bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B136: Sox10 expression labels in vitro mammary stem cell activity
Authors: Dravis Christopher , Johns Claire , Spike Benjamin T. , Smith Michelle Southard , Wahl Geoffrey M. 
Published: May 2015

Abstract
Molecular pathways that guide cell proliferation and programming events during embryonic development to generate specific organs may be aberrantly re-activated in the cancer state of those organs to drive tumor progression. Recently, our laboratory has successfully demonstrated the applicability of this tenet to studies of breast cancer. We have developed an enrichment protocol for fetal mammary stem cells (fMaSCs) from embryonic mammary rudiments, and verified that particular subtypes of breast cancers, including Basal-like triple-negative breast cancers for which targeted therapies do not exist, show strong correlation with expression signatures found in fMaSCs. This suggests that elucidation of the biology behind fMaSC function will yield important insight into better treatment of these aggressive breast cancers. To identify mechanisms that govern fMaSC function, we have performed transcriptome analyses on cell populations enriched for fMaSCs and their surrounding stroma. From this data, we have identified candidate signaling and transcription networks that we are currently validating. Here we describe ongoing work with one candidate to emerge from our analyses, Sox10. Sox10 is specifically expressed in the enriched fMaSC population, and is of particular interest given the well-documented roles for other Sox family transcription factors in: 1) regulating cell fate decisions in embryonic and adult tissue, and 2) mediating the progression of some types of cancer. We show that Sox10 expression specifically correlates with MaSC function in fetal and adult mammary. We further show that Sox10 expression can be utilized to identify the cells maintaining MaSC stem cell properties in culture. Importantly, incorporation of Sox10 into our existing fMaSC purification protocol results in a twofold improvement in fMaSC enrichment. Our discoveries with Sox10 thus represent a molecular focal point around which to build signaling and transcriptional networks underlying fMaSC state and function. They further demonstrate the promise of our approach in identifying novel targets for the development of new therapies for poorly treated cancers.
Citation Format: Christopher Dravis, Claire Johns, Benjamin T. Spike, Michelle Southard Smith, Geoffrey M. Wahl. Sox10 expression labels in vitro mammary stem cell activity. [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 B136.
Abstract IA04: Genomic studies of breast cancer progression
Authors: Mardis Elaine R. 
Published: May 2015

Abstract
Whole genome sequencing of tumor progression samples provides an ability to capture the natural history of cancer evolution. Hence, we can document changes in the cancer cell population by monitoring the changing genotypes detected at different stages of progression. The impact of therapeutic intervention on cancer cell heterogeneity is of interest, and can be indicative of therapy resistance or response. Metastatic progression is of interest as an evolutionary process, wherein the resulting heterogeneity of primary and metastatic tumor is of interest, as is evidence for novel drivers unique to one or more metastases. I will provide results for studies of both types, involving breast cancer samples and integrated analyses from whole genome sequencing and RNA sequencing.
Citation Format: Elaine R. Mardis. Genomic studies of breast cancer progression. [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 IA04.
Abstract IA13: Wnt and Fgf signaling in mammary stem cells and breast cancer
Authors: Rosen Jeffrey M. , Bin Xue , Roarty Kevin 
Published: May 2015

