduced a new platform of multicolor multi-fluid in vivo flow cytometry for real-time ultrasensitive molecular detection and counting of circulating tumor cells (CTCs) and their subpopulations the blood, lymph and cerebrospinal fluid's (CSF) flows. To achieve these goals we integrated multicolor photoacoustic (PA), photothermal (PT) and fluorescent flow cytometry, and combined this technical platform with multiplex molecular targeting strategy using low-toxicity, gold-based functionalized nanoparticles as PA/PT high-contrast agents or genetically encoded proteins (e.g., green fluorescent protein [GFP]) as fluorescent labels. This platform can provide also label-free detection mode using intrinsic (e.g., melanin) molecular labels. The advantages of this new generation of flow cytometries are (1) improving sensitivity by at least a two-order of magnitude compared to available CTC-assays, and (2) significantly extending biomedical applications compared to existing in vivo flow cytometries.
Using preclinical tumor-bearing mouse models of metastatic melanoma and breast cancer, and spiked human blood samples, we demonstrated that our technology can overcome great challenge in cancer research related to monitoring lymph, CSF and blood CTCs at single-cell levels in the natural environment in vivo over the long-term period of metastatic disease development from an early micrometastatic stage to deadly multiple macro-metastases. The obtained results allowed us to estimate in vivo cross-correlations between lymph, CSF and blood CTC counts, size of primary tumor and metastasis (micrometastasis) progression. We also showed that the presented approach can break some important diagnostic limitations of existing methods (e.g., low sensitivity) and potentially permits prevention, or at least inhibition, of metastatic progression. Taking into account the safe nature of the PA technology, we anticipate its quick translation for use in humans.
Citation Format: Ekaterina I. Galanzha. In vivo circulating tumor cells in blood, lymph and cerebrospinal fluid: dynamic cross-correlations and amplification for cancer diagnosis. [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 1455. doi:10.1158/1538-7445.AM2013-1455
Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.
Abstract 1472: Assessment of CTC-based pharmacodynamic biomarkers in NCI clinical trials of targeted anticancer therapeutics.
Authors: Wang Lihua H. , Kummar Shivaani , Pfister Thomas D. , Balasubramanian Priya , Parchment Ralph E. , Tomaszewski Joseph E. , Doroshow James H. , Kinders Robert J. 
Published: August 2014

Abstract
Circulating tumor cells (CTC) potentially represent a substitute for biopsy in assessing drug effects on targets. We have previously reported development and validation of CTC-based pharmacodynamic (PD) biomarker assays that directly examine drug-induced responses (e.g. a DNA damage marker γH2AX, and a tumor suppressor marker p16/INK4a). Here, we summarize our results to date and assess utility of CTC-based biomarkers in patients undergoing clinical trials of targeted anti-cancer therapeutics. Across eight NCI Phase 1 and 2 trials in a variety of solid tumors, the portion of the population statistically evaluable is approximately 30% for all trials; the CTC biomarker statistical evaluation is limited by the total number of CTCs collected from each tube of blood. From data obtained from multiple trials of topoisomerase1 and PARP inhibitors, the γH2AX-positive CTC baseline level was less than 20% in 34 of 50 patients. The fraction of CTCs expressing γH2AX independent of changes in the total CTC count, increased in patients following treatment with different topoisomerase 1 inhibitors alone or in combination with other drugs. Furthermore, correlations between γH2AX levels and overall responses were demonstrated in patients with refractory cancer in a phase II randomized trial of the combination of Veliparib with metronomic oral cyclophosphamide. Pharmacodynamic studies measuring re-expression of the tumor suppressor p16 in response to the epigenetic therapy regimen of 5-fluoro-2-deoxycytidine plus tetrahydrouridine yielded similar results on the number of patients evaluable using CTCs in the NCI intramural patient population. Given the limitations of surface molecule-based CTC methods, we are developing and evaluating an antibody-independent CTC capture technology to analyze biomarkers, starting in small animals using lower blood volumes and in patients with a variety of advanced epithelial and non-epithelial cancers. Our studies indicate that assessment of CTC-based PD biomarkers has value for rapidly assessing proof of mechanism in the clinical development of molecularly targeted anticancer therapeutics. Funded by NCI contract # HHSN261200800001E
Citation Format: Lihua H. Wang, Shivaani Kummar, Thomas D. Pfister, Priya Balasubramanian, Ralph E. Parchment, Joseph E. Tomaszewski, James H. Doroshow, Robert J. Kinders. Assessment of CTC-based pharmacodynamic biomarkers in NCI clinical trials of targeted anticancer therapeutics. [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 1472. doi:10.1158/1538-7445.AM2013-1472
Abstract 1475: Mutant p53 is a regulator of NADPH-oxidase 4 (Nox4) in TGF-beta-mediated migration of human lung and breast epithelial cells.
Authors: Boudreau Howard E. , Casterline Benjamin W. , Burke Devin J. , Leto Thomas L. 
Published: August 2014

Abstract
The epithelial-to-mesenchymal transition (EMT) leads to development of increased cell plasticity that occurs normally during wound healing and embryonic development and can be coopted for cancer invasion and metastasis. TGF-beta induces EMT but the mechanism is unclear. We have previously shown that Nox4, a member of the NADPH oxidase (Nox) family, is a source of reactive oxygen species (ROS) affecting cell migration and fibronectin expression, an EMT marker, in normal and metastatic breast epithelial cells. Recent studies have shown that p53 plays an important role in TGF-beta-mediated signaling and epithelial cell migration. Our current study investigates whether p53 is mechanistically involved in TGF-beta-regulated Nox4 expression and cell migration. Our results indicate that wild-type p53 is a potent suppressor of TGF-beta-induced Nox4 expression, ROS production, and cell migration. In contrast, expression of tumor-associated mutant p53 proteins (R175H or R280K) correlated with enhanced Nox4 expression and cell migration in a TGF-beta dependent manner. Furthermore, knockdown of the endogenous p53 mutant (R280K) in MDA-MB-231 cells by p53-targeted siRNA resulted in decreased Nox4 protein as well as phosphorylated Src and FAK proteins. TGF-beta treatment of MDA-MB-231 cells overexpressing a dominant-negative form of Nox4 also showed a decrease in phosphorylated Src and FAK proteins, thereby indicating mutant p53 (R280K) and Nox4 are regulators of Src and FAK activity. Collectively, our findings suggest important physiological functions for both wild type and mutant p53 proteins in regulating Nox4-dependent signaling in TGF-beta-mediated cell migration.
Citation Format: Howard E. Boudreau, Benjamin W. Casterline, Devin J. Burke, Thomas L. Leto. Mutant p53 is a regulator of NADPH-oxidase 4 (Nox4) in TGF-beta-mediated migration of human lung and breast epithelial cells. [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 1475. doi:10.1158/1538-7445.AM2013-1475