bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B068: Inhibition of GSK-3: A novel therapeutic approach for breast cancer treatment
Authors: Ugolkov Andrey , Gaisina Irina , Malin Dmitry , Kulesza Peter , Kozikowski Alan , Cryns Vincent , Mazar Andrew 
Published: May 2015

Abstract
NF-kappaB is known to regulate human breast cancer progression, metastasis and chemoresistance. Glycogen Synthase Kinase-3beta (GSK-3beta), a serine/threonine protein kinase, is an essential positive regulator of NF-kappaB transcriptional activity and thereby GSK-3beta may represent a potential therapeutic target in human breast cancer. Our objectives were to determine the expression pattern of GSK-3beta in human breast cancer, to assess the effect of GSK-3 inhibition on breast cancer cell proliferation, survival and chemoresistance, and to evaluate our lead GSK-3 inhibitors alone and in combination with chemotherapeutic drugs for the targeted therapy of breast cancer. Using nuclear/cytosolic fractionation, Western immunoblotting and immunohistochemical staining, we observed aberrant nuclear accumulation of GSK-3beta in five breast cancer cell lines and in 7 of 8 primary human breast carcinomas and corresponding lymph node metastases whereas no detectable expression of GSK-3beta was found in benign breast tissue. Pharmacological inhibition of GSK-3 led to a decrease in proliferation and survival of breast cancer cells. Our in vitro comparison studies demonstrated that our lead GSK-3 inhibitor 9-ING-41 was significantly (30 times) more effective than GSK-3 inhibitor LY2090314 (Eli Lilly), currently in mid-stage clinical trials, in terms of growth inhibition of breast cancer cells. Inhibition of GSK-3 resulted in decreased expression of the NF-kappaB target genes Bcl-2 and XIAP and induction of apoptosis. Moreover, our lead GSK-3 inhibitor 9-ING-41 and doxorubicin acted synergistically to suppress growth of breast cancer cells. Our preliminary in vivo experiments demonstrated that monotherapy with our lead GSK-3 inhibitor 9-ING-41 (20 mg/kg) for 48 hours inhibited proliferation (as shown by BrDU assay) and induced apoptosis (as shown by TUNEL assay) in MDA-MB-468 orthotopic xenograft tumors. Moreover, in vivo toxicology study demonstrated that intravenous injections of 9-ING-41 did not adversely affect mouse complete blood counts or cause overt pathological changes in mouse organs. Our results identify GSK-3beta as a new potential drug target in breast cancer and suggest that inhibition of GSK-3 is a novel therapeutic approach to overcome NF-kappaB-mediated chemoresistance in breast cancer.
Citation Format: Andrey Ugolkov, Irina Gaisina, Dmitry Malin, Peter Kulesza, Alan Kozikowski, Vincent Cryns, Andrew Mazar. Inhibition of GSK-3: A novel therapeutic approach for breast cancer treatment. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research: Genetics, Biology, and Clinical Applications; Oct 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2013;11(10 Suppl):Abstract nr B068.
Abstract B082: Role of CD44v6 in acquired resistance to anti-angiogenic therapy of triple-negative breast cancer
Authors: Morello Virginia , Ginestier Christophe , Charafe-Jauffret Emmanuelle , Michieli Paolo 
Published: May 2015

Abstract
Triple-negative breast tumors do not offer many therapeutic opportunities beyond chemotherapy. Lately, new hope for the treatment of this type of cancer has been brought by anti-angiogenic agents. However, clinical trials showed that, although angiogenesis inhibitors increase progression-free survival of triple negative cancer patients, they do not improve overall survival, suggesting the occurrence of acquired resistance. Understanding the molecular mechanisms underlying resistance to angiogenesis inhibitors is an important step towards the development of therapies that prevent this process. Using a vital library of human primary breast cancers, we developed an orthotopic mouse model of triple negative carcinoma that allows studying acquired resistance to angiogenesis inhibitors in a controlled setting. This model unveiled that anti-angiogenic drugs reduce tumor growth on one hand but enhance metastasis on the other. FACS analysis of tumor cells revealed that angiogenesis inhibitors enrich for cells expressing CD44v6, a splice variant of the trans-membrane glycoprotein CD44. Expression of CD44v6 has been associated with tumor invasion and metastasis in a variety of human cancers, including breast. Furthermore, CD44v6 has been shown to be a co-receptor for Hepatocyte Growth Factor (HGF) and to be essential for the activation of c-Met, a master regulator of invasive growth. Interestingly, treatment with HGF/Met inhibitors reduced tumor growth, prevented selection of CD44v6+ cells and suppressed angiogenesis inhibitor-induced metastasis. These results point at a causative role of CD44v6 in acquired resistance to anti-angiogenic therapy and suggest the opportunity of combining HGF/Met inhibitors with anti-angiogenic drugs.
Note:This abstract was not presented at the conference.
Citation Format: Virginia Morello, Christophe Ginestier, Emmanuelle Charafe-Jauffret, Paolo Michieli. Role of CD44v6 in acquired resistance to anti-angiogenic therapy of triple-negative breast cancer. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research: Genetics, Biology, and Clinical Applications; Oct 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2013;11(10 Suppl):Abstract nr B082.
Abstract B087: HER-2/neu expression regulates the immune response and tumor senescence in breast cancer
Authors: Rosemblit Cinthia , Cintolo-Gonzalez Jessica , Xu Shuwen , Czerniecki Brian J. 
Published: May 2015