Abstract
Some of the earliest evidence implicating both Wnt and FGF signaling in mammary tumorigenesis came from the observation of tumors in mouse mammary tumor virus (MMTV)- infected mice. Tumors arising from MMTV proviral insertion often exhibited preferential activation of Wnt and FGF pathway members. Interestingly, tumors with MMTV-induced expression of these FGF pathway ligands also showed MMTV-induced activation of Wnt pathway members, and functional cooperativity of MMTV-driven Wnt 1 and Fgf-3 transgenes in mammary tumorigenesis was observed. High throughput MMTV insertional mutagenesis studies have indicated that activation of Wnt and FGF pathway components is the most common occurrence in resulting tumors, providing definitive genetic proof for the cooperativity between these two pathways. Unraveling the complexity of these pathways in the context of development and tumorigenesis remains an evolving challenge. While the Wnt/ß-catenin cascade plays a central role in a range of biological processes, it has emerged as a key regulator of stem cell dynamics in multiple tissues, including the mammary gland. Significant evidence now implicates the Wnt/ß-catenin pathway in uncontrolled self-renewal of cancer stem cells and their associated radiation resistance during treatment. In the mammary gland, localized Wnt signaling most likely plays a critical role in regulating oriented cell division and cell fate. As with many signaling pathways, this is not an “on and off switch”, but is instead influenced by the level and duration of the signaling event. There are also Wnt-mediated ß-catenin-independent pathways, known as noncanonical Wnt cascades. For instance, noncanonical Wnt signaling through the receptor Ror2 helps to specify the extent and location of canonical Wnt/ß-catenin signaling. With regard to FGF signaling, FGFR1 and FGFR2, the two primary FGFRs expressed in mouse mammary epithelium, also are critical for mammary stem cell maintenance. Cooperation of the FGF and Wnt pathways in mammary tumorigenesis is based in part on the activation of protein translational pathways that result in, but are not limited to, increased expression of Wnt/β-catenin target genes at the level of protein translation. Lastly, Wnt and Fgf ligands can be regulated by systemic steroid hormones and act in a paracrine manner to influence mammary stem cells, providing another layer to the signaling hierarchy. Supported by grant NIH-CA16303.
Citation Format: Jeffrey M. Rosen, Xue Bin, Kevin Roarty. Wnt and Fgf signaling in mammary stem cells and 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 IA13.
Abstract PR07: Integrative functional genomics of breast cancer
Authors: Marcotte Richard , Sayad Azin , Iorio Cathy , Haider Maliha , Moffat Jason , Neel Benjamin G. 
Published: May 2015

Abstract
Cancer is a disease of the genome. Using genomic approaches alone, it is difficult to ascertain which variants drive pathogenesis because most of these are functionally irrelevant passenger mutations. Highly recurrent events point to drivers; however, the majority of genomic alterations in tumors occur at low frequency. In addition, the products of many oncogenes and tumor suppressor genes are not druggable. However, such abnormalities can cause unanticipated gene/pathway dependencies (synthetic lethality), providing alternate avenues for drug development. Lentiviral-based shRNA libraries enables genome-wide screening of cultured cancer cells in a pooled format, facilitating the identification of genes necessary for cancer cell proliferation and survival in cultured cells. We screened a panel of &gt; 75 breast cancer cell lines using an 80,000 lentiviral shRNA library targeting 16,000 genes and integrated these screen results with gene expression, copy-number variation (CNV), and somatic mutations derived from the same lines. We identified several classes of gene dropouts, which are required for survival or growth of all (or some) cell lines, irrespective of subtype and several subtype-specific genes, whose essentiality is restricted to a defined subtype. These include well-known HER2 subtype-specific genes, ERBB2, ERBB3, and TFAP2C and luminal subtype-specific gene FOXA1, SPDEF, GATA3, and ESR1. In addition, the unprecedented number of lines allows the identification of synthetic lethal interaction with common breast cancer somatic mutations or CNV such as PIK3CA and PTEN or 9p21 deletion, respectively, which encodes the CDKN2A, CDKN2B, and MTAP genes. Finally, integration of gene expression, copy number variation, and functional screening results identified potential biomarkers with common genetic changes and functional drivers. Overall, our study represents an extensive functional genetic survey of breast cancer, reveals complexities between genomic and functional genomic results, and uncovers several unexpected gene dependencies and potential novel therapeutic target for each subtype.
This abstract is also presented as Poster A033.
Citation Format: Richard Marcotte, Azin Sayad, Cathy Iorio, Maliha Haider, Jason Moffat, Benjamin G. Neel. Integrative functional genomics of 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 PR07.
Abstract A08: Clonal evolution enhances leukemia propagating cell activity in T-cell acutelymphoblastic leukemia through AKT/mTORC1 pathway activation
Authors: Blackburn Jessica , Liu Sali , Dobrinski Kimberly , Martinez Sarah , Moore Finola , Lobbardi Riadh , Langenau David 
Published: May 2015

