bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A003: Darpp-32 and t-Darpp are differentially expressed in normal and malignant mouse mammary tissue
Authors: Christenson Jessica L. , Susan Kane E. 
Published: May 2015

Abstract
Darpp-32 (dopamine and cAMP regulated phosphoprotein of 32 kD) and t-Darpp are expressed in various types of cancer, including several forms of breast cancer. Both are transcribed from the gene PPP1R1B (Protein phosphatase 1, regulatory (inhibitor) subunit 1B) via alternative promoters, t-Darpp being an N-terminally truncated version of the full length protein, Darpp-32. Although Darpp-32 is a well-known regulator of neurotransmission, its role in cancer is less well understood. t-Darpp is believed to be a putative oncogene: increasing cellular growth, inhibiting apoptosis and contributing to acquired drug resistance. In humans, Darpp-32 is found in both normal and malignant breast tissue, whereas t-Darpp has only been found in malignant breast tissue. Overall, however, the exact biological functions of these proteins in normal and malignant breast tissues are not well understood, and to date they have only been examined in patient samples, cell lines and xenograft mouse models. The use of transgenic mouse mammary tumor models, such as MMTV-PyVT and MMTV-Neu, to study the roles of Darpp-32 and t-Darpp in breast cancer in vivo have been limited by the lack of knowledge regarding t-Darpp expression in mice. In this study, we investigated Darpp-32 and t-Darpp mRNA and protein expression in normal and malignant mouse mammary tissue. We found that Darpp-32 was expressed in normal mouse mammary tissue and in some breast tumors, whereas t-Darpp was found only in the malignant mammary tissue. t-Darpp was expressed in the majority of breast tumors often at equal or higher levels than Darpp-32. t-Darpp expression did not seem to be correlated with either tumor location or tumor size. This shift in expression from Darpp-32 to t-Darpp during mouse mammary malignant transformation is reminiscent of the expression patterns observed in human breast tissue, suggesting that transgenic mouse mammary tumor models might be an ideal tool for future investigation of Darpp-32 and t-Darpp in breast cancer.
Citation Format: Jessica L. Christenson, Kane E. Susan. Darpp-32 and t-Darpp are differentially expressed in normal and malignant mouse mammary tissue. [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 A003.
Abstract A014: A clinically relevant prognostic mRNA signature for triple-negative breast cancer developed from the patient-derived xenograft model
Authors: Moon Hyeong-Gon , Oh Keunhee , Lee Dong-Sup , Han Wonshik , Noh Dong-Young 
Published: May 2015

Abstract
Triple-negative breast cancer (TNBC) is a unique subtype of breast cancer which lacks effective targeted agent and has a relatively worse prognosis when compared to other subtypes. Identifying a molecular characteristic associated with poor prognosis and classifying TNBC patients accordingly can help the clinicians to provide tailored therapeutic approach.
Using a patient-derive xenograft model which use patients' primary breast cancer tissues xenotransplanted into the immunodeficient mice, the xenograft take rates of various molecular subtypes of breast cancer were examined. Also, the mRNA expression profile associated with the xenograft tumor formation was investigated in 13 TNBC patients. The genes showing differential expression according to the xenograft tumor formation were tested in an independent publicly available TNBC mRNA expression datasets to assess the prognostic importance.
Among the 81 primary breast cancer tissues used for the xenotransplantation experiments, 19 (23.4%) developed xenograft tumors. Cancer tissues from TNBC patients were more likely to develop xenograft tumors (48%) when compared to other subtypes. The TNBC-derived xenograft tumors showed rapid and exponential tumor growth when compared to luminal type cancers. The genetic characteristics of the primary tumor were maintained after serial xenotransplantation in the immunodeficient mice suggesting the validity of the patient-derived xenograft model for translational research. In 13 TNBC tumors, the mRNA expression profiles were obtained by using microarray chip experiment to identify a genetic characteristic associated with the xenograft tumor formation. Gene involved in immune-reponse, cell migration, angiogenesis and vascular formation were significantly up or downregulated according to the xenograft tumor formation. Among the 13 TNBC patients, the distant metastases were developed only in tumors which formed xenograft tumors. The individual genes showing differential expression, as well as the global expression profile of xenograft tumor formation, was associated with the distant metastasis risk in an independent TNBC mRNA expression datasets.
In conclusion, the present study has identified a set of genes that carry prognostic implication in TNBC patients by using the patient-derived xenograft models.
Citation Format: Hyeong-Gon Moon, Keunhee Oh, Dong-Sup Lee, Wonshik Han, Dong-Young Noh. A clinically relevant prognostic mRNA signature for triple-negative breast cancer developed from the patient-derived xenograft model. [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 A014.
Abstract A037: YB-1 transforms mammary epithelial cells through chromatin remodeling leading to the development of basal-like breast cancer
Authors: Davies Alastair H. , Reipas Kristen M. , Firmino Natalie , Stratford Anna L. , Berns Rachel , Fotovati Abbas , Pambid Mary , Hu Kaiji , Maxwell Chris , Mills Gordon B. , Dunn Sandra E. 
Published: May 2015

