bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A102: Osteopontin produced by myeloid cells determines the outcome of breast cancer metastases
Authors: Colombo Mario P. , Chiodoni Claudia 
Published: May 2015

Abstract
The matricellular protein osteopontin (OPN) combines regulatory and structural functions in the extracellular matrix and, when produced by tumor cells, concurs to progression, cell invasion and metastasis. Little is known about its activity when produced by host cells including that component of tumor stroma. Combining gene silencing in tumor cells and mice deficient for OPN we have dissected the role of tumor and host produced OPN in breast cancer metastasis using 4T1 and BJMC3879 spontaneously metastatic models. While tumor produced OPN favors lung metastasis promoting tumor cell survival in the blood stream, stromal OPN greatly affects the immusuppression at the metastatic site. Immunosuppression is often associated with the expansion of a heterogeneous myeloid population called myeloid derived suppressor cells (MDSC) comprising a granulocytic (Gr-1high) and a monocytic (Gr-1int/low) subset, the latter endowed with higher immune suppressive capacity and characterized by OPN expression. Analysis of MDSC showed that inhibition of lung metastases in OPN-deficient mice goes along with a skewing toward the Gr1high subset, whereas the Gr1int/low subset is more expanded in wild type mice. Moreover, the latter subset, in lungs of tumor-bearing OPN-deficient animals, is less suppressive than its wild type counterpart, and associated with a lower expression of arginase-1, IL-6 and phospho-STAT3. Our results find correlation with human tumors and underscore that different mechanisms characterize tumor- and host-produced OPN activities in breast cancer metastasis and reveal a new function for host-derived OPN as regulator of the local immune response in the metastatic lung niche.
Citation Format: Mario P. Colombo, Claudia Chiodoni. Osteopontin produced by myeloid cells determines the outcome of breast cancer metastases. [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 A102.
Abstract A103: The neurotransmitter norepinephrine and β2-AR activation of MB-231 breast cancer cells alters fibrillar collagen structure
Authors: Dawes Ryan P. , Burke Kathleen A. , Stastka Petr , Brown Edward B. , Madden Kelley S. 
Published: May 2015

Abstract
The impact of psychosocial stress on breast cancer pathogenesis has become an area of intense research in the past several years. Sympathetic nervous system (SNS) activation and release of the catecholamine norepinephrine (NE) is a major stress pathway that promotes breast cancer pathogenesis. We have evidence that SNS activation can regulate breast tumor growth and metastasis by altering the tumor extracellular matrix (ECM), specifically fibrillar collagen. Alterations in fibrillar collagen microstructure can be detected using second harmonic generation multiphoton laser scanning microscopy (SHG MPLSM). This non-linear optical technique takes advantage of endogenous light scattering by non-centrosymmetric structures, including collagen. Stress-induced changes to the tumor collagen microstructure can be quantified by measuring the ratio of forward- to backward-scattered light (F/B ratio), as well as the directional coherence of resident collagen fibers. Here, we demonstrate that NE can directly stimulate breast cancer cells and tumor stromal cells to elicit changes in collagen microstructure. In these experiments, cells were pretreated with NE, washed to remove NE, and placed in 3D-type I collagen matrices. Pretreatment of MDA-MB-231 metastatic breast cancer cells with NE significantly lowered the F/B ratio and decreased fiber directional coherence of type I collagen gels. Treatment of MB-231 cells with the β2-adrenergic receptor (β2-AR) selective agonist, terbutaline, mimicked the effects of NE. Furthermore, NE pretreatment of the β-AR-negative metastatic breast cancer line, 4T1, did not elicit alterations in SHG F/B ratio or fiber coherence in collagen gels, compared to control cells. These results suggest that NE acts through tumor cell β2-AR to alter collagen microstructure. Future experiments will elucidate the molecular mediators of this collagen reorganization and determine the impact of such changes on tumor metastatic capacity. These experiments will provide new insights into mechanisms underlying stress-induced tumor pathogenesis that may reveal new therapeutic avenues for the treatment of breast cancer.
Citation Format: Ryan P. Dawes, Kathleen A. Burke, Petr Stastka, Edward B. Brown, Kelley S. Madden. The neurotransmitter norepinephrine and β2-AR activation of MB-231 breast cancer cells alters fibrillar collagen structure. [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 A103.
Abstract A121: Retinoic acid signaling and initiation of mammary gland development
Authors: Cho Kyoung-Won , Moon Woo-Kyung 
Published: May 2015