Abstract
This abstract is being presented as a short talk in Session 3: Mechanisms of Resistance. A full abstract is printed in the Proffered Abstracts section (PR06) of the Conference Proceedings.
Citation Format: Jessica Blackburn, Sali Liu, Kimberly Dobrinski, Sarah Martinez, Finola Moore, Riadh Lobbardi, David Langenau. Clonal evolution enhances leukemia propagating cell activity in T-cell acutelymphoblastic leukemia through AKT/mTORC1 pathway activation. [abstract]. In: Proceedings of the AACR Special Conference: The Translational Impact of Model Organisms in Cancer; Nov 5-8, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2014;12(11 Suppl):Abstract nr A08.
Abstract A10: Suppressor of cytokine signaling (SOCS)-3 and the C-X-C chemokines CXCL1 and CXCL2 promote tumor aggressiveness and radiation resistance in pancreatic cancer
Authors: Jiang Sisi , Coppola Giovanni , Mose Evangeline , Lowy Andrew , Jamieson Christina , Cacalano Nicholas 
Published: May 2015

Abstract
Despite recent advances in our understanding of pancreatic ductal adenocarcinoma (PDA), it remains a poorly understood, devastating disease that is largely resistant to all standard treatment modalities. Much effort has been made to identify novel tumor suppressor genes, biomarkers of metastatic behavior, and targets for molecular therapeutics that can improve prognosis and quality of life for PDA patients. Despite the finding that the pro-inflammatory C-X-C family chemokines CXCL1 and CXCL2 are expressed in a significant fraction of human PDA tissues and are known to promote metastasis in bladder and breast cancer, very little is known of its regulation and its role in the progression of PDA. Our laboratory has identified a mechanism by which CXCL1 and CXCL2 expression is regulated in human PDA. CXCL1/2 expression is repressed by the Signal Transducer and Activator of Transcription (STAT)-3 and conversely, the Suppressor of Cytokine Signaling (SOCS)-3, a STAT3 inhibitor, promotes CXCL1/2 gene activation and pro-inflammatory signaling in murine embryonic fibroblasts (MEFs) and human PDA cell lines. Ectopic expression of SOCS3 in the ASPC1 PDA cell line induces CXCL1 and CXCL2 expression and drives resistance to radiation and gemcitibine treatment. Treatment with neutralizing antibodies against CXCL1 or its receptor, CXCR2, sensitizes these cells to ionizing radiation. Further, using an orthotopic xenograft model of human PDA in immunodeficient mice, we demonstrated the in vivo relevance of this pathway. We found that mice injected with human SOCS3-positive human PDA cells have a shorter survival time and develop more aggressive disease compared to mice injected with control cells. We also have shown increased numbers of CD11b-positive granulocytes in the tumor microenvironment of SOCS3+ PDA tumors. We hypothesize that SOCS3 and CXCL1and CXCL2 promote human PDA pathogenesis by two mechanisms: (i) autocrine activation of the CXCR2 receptor expressed on human pancreatic cancer cells and (ii) pro-inflammatory recruitment of neutrophils to the tumor microenvironment.
Citation Format: Sisi Jiang, Giovanni Coppola, Evangeline Mose, Andrew Lowy, Christina Jamieson, Nicholas Cacalano. Suppressor of cytokine signaling (SOCS)-3 and the C-X-C chemokines CXCL1 and CXCL2 promote tumor aggressiveness and radiation resistance in pancreatic cancer. [abstract]. In: Proceedings of the AACR Special Conference: The Translational Impact of Model Organisms in Cancer; Nov 5-8, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2014;12(11 Suppl):Abstract nr A10.
Abstract A14: Canonical WNT/β-catenin pathway activation suppresses embryonal rhabdomyosarcoma growth and self-renewal
Authors: Chen Eleanor , DeRan Michael , Grandinetti Katherine Brooke , Ignatius Myron , Clagg Ryan , McCarthy Karin , Lobbardi Riadh , Wu Xu , Langenau David 
Published: May 2015