Abstract
There is growing evidence that cancer-initiation could result from epigenetic changes. Y-box binding protein-1 (YB-1) is a transcription/translation factor that promotes the formation of tumors in transgenic mice; however, the early molecular events leading up to this are not understood. To address this in a human model system, YB-1 was expressed in mammary epithelial cells under a tetracycline-inducible promoter. The induction of YB-1 drove the development of ductal carcinoma in situ (DCIS) in vitro. Underlying these events, YB-1 induced p300, promoted its nuclear localization, and heightened histone acetylation leading to chromatin relaxation. Subsequently, chromatin relaxation allowed YB-1 to bind to the BMI1 promoter based on chromatin immunoprecipitation. The induction of BMI1 engaged the PRC1 complex as histone H2A was ubiquitinated and p16INK4a was silenced. These events manifested functionally in sustained self-renewal that occurred in a BMI1 dependent manner. Conversely, p300 inhibition with anacardic acid prevented YB-1 from binding to the BMI1 promoter and thereby subverted self-renewal. Accordingly, transient expression of YB-1 in the normal mammary 184hTERT and MCF10A cells had the same effect on chromatin remodeling and self-renewal. Despite these early changes, full malignant transformation was not achieved until RSK2 was expressed leading to elevated hTERT activity. The YB-1/RSK2/hTERT expressing cells formed DCIS and invasive ductal carcinoma in mice that were molecularly subtyped as basal-like breast cancer (BLBC). We conclude that YB-1 cooperates with p300 to allow BMI1 to over-ride p16INK4a enabling self-renewal and the formation of tumors.
Citation Format: Alastair H. Davies, Kristen M. Reipas, Natalie Firmino, Anna L. Stratford, Rachel Berns, Abbas Fotovati, Mary Pambid, Kaiji Hu, Chris Maxwell, Gordon B. Mills, Sandra E. Dunn. YB-1 transforms mammary epithelial cells through chromatin remodeling leading to the development of basal-like 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 A037.
Abstract A042: Role of mTOR as a transcriptional regulator in breast cancer
Authors: Alalem Mohamed , Ray Alpana , Ray Bimal 
Published: May 2015

