bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract IA12: Mammary epithelial subtypes and their implications for breast cancer
Authors: Rios Anne , Fu Naiyang , Pal Bhupinder , Lindeman Geoffrey , Visvader Jane 
Published: May 2015

Abstract
To understand relationships between breast tissue and ‘cells of origin’ of breast cancer, it is important to dissect the normal mammary epithelial hierarchy. Discrete populations of mouse and human mammary epithelial cells can be isolated on the basis of cell surface markers and subsets that are highly enriched for mammary stem (MaSC), luminal progenitor and mature luminal cells have been identified. These are functionally analogous across species and have highly conserved transcriptomes.
Lineage tracing is an important approach for assessing the stem cell hierarchy as it allows stem and progenitor cell fate to be studied in situ in the context of development, tissue maintenance and disease. Indeed, recent studies in the mammary gland have described unipotent stem cells that appear to control the different stages of development. Here we have combined lineage tracing with a novel three-dimensional (3D) imaging strategy to explore the relative contributions of stem and progenitor cells in the post-natal mammary gland. Newly generated transgenic strains harboring lineage-specific gene regulatory regions are also being used to direct the expression of specific mammary oncogenes to discrete epithelial cell types to gain insight into cells of origin of breast cancer.
Citation Format: Anne Rios, Naiyang Fu, Bhupinder Pal, Geoffrey Lindeman, Jane Visvader. Mammary epithelial subtypes and their implications for 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 IA12.
Abstract IA26: Stroma-targeted immunotherapy
Authors: Gottschalk Stephen , Karkala Sunitha , Williams LaTerrica , Song Xiao-Tong 
Published: May 2015

Abstract
The tumor-associated stroma has garnered increasing attention for its role in initiating and sustaining tumor growth. Occupying up to 90% of the tumor mass, the stroma is composed of heterogeneous cell types, of which cancer associated fibroblasts (CAFs) are preponderant. CAFs support tumor progression directly through paracrine secretion of cytokines, growth factors etc., and indirectly by mediating resistance to chemo-, radio- and immunotherapy. Additionally, therapies directed to cancer cells often fail to eradicate CAFs, which can reinstate a tumorigenic milieu and favor recurrence.
CAFs express markers that distinguish them from their normal counterparts, allowing them to be selectively targeted. One such marker is fibroblast activation protein-α (FAP), a type II dipeptidyl peptidase originally isolated from CAFs in human sarcomas. FAP expression was subsequently detected on CAFs in over 90% of common epithelial cancers including colorectal, breast, pancreatic, skin and lung tumors, and is often correlated with poor prognosis. Selective ablation of FAP-positive stromal cells in a transgenic mouse model permitted immunological control of tumor growth, indicating their significant immunosuppressive function in the microenvironment. Targeting FAP-positive CAFs therefore presents an attractive strategy to augment current cancer-targeted therapies. While ‘unarmed’ FAP-specific monoclonal antibodies had no antitumor activity in humans, several groups have demonstrated the benefit of FAP-targeted vaccines or FAP-specific immunotoxins in preclinical animal models. In this presentation we will summarize current efforts to target FAP-positive CAFs with vaccines and adoptive T-cell therapy in preclinical animal models. In addition, we will review other potential immunotherapeutic targets within the tumor stroma.
Citation Format: Stephen Gottschalk, Sunitha Karkala, LaTerrica Williams, Xiao-Tong Song. Stroma-targeted immunotherapy. [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 IA26.
Abstract PR01: Loss of the hippo pathway scaffold “Kibra” in a mouse model of human claudin-low breast cancer
Authors: Knight Jennifer F. , Lesurf Robert , Saleh Sadiq M. , Davis Ryan R. , Zhao Hong , Zuo Dongmei , Cardiff Robert D. , Gregg Jeff , Hallett Michael , Park Morag 
Published: May 2015