Abstract
Embryonal rhabdomyosarcoma (ERMS) is a common pediatric malignancy of muscle with relapse being the major clinical challenge. Self-renewing tumor-propagating cells (TPCs) drive cancer relapse and are confined to a molecularly definable subset of ERMS cells. To identify drugs that suppress TPC function, a large-scale chemical screen comprising of ~40,000 compounds including 47% FDA-approved drugs was completed, identifying GSK3-inhibitors as potent suppressors of ERMS growth through inducing terminal differentiation of TPCs into myosin-expressing cells. In support of GSK3 inhibitors functioning through activation of the canonical WNT pathway, recombinant WNT3A and a stabilized β-catenin enhanced differentiation and reduced self-renewal in human ERMS cell lines. Moreover, treatment of tumor-bearing zebrafish with a GSK3 inhibitor activated the WNT/β-catenin pathway, resulting in suppressed ERMS growth, depleted TPCs, and diminished self-renewal capacity in vivo. As canonical WNT signaling is essential for transition from muscle stem cell proliferation to myogenic differentiation during regeneration, our findings suggest that the same developmental pathways that regulate muscle stem cell self-renewal also contribute to tumorigenesis in ERMS. GSK3 inhibitors are being assessed for their efficacy in inhibiting growth as well as inducing differentiation of human ERMS in xenograft mouse models. Our work has identified the vital role of canonical WNT pathway in regulating differentiation and self-renewal of ERMS and demonstrated the effective application of small molecule inhibitors to target differentiation of TPCs in ERMS.
Citation Format: Eleanor Chen, Michael DeRan, Katherine Brooke Grandinetti, Myron Ignatius, Ryan Clagg, Karin McCarthy, Riadh Lobbardi, Xu Wu, David Langenau. Canonical WNT/β-catenin pathway activation suppresses embryonal rhabdomyosarcoma growth and self-renewal. [abstract]. In: Proceedings of the AACR Special Conference: The Translational Impact of Model Organisms in Cancer; Nov 5-8, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2014;12(11 Suppl):Abstract nr A14.
Abstract A19: Progesterone receptor signaling inhibits cervical cancer
Authors: Mehta Fabiola , Yoo Young A , Son Jieun , DeMayo Francesco J. , Lydon John P. , Chung Sang-Hyuk 
Published: May 2015

Abstract
Human papillomavirus (HPV) is the major etiological factor for cervical cancer, which remains third most frequent and fourth most deadly malignancy in women worldwide. However, evidence indicates that other non-viral cofactors are also required for the disease. The uterine cervix is sensitive to female hormones, which have been implicated in cervical carcinogenesis. A transgenic mouse model expressing HPV oncogenes E6 and/or E7 is relevant to human cancer. We use this model to study a mechanism of hormone actions in the context of this common malignancy. Estrogen and estrogen receptor α (ERα) are required for the development of cervical cancer in this mouse model. ERα is known to upregulate expression of the progesterone receptor (PR), which, upon activation by its ligands, either promotes or inhibits carcinogenesis depending on the tissue context. In the present study, we demonstrate that progesterone-PR signaling inhibits cervical and vaginal epithelial cell proliferation in a ligand-dependent manner. We also demonstrate that synthetic progestin medroxyprogesterone acetate (MPA) promotes regression of cancers and precancerous lesions in the female lower reproductive tracts (i.e., cervix and vagina). Our results provide the first experimental evidence supporting that the progesterone signaling is inhibitory for cervical cancer in vivo. Our results also suggest that cervical cancer recurs if MPA treatment is ceased. They imply that MPA efficiently get rid of bulk of disease, yet cancer progenitor/stem cells remain. Our mouse model provides a unique opportunity to interrogate mechanism of PR and PR ligands in cervical cancer.
Citation Format: Fabiola Mehta, Young A Yoo, Jieun Son, Francesco J. DeMayo, John P. Lydon, Sang-Hyuk Chung. Progesterone receptor signaling inhibits cervical cancer. [abstract]. In: Proceedings of the AACR Special Conference: The Translational Impact of Model Organisms in Cancer; Nov 5-8, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2014;12(11 Suppl):Abstract nr A19.
Abstract A29: Interrogating therapeutic response for advanced prostate cancer in vivo using cross-species regulatory models
Authors: Mitrofanova Antonina , Floch Nicolas , Aytes Alvaro , Shen Michael , Abate-Shen Cory , Califano Andrea 
Published: May 2015