Abstract
There is substantial evidence that metformin, an anti-diabetic biguanide, correlates with improved breast cancer response to chemotherapy. The exact mechanism of metformin's beneficial effect in breast cancer is yet to be fully understood. Metformin inhibits a serine/ threonine kinase called mammalian target of rapamycin (mTOR), which is a central regulator of various intracellular and extracellular stimuli. mTOR transduces signaling from growth factors, such as insulin, to stimulate mRNA translation. Insulin activates mTOR through PI3K-Akt-mediated phosphorylation and consequent activation of protein machinery to promote protein synthesis. Increased protein synthesis in cancer cells contributes to cancer progression. Improved response of breast cancer cells response to chemotherapy following metformin treatment suggests inhibition of mTOR in breast cancer regression. Being a serine / threonine kinase, mTOR may also have a potential role in the regulation of gene transcription via modulating the activity of some transcription factors, particularly, those involved in cell proliferation and differentiation. Kruppel-like factor 4 (KLF-4) is one such transcription factor which is involved in epithelial cells differentiation and proliferation and it is potentially regulated by mTOR. The objective of this study, therefore, was to investigate whether mTOR regulates gene expression by modulating the activity of KLF-4 in breast cancer.
Our hypothesis was that mTOR inhibition by metformin results in the upregulation of KLF-4, which functions as a tumor suppressor. Elucidation of the molecular basis of metformin's effect on KLF-4 could provide the basis for adjuvant therapy in breast cancer.
Western blot (WB) studies indicate overexpression of mTOR in some breast cancer cells compared to normal breast epithelial cells. In contrast, WB and Immunohistochemistry studies indicate overexpression of KLF-4 in normal breast cells compared to cancer breast cells. Metformin treatment, with and without insulin, resulted in decreased mTOR level with a concomitant increase in KLF-4 level in breast cancer cells. These results suggest a role of metformin in mediating the inverse relationship between mTOR and KLF-4 in breast cancer.
Citation Format: Mohamed Alalem, Alpana Ray, Bimal Ray. Role of mTOR as a transcriptional regulator 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 A042.
Abstract A043: Targeting defective DNA repair for the prevention of BRCA1-mutated breast cancer
Authors: Alli Elizabeth , Solow-Cordero Dave 
Published: May 2015

Abstract
Carriers of germline mutations in the Breast Cancer Susceptibility Gene 1 (BRCA1) have an increased risk for developing breast cancer. Unfortunately, BRCA1-mutated cancers are not amenable to current chemoprevention options, often associate with an aggressive clinical course, and thus, are in need of an effective prevention strategy. We previously found that BRCA1 plays a role in DNA base-excision repair (BER) of oxidative DNA damage (ODD), and that BRCA1-mutated breast cancers exhibit a compromised ability for BER of ODD. Given that excessive ODD leads to tumorigenesis, we hypothesized that repair of ODD may be enhanced to prevent tumorigenesis of BRCA1-mutated breast cancer. To test this hypothesis, we first identified drugs that enhance BER of ODD in the presence of mutant BRCA1. To do so, we conducted a high-throughput chemical screen using small molecules with known pharmacological activity. Two of these compounds, which have been approved for other clinical indications, enhanced BER in mutant BRCA1 but not wild-type BRCA1 cell lines. These molecules also decreased basal levels of ODD as determined by flow cytometry using a FITC-conjugated 8oxoG-binding protein and decreased H2O2-induced ODD as determined by the alkaline comet assay modified for detection of oxidized lesions. Second, we analyzed certain effects of these drugs that would negatively affect their ability to function as chemoprevention agents. Both drugs showed no cytotoxicity at concentrations that enhanced BER of ODD as seen by the MTT assay and Hoechst-staining for live cells. Both drugs directly activated BER, rather than indirectly as a result of induction of DNA damage, as evidenced by the alkaline comet assay for DNA strand breaks. Finally, at least one of these drugs decreased in vitro tumorigenesis of BRCA1-mutant and isogenic BRCA1-deficient cells using the soft agar colony formation assay and simultaneously had no significant effect on cell viability as determined by the trypan blue exclusion assay. Taken together, these data suggest a novel strategy for the targeted chemoprevention of BRCA1-associated breast cancers.
Citation Format: Elizabeth Alli, Dave Solow-Cordero. Targeting defective DNA repair for the prevention of BRCA1-mutated 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 A043.
Abstract A045: Cadherin-11, a common therapeutic target in poor prognosis malignancies and rheumatoid arthritis
Authors: Assefnia Shahin , Dakshanamurthy Sivanesan , Auvil Jaime M. Guidry , Hampel Constanze , Anastasiadis Panos , Kallakury Bhaskar , Uren Aykut , Foley David W. , Brown Milton , Shapiro Lawrence , Brenner Michael , Haigh David , Byers Stephen W. 
Published: May 2015