Abstract
Human claudin-low breast cancers belong to the triple negative subclass of the disease. Triple negative breast cancers (TNBCs) cannot be treated with targeted therapies that exist for estrogen receptor and Her2-positive breast cancers, emphasizing the need for new therapeutic targets. We generated a mouse model which recapitulates key features of the claudin-low subtype (Knight et al., PNAS 2013). In this model, expression of the Met receptor tyrosine kinase synergizes with loss of the tumor suppressor gene p53 (MMTV-Met;Trp53fl/+;MMTV-Cre) in driving mammary tumorigenesis. MMTV-Met;Trp53fl/+;Cre mammary tumors have a predominately spindloid pathology, with low expression of cell junction molecules and epithelial markers, and high expression of an epithelial-to-mesenchymal transition (EMT) signature.
Use of array-CGH to assess the genomic landscape of MMTV-Met;Trp53fl/+;Cre claudin-low tumors identified amplification of the endogenous Met locus, suggestive of oncogene addiction. Consistent with this, primary cells derived from these tumors were dependent upon Met signaling for proliferation and survival. Furthermore, Met inhibition in these cells was able to partially restore cell-cell junctions.
In addition to Met amplification, a consistent genomic event in MMTV-Met;Trp53fl/+;Cre tumors was loss of a chromosome 11 region, syntenic with human chromosome 5q, loss of which is a frequent event in human TNBC. Located within this region is the gene Wwc1, also known as Kibra, which encodes a scaffold protein known to positively regulate the Hippo tumor suppressor pathway. To understand the contribution of Kibra loss to claudin-low biology, we performed Kibra RNA interference in MMTV-Met (wildtype p53) solid carcinoma cells, in which Kibra expression is retained. Knockdown of Kibra led to weakening of cell-cell junctions and colony dispersal, consistent with EMT induction.
This work supports that Kibra loss and consequential disruption of the Hippo pathway, may play a significant role in claudin-low biology. Our work now focuses on re-induction of Hippo signaling in human and mouse claudin-low tumor cells to increase our understanding of the role of this pathway in tumor promotion and to provide new possibilities for therapeutic intervention in TNBCs.
This abstract is also presented as Poster A010.
Citation Format: Jennifer F. Knight, Robert Lesurf, Sadiq M. Saleh, Ryan R. Davis, Hong Zhao, Dongmei Zuo, Robert D. Cardiff, Jeff Gregg, Michael Hallett, Morag Park. Loss of the hippo pathway scaffold “Kibra” in a mouse model of human claudin-low 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 PR01.
Abstract PR06: Overcoming resistance to PI3K inhibitors in breast cancer: Results of a pooled shRNA screen and combinatorial drug screen
Authors: Vora Sadhna , Elkabets Moshe , Kim Nayoon , Costa Carlotta , Liu Manway , Xiaoyan Li , Cao Alex , Schlegel Robert , Scaltriti Maurizio , Baselga Jose , Huang Alan , Engelman Jeffrey A. 
Published: May 2015

Abstract
The phosphatidylinositol 3-kinase (PI3K) pathway is deregulated across a broad spectrum of human cancers. Therefore, there have been strong efforts to inhibit this pathway, with many novel targeted agents, including isoform-specific PI3K inhibitors, pan-PI3K inhibitors, and dual PI3K/mTOR inhibitors, entering the clinic. Although initial responses have been observed in PIK3CA and HER2 amplified cancers, resistance frequently emerges, thereby limiting the benefit from these drugs. We developed several PI3K inhibitor resistant cell lines by culturing sensitive PIK3CA mutant cells in gradually escalating doses of PI3K inhibitor until resistance emerges, typically over a period of several months. We then used a drug screen utilizing ~40 targeted agents to identify drugs that synergize with PI3K inhibitors in the resistant cells. Subsequently, to elucidate mechanisms of resistance to PI3K inhibitors, we used a pooled shRNA screen to identify hairpins that sensitize the resistant cells to PI3K inhibition. These two complementary screens have identified mTORC as a likely mediator of resistance to PI3K inhibition: mTORC inhibitors synergize with PI3K inhibitors in the resistant cells, and furthermore, hairpins directed against mTORC (FRAP1) sensitize resistant cells to PI3K inhibition. Other promising therapeutic targets identified by these screens that may contribute to resistance to PI3K inhibitors include IGF1R and AKT.
This abstract is also presented as Poster B069.
Citation Format: Sadhna Vora, Moshe Elkabets, Nayoon Kim, Carlotta Costa, Manway Liu, Li Xiaoyan, Alex Cao, Robert Schlegel, Maurizio Scaltriti, Jose Baselga, Alan Huang, Jeffrey A. Engelman. Overcoming resistance to PI3K inhibitors in breast cancer: Results of a pooled shRNA screen and combinatorial drug screen. [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 PR06.
Abstract A18: A novel, human-compatible mouse model for preclinical research on prolactin in breast cancer
Authors: Christensen Heather R. , Murawsky Michael K. , Gregerson Karen A. 
Published: May 2015