Abstract
While most men diagnosed with localized prostate cancer now have favorable outcomes, those with advanced disease often undergo androgen deprivation therapy, which initially leads to tumor regression but ultimately results in the emergence of a castration-resistant form of the disease that is highly metastatic and ultimately fatal. Our research is focused on generating mouse models of advanced prostate cancer to evaluate new therapeutic approaches for its treatment. Toward this end, we have generated state-of the-art genetically-engineered mouse (GEM) models, which are based on biologically-relevant signaling pathways and recapitulate prostate cancer from its earliest to most advanced stages. Indeed these mice recapitulate lethal prostate cancer as they display distant metastases with 100% penetrance as well as disseminated cells in the bone marrow. By pursuing preclinical studies in these GEM mice we have found that combinational targeted of key signaling pathways is significantly more effective than standard of care (i.e., chemotherapy) for blocking cancer progression, improving survival and inhibiting metastases in vivo.
However, one of the main obstacles for effectively translating results from preclinical studies in genetically-engineered mouse models is difficulties in overcoming inherent species differences that may preclude direct comparisons from mice to man. To overcome this limitation, we have assembled regulatory networks (called interactomes) for both mouse and human prostate cancer to enable cross-species analyses for identification of master regulators (driver genes) that underlie the therapeutic response. In particular, using these computational resources we have interrogated gene expression profiles from preclinical studies in our genetically-engineered mice, and have identified molecular regulators that predict therapeutic response in the mice and are conserved in human prostate cancer. Our approach highlights the value of cross-species analyses of preclinical studies in mice and human clinical data for predicting drug response.
Citation Format: Antonina Mitrofanova, Nicolas Floch, Alvaro Aytes, Michael Shen, Cory Abate-Shen, Andrea Califano. Interrogating therapeutic response for advanced prostate cancer in vivo using cross-species regulatory models. [abstract]. In: Proceedings of the AACR Special Conference: The Translational Impact of Model Organisms in Cancer; Nov 5-8, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2014;12(11 Suppl):Abstract nr A29.
Abstract A37: Role of autophagy inhibition in metastatic disease utilizing mouse models
Authors: Barnard Rebecca , Hansen Ryan J. , Maycotte Paola , Thorburn Andrew , Gustafson Daniel L. 
Published: May 2015

Abstract
Modification of autophagy to enhance cancer treatment is being aggressively pursued in the laboratory and clinic; however, it remains to be seen if inhibition or induction of autophagy is going to result in better outcomes. In addition, the advantages of autophagic modification with neoadjuvant chemotherapy vs. surgical adjuvant chemotherapy have yet to be reported. The 4T1-luc metastatic mammary mouse cell line modified to express luciferase was used to induce lung metastases, both from orthotopic growth of primary tumors or experimentally induced via tail vein injection. Both pharmacologic inhibition (chloroquine (CQ) administered 60 mg/kg daily to mice) and genetic knockdown of a key protein necessary for autophagy alone (4T1-luc-shBeclin-1 cells) did not alter time to metastasis (as determined by luciferase positive lungs) when 4T1-luc cells were injected via tail vein. In addition, inhibiting autophagy in 4T1-luc cells with CQ in vitro prior to injection via the tail did not alter time to metastasis. Similar results were observed with pharmacologic inhibition on experimentally induce lung metastases using the metastatic mouse melanoma B16-F10 cell line. In vitro work, by us and others, has lead us to conclude that pharmacologic inhibition plus cisplatin leads to greater growth inhibition and cell kill in vitro than either alone. Effect of autophagy inhibition in combination with cisplatin on metastatic formation in a neoadjuvant setting was tested by treating mice with daily with CQ and cisplatin (q14d) one day post tumor cell injection in the mammary fat pad. Additional experiments were conducted to determine if autophagy inhibition plus cisplatin in a surgical adjuvant setting delays metastasis formation. In each instance, primary tumors were removed at ~100mm3 and mice were followed until luciferase positive lungs were observed. From these results we conclude that autophagy inhibition, using CQ, does not alter metastatic growth alone and appears to slightly enhance the efficacy of cisplatin on treating metastases. It remains to be seen if autophagy inhibition with other compounds would alter results.
Citation Format: Rebecca Barnard, Ryan J. Hansen, Paola Maycotte, Andrew Thorburn, Daniel L. Gustafson. Role of autophagy inhibition in metastatic disease utilizing mouse models. [abstract]. In: Proceedings of the AACR Special Conference: The Translational Impact of Model Organisms in Cancer; Nov 5-8, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2014;12(11 Suppl):Abstract nr A37.