Abstract
Rational: Poor prognosis epithelial-derived cancers often exhibit morphologic and molecular changes characteristic of an epithelial to mesenchymal transition (EMT). EMT markers are predominantly found in tumors with a basal-like phenotype. Increased expression of the mesenchymal cadherins N-cadherin and/or Cadherin-11 (CDH11) and decreased E-cadherin, have been associated with both EMT and tumor progression. Importantly, CDH11 is a therapeutic target in rheumatoid arthritis (RA), an inflammatory disease with properties often compared with cancer. As CDH11 antibody based therapeutics are in clinical trials for RA and we recently showed that the arthritis drug celecoxib has the structural potential to bind CDH11, there is a strong possibility that, if CDH11can be shown to drive malignant progression rather than simply be associated with it, therapeutic options may be rapidly developed.
Results: We show that CDH11 is increased early in breast cancer and ductal carcinoma in-situ. CDH11 knockdown and antibodies effective in RA slowed the growth of basal-like breast tumors. CDH11 attenuation decreased proliferation and colony formation of breast, glioblastoma and prostate cancer cells. The arthritis drug celecoxib, which has characteristics consistent with CDH11 binding, an analogue without COX-2 inhibitory activity and other molecules that target CDH11, preferentially affect CDH11 positive cancer cells.
Conclusion: Our work demonstrates that cadherin-11 is important for malignant progression, is a therapeutic target in several aggressive tumors and introduces an antibody, novel small molecules and an approved arthritis drug that inhibit its function with potential for rapid clinical translation.
Citation Format: Shahin Assefnia, Sivanesan Dakshanamurthy, Jaime M. Guidry Auvil, Constanze Hampel, Panos Anastasiadis, Bhaskar Kallakury, Aykut Uren, David W. Foley, Milton Brown, Lawrence Shapiro, Michael Brenner, David Haigh, Stephen W. Byers. Cadherin-11, a common therapeutic target in poor prognosis malignancies and rheumatoid arthritis. [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 A045.
Abstract A047: Targeting androgen receptor decreases proliferation of triple-negative breast cancer
Authors: Barton Valerie , D'Amato Nicholas , Richer Jennifer 
Published: May 2015

Abstract
Recent studies demonstrate that the androgen receptor (AR) is expressed in up to a third of triple negative breast cancer (TNBC) and define a subtype of TNBC with a “luminal AR” gene signature. We hypothesized that AR+TNBC are dependent on AR for growth and that inhibiting AR activity by preventing nuclear localization and DNA binding will decrease proliferation and tumor burden in preclinical models of breast cancer. Indeed, knock down of AR expression using a lentiviral shRNA significantly reduced proliferation in cell line models of TNBC compared to cells transduced with a non-targeting control (2-fold reduction, p&lt;0.001). Propidium iodide cell cycle analysis demonstrated that TNBC cells with reduced AR expression had a 22% increase in the percentage of cells in S-phase (p&lt;0.001). In TNBC cells that exhibit androgen-stimulated growth, reduced AR expression inhibited response to ligand. Enzalutamide, an AR inhibitor, inhibited ligand mediated nuclear translocation of AR as assessed by nuclear cytosolic fractionation and significantly decreased baseline proliferation of TNBC in vitro (p&lt;0.001). In MDA453 xenografts, enzalutamide significantly decreased tumor volume and weight by up to 85% and increased apoptosis as measured by cleaved caspase-3 by 60% compared to mice that received DHT alone. In addition, a 50% reduction in nuclear AR was observed in the tumors of mice treated with enzalutamide. Thus AR may play an important role in a subset of TNBC and presents an opportunity for targeted therapy.
Citation Format: Valerie Barton, Nicholas D'Amato, Jennifer Richer. Targeting androgen receptor decreases proliferation 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 A047.
Abstract A053: ErbB3 downregulation enhances luminal breast tumor response to antiestrogens
Authors: Morrison Meghan M. , Stanford Jamie , Young Christian , Vaught David , Williams Andrew , williams michelle , Perou Chuck M. , Arteaga Carlos L. , Cook Rebecca S. 
Published: May 2015