Abstract
Background: Over-expression of the receptor tyrosine kinase ErbB2 (HER-2) has been widely implicated in malignant transformation, cell survival, motility and invasion in breast cancers. Intermediate expression of HER-2 has been identified in luminal breast cancer stem cells. HER-2 over-expression down regulates major histocompatibility complex class I molecules (MHCI) expression in breast cancer cells.
Results: We investigated the expression of HER-2 in various HER-2 expressing cell lines and measured HLA A-2 MHC class I expression. High Her-2 expressing cell lines SKBR3 and SKOVA3 and intermediate expressing cell lines MCF7 demonstrated extremely low HLA A-2 expression, while low Her-2 expressing MDAMB231 demonstrated low HER-2 expression and high HLA A2 expression. Anti-HER-2 CD8 T cells recognize the latter cells but not high or intermediate expressing HER-2 expressing cells. Treatment of intermediate expressing cell lines but not high HER-2 expressing cells with interferon-gamma; (IFN- gamma) and TNF-alpha; result in markedly increased HLA A2 expression and 3 fold increase in CD8 T cell killing of the MCF7 cells. Treatment of high expressing HER-2 cells with trastuzumab but not lapatinib decreased HER-2 expression and combined with IFN-gamma; and TNF-alpha; result in increased HLA- A2 expression and dramatic increase in CD8 T cell recognition. In contrast, high and intermediate HER-2 expressing cells are sensitive to lysis and tumor senescence induction when treated with combinations of IFN-gamma; and TNF-alpha; in a dose dependent manner. Low HER-2 expressing cells are less sensitive to senescence induction.
Conclusions: In conclusion, our results establish a potential role for HER-2 in regulating the immune response against breast cancer and suggest that CD8 T cells are more effective in eliminating low and intermediate HER-2 expressing cells while CD4 T cell derived IFN-gamma; and TNF-alpha; together with trastuzumab may be more effective in eliminating high expressing HER-2 breast cancer cells and inducing tumor senescence preventing recurrence.
Citation Format: Cinthia Rosemblit, Jessica Cintolo-Gonzalez, Shuwen Xu, Brian J. Czerniecki. HER-2/neu expression regulates the immune response and tumor senescence in breast cancer. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research: Genetics, Biology, and Clinical Applications; Oct 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2013;11(10 Suppl):Abstract nr B087.
Abstract B091: Analysis of glial activation in a murine model of brain metastatic breast cancer
Authors: Shapovalov Yuriy , Amico-Ruvio Stacy A. , Spielman Sara C. , Lamantia Cassandra E. , Brown Edward B. , Majewska Ania K. 
Published: May 2015