Abstract
Over 90% of all human breast cancers express receptors for prolactin (PRL). This mitogenic hormone has been associated with an increased risk for breast cancer (as supported by epidemiological and molecular biology research). Despite this evidence, knowledge of the precise mechanisms of action for PRL in human breast cancer is limited. This is likely due to the lack of a suitable experimental model for studying the potential role of PRL in breast cancer growth and metastasis in vivo. For other reproductive hormones, the research model that has proven to be critical for preclinical studies of cancer is the grafting of human cancer cells into immunodeficient mice. Currently, no such xenograft model exists for the study of human PRL (hPRL) in breast cancer. The primary reason for this is the significant structural differences between rodent and hPRL. The mouse PRL (mPRL) hormone does not activate the hPRL receptor. Thus, grafted human cancer cells cannot respond to circulating PRL produced by the mouse host. To address this void in the repertoire of research tools, we have generated a novel set of mouse strains that have been “humanized” with regard to the structural gene, tissue expression, and secretory patterns of PRL. These mice were created using bacterial artificial chromosome technology and have been crossed onto the mouse PRL knockout background, resulting in mice that synthesize and secrete hPRL in the absence of mPRL. Our characterization studies demonstrate that the hPRL within the mice is: (1) expressed in a human-like pattern (including local production in the mammary gland), (2) secreted in a physiological fashion, and (3) controlled by known regulators (estrogen / dopamine). Further, we have shown that the hPRL produced in the mice is fully bioactive at the hPRL receptor within human breast cancer cells (T47D). We propose that these innovative models will be superior tools for examining the effects of hPRL on the growth and metastasis of human breast cancer xenografts. To this end, we have bred these mice onto the NOD/SCID immunodeficient background to allow for such preclinical studies of PRL in cancer. These novel mouse lines represent a major advancement in the research models available for the study of human breast cancer. As such, we expect that their use will have a significant impact on future diagnosis, prognosis and treatment of hormone-dependent breast cancers.
Citation Format: Heather R. Christensen, Michael K. Murawsky, Karen A. Gregerson. A novel, human-compatible mouse model for preclinical research on prolactin in breast 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 A18.
Abstract A21: Transgenic Onco-Pig cells mimic human cancer
Authors: Collares Tiago , Seixas Fabiana K. , Rund Laurie A. , Hu Wenping , Rodrigues Fernanda M. , Liang Ying , Singh Kuldeep , Counter Cristopher M. , Schook Lawrence B. 
Published: May 2015