Abstract
HER3/ErbB3 is required in luminal mammary epithelial cells (MECs). Given that breast cancer phenotypes may reflect biological traits of the MECs from which they originate, we tested the hypothesis that HER3/ErbB3 drives luminal breast cancer growth. We found higher ERBB3 expression and frequent ERBB3 gene copy gains in clinical Luminal A/B breast cancers over other molecular subtypes. ErbB3 increased growth of luminal breast cancer cells, while ErbB3 targeting using U3-1287, a fully-human monoclonal anti-ErbB3 antibody, decreased three-dimensional colony growth, increased apoptosis, and decreased tumor growth in vivo. In response to the anti-endocrine fulvestrant, ErbB3 expression increased in clinical breast tumors, as did phosphatidylinositol 3-kinase (PI3K)/mTOR signaling. However, ErbB3 targeting with U3-1287 blocked compensatory PI3K/mTOR signaling in fulvestrant-treated tumor cells, transcriptional responses to fulvestrant, tumor cell survival and tumor growth. U3-1287 produced these effects in tumor cells with and without genetic PI3K pathway aberrations (PIK3CAH1047R, PIK3CAE545K, PTEN loss). Although fulvestrant increased phosphorylation of all ErbB family RTKs and insulin-like growth factor-1 receptor, phospho-RTK upregulation was not seen in tumors treated with U3-1287 and fulvestrant. Therefore, luminal breast cancer cells utilize ErbB3 for growth, survival, and to limit response to fulvestrant, thus defining a novel role for ErbB3 in breast cancer.
Citation Format: Meghan M. Morrison, Jamie Stanford, Christian Young, David Vaught, Andrew Williams, michelle williams, Chuck M. Perou, Carlos L. Arteaga, Rebecca S. Cook. ErbB3 downregulation enhances luminal breast tumor response to antiestrogens. [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 A053.
Abstract A057: Therapeutic potential of genistein via targeting the microRNA miR-155 in breast cancer
Authors: Parra Columba de la , Castillo-Pichardo Linette , Cubano Luis A. , Calin George A. , Dharmawardhane Suranganie 
Published: May 2015

Abstract
We previously reported that dietary genistein significantly inhibits mammary tumor growth and metastasis of estrogen receptor (ER) (-) MDA-MB-435 metastatic cancer cells in immunocompromised mice. The purpose of the present study is to investigate the molecular mechanisms of genistein in ER (-) breast cancer cells. We report that at low physiologically relevant concentrations, genistein significantly inhibits cell growth and induces apoptosis in MDA-MB-435 and Hs578t breast cancer cells. To investigate the mechanism by which genistein regulates cancer cell viability, a panel of microRNAs (miRNAs) were tested for differential expression in response to genistein treatment. We found that miR-155, a designated oncomiR in breast cancer, is significantly downregulated by genistein in MDA-MB-435 and Hs578t cells. Concomitantly, pro-apoptotic and anti-cell proliferative miR-155 targets FOXO3, PTEN, casein kinase (CK1alpha), and p27 are upregulated by genistein. Moreover, the CK1alpha target beta catenin is downregulated in the MDA-MB-435 cells, thus further contributing to the anticancer effects of genistein by inhibiting wnt signaling. Stable ectopic expression of miR-155 in MDA-MB-435 and Hs578t cells decreases the inhibitory effect of genistein on cell viability, and abrogates the effect of genistein on apoptosis and expression of pro-apoptotic proteins. Therefore, genistein acts as a potential anti breast cancer therapeutic via downregulation of miR-155, a critical suppressor of apoptosis. This study was sponsored by United States Army/BCRP W81XWH-11-1-0199 (to CDP), NIH/NIGMS SC3GM084824 (to SD), NIH/NIGMS G12RR035051 (to UPR MSC), and NIH/NIGMS G12RR003035 and Title V PPOHA US Department of Education #P031M105050 (to UCC).
Citation Format: Columba de la Parra, Linette Castillo-Pichardo, Luis A. Cubano, George A. Calin, Suranganie Dharmawardhane. Therapeutic potential of genistein via targeting the microRNA miR-155 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 A057.