Abstract
Brain metastasis represents a particularly challenging complication of breast cancer. It is estimated that in certain populations of cancer patients, approximately 10-15% have symptomatic brain metastases and as many as 30% reveal metastases on autopsy. The brain provides a unique microenvironment for tumor growth. It is a particularly difficult therapeutic target due to the complexity of brain function as well as the reduced access of therapeutic agents through the blood brain barrier (BBB). In fact, many of the newest and most effective treatments for primary breast cancer are ineffective in treating tumor metastases in the brain. It is becoming increasingly clear that prevention and treatment of brain metastatic breast cancer requires development of new, brain-specific treatments which can take into account this unique metastatic milieu and exploit innate mechanisms to fight tumor cell seeding, extravasation, and growth in the brain.
In this study, we characterized pattern of glial activation in a murine model of brain metastatic breast cancer. We used a human breast adenocarcinoma cell line, MDA-MB-231BR-GFP, that exhibits selective metastatic tropism toward the brain. Three weeks after intracardiac injection of the cells into Nu/Nu mice, we observed the development of brain metastases. Using immunohistochemistry, we analyzed expression of glia-specific markers in the immediate vicinity of and away from metastatic breast tumors. We discovered that microglia and astrocytes are activated in the areas adjacent to tumor cells. The degree of activation diminishes considerably away from the tumors.
The experimental data provide an insight into the pattern of glial activation in the setting of brain metastatic breast cancer. The results of our experiments also necessitate additional studies to improve our understanding about breast tumor metastasis to the brain. We are currently investigating mechanisms whereby glial activation may promote increased metastatic seeding of breast cancer cells. Our research focus has been on pro-inflammatory markers as potential mediators of glial activation on the entry of cancer cells to the brain. In addition, we have been examining possible contribution of glia in the disruption of the BBB and the increase in brain metastasis of breast cancer. These results provide a starting point for evaluating whether glia may directly contribute to breast cancer metastasis to the brain.
Citation Format: Yuriy Shapovalov, Stacy A. Amico-Ruvio, Sara C. Spielman, Cassandra E. Lamantia, Edward B. Brown, III, Ania K. Majewska. Analysis of glial activation in a murine model of brain metastatic breast cancer. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research: Genetics, Biology, and Clinical Applications; Oct 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2013;11(10 Suppl):Abstract nr B091.
Abstract B092: Beta-blockade of breast cancer metastasis: Receptor regulation and downstream signaling pathways
Authors: Chai Ming Gene , Le Caroline P. , Creed Sarah J. , Finnin Benjamin A L , Pimentel Matthew A. , Shackleford David , Moeller Andreas , Haviv Izhak , Lane J. Robert , Sloan Erica K. 
Published: May 2015

Abstract
Chronic stress accelerates breast cancer metastasis through beta-adrenergic signaling and recent clinical studies found that beta-blockade reduced metastasis in women with breast cancer. However, the specific beta-adrenergic receptor subtype(s) through which stress-responsive neurotransmitters mediates effects on cancer remain unknown. To identify the receptor that transmits beta-adrenergic signaling to primary mammary tumors, we used bioluminescence imaging to longitudinally quantify the effect on metastasis of beta-blockers that selectively inhibit beta1 vs. beta 2 adrenergic receptors in an orthotopic mouse model of breast cancer progression. Non-specific beta-blockade with propranolol reduced metastasis by &gt;90% (p = .03), confirming a key role for beta-adrenergic signaling pathways in stress-enhanced metastasis. Treatment with the beta2-selective antagonist ICI118551 similarly reduced stress-enhanced metastasis to control levels. In contrast, beta-1 selective blockade failed to protect against metastasis. Pharmacological intervention studies and gene expression analyses have started to define the downstream signaling pathways of beta-adrenergic regulation of metastasis. These studies may provide mechanistic explanation for recent clinical findings that not all beta-blockers protect against metastasis and provide a framework for selection of cancer patients who may optimally benefit from beta-blockade.
Citation Format: Ming Gene Chai, Caroline P. Le, Sarah J. Creed, Benjamin A L Finnin, Matthew A. Pimentel, David Shackleford, Andreas Moeller, Izhak Haviv, J. Robert Lane, Erica K. Sloan. Beta-blockade of breast cancer metastasis: Receptor regulation and downstream signaling pathways. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research: Genetics, Biology, and Clinical Applications; Oct 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2013;11(10 Suppl):Abstract nr B092.
Abstract B100: Subtype specific expression of HRH1 contributes to increased chemoresistance of breast cancer cells
Authors: Mancino Mario , Fernandez-Nogueira Patricia , Enreig Estel , Ametller Elisabet , Gascón Pedro , Almendro Vanessa 
Published: May 2015