Abstract
In order to take full advantage of the potential for new therapeutics and biotechnology applications, there is an urgent need for new animal models supporting cancer research. Pigs share many genetic and physiological similarities with humans. Our previous studies have shown that overexpression of several human oncogenes led to tumor development in pigs. Transgenic pigs were engineered to contain oncogenic KRASG12D and dominant-negative p53R167H, downstream of a LoxP-polyA (STOP)-LoxP sequence (LSL) and CAG promoter, such that exposure to Cre-recombinase induces their expression in desired tissues. Fibroblast cell strains generated from four such clones were infected with an adenovirus vector (Ad-Cre-GFP) encoding Cre recombinase and GFP protein or control vector (Ad-GFP) with GFP alone. Cells were analyzed for cell migration rates, cell proliferation, growth in soft agar, tumor development in immunodeficient mice, histopathological and characterization tumor and RT-PCR from tumor. All four cell strains expressed KRASG12D and p53R167H mRNA, transformed phenotypes such as increased cell migration rates, increase cell proliferation, and growth in soft agar. Migration rates in a wound assay were significantly different (184 vs 67 at 24 hr (p ≤ 0.01). CFSE assay determined that CRE cells divided twice as many times as control GFP cells in a 73 hr period (p ≤ 0.01). Additionally, GFP cells were unable to form colonies in soft agar, while each of the CRE cell lines formed over 100 colonies (p ≤ 0.01). CRE cell lines produced tumors in the mice (13/14) while no tumors developed from the GFP lines. Histopathological analyses revealed the tumors to be sarcomas, which were non-encapsulated, densely cellular and locally infiltrative with marked cellular and nuclear pleomorphism. Genetic analysis of tumor DNA showed the presence of CAG, KRASG12D and p53R167H transgene sequences. RT-PCR of tumor cDNA confirmed expression of the oncogenic KRASG12D and dominant-negative p53R167H mRNA from each tumor; therefore, demonstrating that induction of the transgenes in these porcine cells triggered a tumorigenic phenotype. Our next step will be to monitor tumor incidence following site-specific transgene induction in these Onco-pigs that can then be challenged with new anticancer therapies and interventional strategies.
Citation Format: Tiago Collares, Fabiana K. Seixas, Laurie A. Rund, Wenping Hu, Fernanda M. Rodrigues, Ying Liang, Kuldeep Singh, Cristopher M. Counter, Lawrence B. Schook. Transgenic Onco-Pig cells mimic human 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 A21.
Abstract A40: Pancreatic cancer patient-derived orthotopic xenograft (PDOX™) is effectively targeted by Salmonella typhimurium A1-R
Authors: Hiroshima Yukihiko , Zhao Ming , Maawy Ali , Zhang Yong , Katz Matthew H.G. , Fleming Jason B. , Uehara Fuminari , Miwa Shinji , Yano Shuya , Momiyama Masashi , Suetsugu Atsushi , Chishima Takashi , Tanaka Kuniya , Bouvet Michael , Endo Itaru , Hoffman Robert M. 
Published: May 2015

Abstract
The aim of this study is to determine the efficacy of tumor-targeting Salmonella typhimurium A1-R (A1-R) (Cancer Disc. 2, 588-590, 2012) on pancreatic cancer PDOX™ compared to standard chemotherapy. The PDOX™ was grown in transgenic nude red fluorescent protein (RFP) mice in order that the PDOX™ acquire RFP-expressing stroma in order to label the tumor. The RFP-PDOX™ were then orthotopically transplanted to non-transgenic nude mice in order to image tumor growth and drug efficacy. The RFP labeled stroma are stable upon passage. A1-R treatment significantly reduced tumor weight as well as tumor fluorescence area compared to untreated control (p = 0.011), with comparable efficacy of gemcitabine, cisplatin and 5-FU. A1-R had the highest efficacy compared to any of the chemotherapy drugs tested based on Evan's histological response criteria. The present report demonstrates Salmonella typhimurium A1-R was effective for human pancreatic PDOX™ and is a promising therapy for this highly treatment-resistant disease.
Citation Format: Yukihiko Hiroshima, Ming Zhao, Ali Maawy, Yong Zhang, Matthew H.G. Katz, Jason B. Fleming, Fuminari Uehara, Shinji Miwa, Shuya Yano, Masashi Momiyama, Atsushi Suetsugu, Takashi Chishima, Kuniya Tanaka, Michael Bouvet, Itaru Endo, Robert M. Hoffman. Pancreatic cancer patient-derived orthotopic xenograft (PDOX™) is effectively targeted by Salmonella typhimurium A1-R. [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 A40.
Abstract A44: Directing personalized breast cancer treatment with pathway signatures
Authors: Jhan Jing-Ru , Andrechek Eran 
Published: May 2015