Abstract
Background: Histamine is a monoamine produced by α-decarboxylation of histidine by the enzyme histidine decarboxylase (HDC). Histamine acts as an autocrine regulator of cell proliferation through its binding to HRH1-4 receptors. In breast cancer (BC), there are controversial results about the therapeutic efficacy of HRH1 or HRH2 inhibitors and the role of histamine receptors in tumor progression.
Given the phenotypic heterogeneity of BC and the presence of different molecular subtypes with different clinical outcome, we aimed to investigate the contribution of histamine receptors in the proliferation, migration and cell survival of BC cells of different molecular subtypes.
Methods: The expression of histamine receptors HRH1-4 and HDC in human breast tumors of different subtypes, and their correlation with clinical variables were gathered through informatics analysis using the “Gene expression based Outcome for Breast cancer Online” (GOBO) web-based tool. The measurement of the mRNA levels of HRH1-4 and HDC in a panel of breast cancer cell lines was used to confirm the subtype specific expression of each protein. Using specific HRH inhibitors in luminal and basal-like breast cancer cell lines we assessed the functional role of histamine receptors in cell proliferation, migration and survival.
Results: HRH1 was highly expressed in ER+ tumors while HDC was highly expressed in the ER- tumors. In any case, the high expression of HRH1 or HDC was significantly correlated with lower overall survival only in ER+ tumors. The same pattern of expression was observed in BC cell lines, where HRH1 was highly expressed in basal-like BC cells compared to the luminal ones. HRH2 and HRH3 were highly expressed in the estrogen-dependent MCF7 cell line, while HRH4 was not detected in any breast cancer cell line. Only the antagonism of HRH1 induced apoptosis, and decreased proliferation and migration, while HRH2 or HRH3 inhibition had no effect on cell survival. Interestingly, the luminal cell lines were more sensitive than the basal-like cell lines to HRH1 antagonism, even though the low expression of HRH1 in these cells.
Conclusion: Taken together, these findings suggest a complex role of the autocrine histamine signaling system in the progression of BC tumors of different subtype through the activation of HRH1.
Citation Format: Mario Mancino, Patricia Fernandez-Nogueira, Estel Enreig, Elisabet Ametller, Pedro Gascón, Vanessa Almendro. Subtype specific expression of HRH1 contributes to increased chemoresistance of breast cancer cells. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research: Genetics, Biology, and Clinical Applications; Oct 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2013;11(10 Suppl):Abstract nr B100.
Abstract B107: STAT3-induced production of hyaluronan contributes to FGFR-induced migration, proliferation, and therapeutic resistance in breast cancer
Authors: Bohrer Laura , Chuntova Polly , McCarthy James , Schwertfeger Kaylee 
Published: May 2015

Abstract
Aberrant activation of fibroblast growth factor receptors (FGFRs) has been linked to breast cancer growth and progression. FGFR activation in tumor cells acts through both autocrine and paracrine mechanisms to contribute to tumor growth. Our previous studies suggesting that FGFR activation leads to increased inflammation led us to evaluate the mechanisms that drive FGFR-induced inflammation in the tumor setting. We demonstrate here that FGFR activation leads to phosphorylation of STAT3Tyr705 in a number of breast cancer cell lines. Furthermore, we demonstrate that phosphorylation of STAT3Tyr705 is mediated indirectly through FGFR-induced production of IL-6 family cytokines. Using a novel in vivo model of FGFR-dependent tumor growth, we demonstrate that pharmacological inhibition of STAT3 leads to decreased FGFR tumor growth. Further examination of the function of STAT3 in this model revealed that STAT3 regulates expression of hyaluronan synthase 2 (Has2) and subsequent production of the extracellular matrix component hyaluronan (HA). Increased HA production by the tumor cells was found to contribute to FGFR-induced proliferation, migration and therapeutic resistance. Finally, analysis of human breast cancer samples reveals a correlation between activated FGFR signaling and tumor-associated expression of HA. In conclusion, our studies demonstrate that FGFR activation leads to STAT3 activity, which regulates expression of Has2 and production of tumor cell-derived HA. Together, these results identify a novel pathway by which FGFR induces proinflammatory signaling pathways and modifies the microenvironment, leading to enhanced FGFR-induced tumor growth.
Citation Format: Laura Bohrer, Polly Chuntova, James McCarthy, Kaylee Schwertfeger. STAT3-induced production of hyaluronan contributes to FGFR-induced migration, proliferation, and therapeutic resistance in breast cancer. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research: Genetics, Biology, and Clinical Applications; Oct 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2013;11(10 Suppl):Abstract nr B107.
Abstract B118: An efficient resource to accelerate research into the cause and prevention of breast cancer: The Love Army of Women
Authors: Love Susan M. 
Published: May 2015

Abstract
Background: It is well established that more research into the cause and prevention of breast cancer is needed. While studies are done in cell lines and lab animals, translation of findings to women is often delayed due to difficulty in recruitment. To address this problem, the Dr. Susan Love Research Foundation formed the Love Army of Women (AOW); an on-line recruitment resource designed to partner women with researchers in order to accelerate breast cancer research.
Methods: Researchers submit a proposal to the Dr. Susan Love Research Foundation's Scientific Advisory Committee. If a study is accepted, a mass e-mail describing the study procedures and inclusion/exclusion criteria is sent to the entire AOW database. Women sign up at www.armyofwomen.org to join and receive AOW e-mails about breast cancer research studies. Women self-select based on interest and study criteria, and undergo a secondary on-line screening before contact information is passed on to the researcher for the enrollment process.
Results: Over 373,000 women have signed up, including survivors and women without a history of breast cancer, ranging from ages 18 to 100, representing all 50 US states and 49 countries. To date, the AOW has recruited for 76 studies. The diversity of the AOW members has proved beneficial for many studies, such as those needing to enroll racial/ethnic minorities, women of varying sexual orientations, or young survivors.
A secondary goal of the AOW is to assist researchers new to research with human subjects. The AOW has successfully helped researchers cross the chasm, coaching them on what it takes to transition their research from animal models to human subjects.
Conclusions: The AOW has proved to be a successful resource for scientists to accelerate accrual, expand the number and diversity of their subject population and to obtain exactly the type of specimens they need when they need it. This partnership between women and scientists has revolutionized research and accelerated efforts to eradicate breast cancer. The public is ready and willing to partner with the research community to find the answers to urgent clinical problems.
Citation Format: Susan M. Love. An efficient resource to accelerate research into the cause and prevention of breast cancer: The Love Army of Women. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research: Genetics, Biology, and Clinical Applications; Oct 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2013;11(10 Suppl):Abstract nr B118.
Abstract B133: Metalloprotease-disintegrin ADAM12-L in breast cancer cells: Regulation of expression by microRNA-200b/c
Authors: Duhachek-Muggy Sara , Zolkiewska Anna 
Published: May 2015

Abstract
ADAM12-L, a member of the cell surface ADAM metalloprotease family, is selectively up-regulated in claudin-low breast cancers and in residual breast tumors after conventional therapy. In vitro, ADAM12-L is enriched in breast cancer cells grown in suspension as mammospheres and after induction of epithelial-to-mesenchymal transition (EMT) by transforming growth factor β or Twist. The mechanisms responsible for this pattern of ADAM12-L expression are not known. The 3'-UTR of ADAM12-L mRNA contains several predicted target sites for miR-200b/c, important regulators of EMT, tumor invasion, metastasis, and chemosensitivity. The mRNA splice variant encoding the secreted isoform ADAM12-S and lacking miRNA-200b/c target sites in the 3'UTR shows a different expression pattern than ADAM12-L. The purpose of this study was to determine whether ADAM12-L expression in breast cancer cells is regulated by miR-200b/c. To achieve this goal, breast cancer cells with high expression of ADAM12-L and low levels of miR-200b/c (SUM159PT, SUM1315MO2, and Hs578T) were treated with miR-200b/c mimics. Cells with low expression of ADAM12-L and high levels of miR-200b/c (SUM225PT, SUM149PT, and MCF7) were treated with miR-200b/c inhibitors. To determine whether ADAM12-L mRNA is a direct target of miR-200b/c, we performed co-transfection experiments using miR-200b/c mimics/inhibitors and ADAM12-L 3'UTR reporter constructs with intact or mutated miR-200b/c target sites. Our results indicate that miR-200b/c down-regulates ADAM12-L levels in breast cancer cells, but the mechanism does not seem to involve direct targeting of its 3'UTR. As ADAM12-L is virtually not present in normal breast tissue, we propose that ADAM12-L may be considered as a novel cell surface marker of tumor cells undergoing EMT and/or as a read-out for miR-200b/c activity in breast tumors.
Citation Format: Sara Duhachek-Muggy, Anna Zolkiewska. Metalloprotease-disintegrin ADAM12-L in breast cancer cells: Regulation of expression by microRNA-200b/c. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research: Genetics, Biology, and Clinical Applications; Oct 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2013;11(10 Suppl):Abstract nr B133.