Abstract
One of the major limitations in the treatment of breast cancer is the patient to patient heterogeneity of the tumors. This is evidenced by the well-known intrinsic subtypes of breast cancer, including luminal A and B, basal, claudin-low, HER2 and normal like. If one considers the hormonal status (ER / PR) of the breast cancers in addition to the intrinsic subtypes, then additional classifications are apparent. Indeed, recent work has suggested that there are approximately 17 subtypes of breast cancer. With these various types of breast cancer, clinicians are faced with the challenge of determining the optimal treatment strategy for the individual breast cancer patient. When treatment options are considered in this way, it becomes readily apparent that breast cancer, and cancer in general, needs to be treated with a personalized approach. We believe that one mechanism to address the requirement for personalized therapy is to employ cell signaling pathway signatures to differentiate the tumors into treatment groups. As a proof of principle experiment, we have used pathway signatures in a mouse model of breast cancer. The signatures clearly predict various subtypes of cancer in the MMTV-Myc model system with elevation of the EGFR, TNF and Ras pathway in one subtype of tumor whereas these pathways are not predicted to be active in a second subtype of cancer from the same model system. In the second tumor subtype, there is a high predicted activity for other pathways, including Myc, Stat3 and AKT. To demonstrate that these predictive signatures can be used to guide clinical therapy, we then took an approach where we targeted each of the pathways in a combinatorial approach with small molecule inhibitors in transplantable tumors from the initial tumor subtypes. Thus, we have two therapies, each tailored to a specific subtype of a mouse model breast cancer. Safety trials for the combination of the three drugs in each treatment arm revealed that there were no significant side effects when inhibitors were used at the low doses designed for use in therapy. Importantly, we have shown that the predicted combination therapy is effective in blocking tumor growth in the tumor type that is predicted to be responsive while it is ineffective in blocking tumor growth in the other subtype of tumors. These results clearly demonstrate in a proof of principle experiment that using pathway signatures is a viable mechanism for identifying and directing treatment for breast cancer.
Citation Format: Jing-Ru Jhan, Eran Andrechek. Directing personalized breast cancer treatment with pathway signatures. [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 A44.
Abstract B14: Gain of function contribution of mutant AKT-E17K to lung and mammary tumorigenesis in mouse models
Authors: Malanga Donatella , Belmonte Stefania , Belmonte Stefania , Marco Carmela De , Paciello Orlando , Baldi Alfonso , Viglietto Giuseppe 
Published: May 2015

Abstract
The hotspot Akt1-E17K mutation that results in a glutamic acid to lysine substitution in the seventeenth amino acid position in the pleckstrin homology domain of Akt1 occurs in approximately 0.6-2% of human lung cancers and in 6-8% of human breast cancer. To determine whether this Akt1 variant is a bona-fide activating mutation and to investigate the mechanistic basis of the Akt1 gain of function dependent mechanisms in lung and breast tumorigenesis we generated a transgenic Cre-inducible murine strain in the ROSA26 (R26) locus (R26-Akt1-E17K mice). To analyse the effects of mutant Akt1 in lung epithelium, we made use of two different systems to activate the transgene into pulmonary cells: intranasal instillation of an Adenovirus carrying the Cre recombinase (Ad-Cre) and the mating of R26-Akt1-E17K mice with Thyroid transcription factor-1 (TTF-1)-Cre mice that allow expression of the transgenes in lung epithelium. We report that in murine lung epithelium, mutant Akt1-E17K induces bronchial and/or bronchiolar hyperplastic lesions that at low frequency progress to frank carcinoma and accelerates tumor formation induced by chemical carcinogens. To assess the potential role of Akt1 as an oncogene in mammary epithelium, we examined the consequences of the mutant Akt1-E17K in the mammary gland of mice by mating of R26-Akt1-E17K mice with Mouse mammary tumor virus (MMTV)-Cre mice. We provide strong evidences that the expression of mutant Akt1-E17K in the mammary gland, driven by the MMTV promoter, was sufficient to produce a tumoral response in mice starting from 5-6 months of age. Transgenic mice developed invasive and in situ carcinoma in 45% of the cases and, in agreement with these results, mice that express activated Akt1 in the mammary gland showed poor survival
Citation Format: Donatella Malanga, Stefania Belmonte, Stefania Belmonte, Carmela De Marco, Orlando Paciello, Alfonso Baldi, Giuseppe Viglietto. Gain of function contribution of mutant AKT-E17K to lung and mammary tumorigenesis in 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 B14.