Abstract
Mammary glands are skin appendages whose development is initiated through continuous cell-cell interactions between ectoderm and adjacent mesenchyme. Considerable progress has been made in uncovering the molecular basis of these interactions in mammary gland formation in mouse embryos, including the network of initiating signals comprising Fgfs and Wnts, Bmps involved in gland positioning and transcription factors, Tbx3 and Lef1, essential for mammary gland development. Here we provide evidence that retinoic acid signaling may also be involved. Raldh2 is expressed in E10-E10.5 mouse embryos in ventral hypaxial extensions of somites adjacent to the flank region where mammary buds 2, 3 and 4 develop. This pattern of expression overlaps with that of Fgf10, known to be required for mammary gland formation. Manipulation of retinoic acid levels in organ cultures of E10.5 mouse embryo flank by adding either retinoic acid or citral, a retinoic acid synthesis inhibitor, resulted in changes in expression of genes involved in retinoic acid homeostasis and also showed that retinoic acid signaling is required for Tbx3 expression while high levels of retinoic acid signaling inhibit Bmp4 expression and repress Wnt signaling. The results of experiments using RNAi against Tbx3 and Wnt10b suggest that manipulating RA signaling in the mammary gland forming regions. Furthermore, RA affects expression of genes involved in mammary gland initiation. We produce a molecular model for mammary gland initiation incorporating retinoic acid signaling.
Citation Format: Kyoung-Won Cho, Woo-Kyung Moon. Retinoic acid signaling and initiation of mammary gland development. [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 A121.
Abstract A129: Contributions of RON downstream signaling to breast cancer progression
Authors: Faham Najme , Bieniasz Magdalena , Welm Alana 
Published: May 2015

Abstract
Since its discovery in 1993, various investigations have explored different roles of RON receptor tyrosine kinase in cancer pathogenesis. RON (also known as MST1R), a receptor tyrosine kinase with significant homology to c-Met, exhibits increased expression in at least 47% of human breast cancers, and deregulated expression of the RON signaling axis has been correlated with reduced metastasis-free survival. RON is known to activate multiple signaling pathways in vitro, including MAPK, phosphatidylinositol-3 kinase (PI3K), Src tyrosine kinase, phospholipase C-γ (PLC-γ) and β-catenin, largely through direct binding of SH2-domain containing adaptor proteins to the C-terminal docking site. However, the relationships of each of these signal transduction pathways to specific biologic responses relevant to cancer progression and metastasis are still poorly defined. To this end, we have taken advantage of a strategy used for c-Met in order to increase the binding affinity of individual adaptors to the docking site, which promotes signaling through one pathway at the expense of the others. The C-terminal part of RON contains two tandem tyrosines in a degenerate motif that when phosphorylated bind different SH2-containing molecules in a competitive manner. To amplify the signaling through particular pathways, we mutated the multifunctional docking site of RON to optimal binding motifs for PI3K, Src, Grb2 or PLC-γ. Mutations were introduced to the docking site using pMSCV retroviruses expressing human wild type Ron cDNA. As a negative control, two essential tyrosines in the docking site were replaced by phenylalanine to eliminate the transforming capability of RON. Viral transduction of the generated mutants or wild type RON was performed in MCF-7 and T47D breast cancer cells and LoVo colon cancer cells. Analysis of mRNA and protein showed the same expression levels among the mutants and wild type infected cells, indicating similar stability of the mutants compared with WT-RON. We report an analysis of RON signaling through the aforementioned pathways in the presence and absence of its ligand, macrophage stimulating protein (MSP). Our data indicate that the MAPK, PI3K, PLC-γ and Src pathways are differentially activated in the various cellular contexts we tested. Moreover, the activation of each signaling pathway occurs with different kinetics and with differential responses to MSP concentration.
Citation Format: Najme Faham, Magdalena Bieniasz, Alana Welm. Contributions of RON downstream signaling to 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 A129.
Abstract A132: The HER4 intracellular domain (4ICD) functions as a potent estrogen receptor coactivator mediating estrogen stimulated proliferation of breast tumor cells
Authors: Han Wen , Jones Frank 
Published: May 2015

Abstract
Among women with breast cancer more than 70% present with tumors expressing the estrogen receptor (ER) and will be treated with a therapeutic combination that includes endocrine therapy. Unfortunately, over 50% of these women fail therapy and develop incurable and often lethal metastatic disease. Disengaging ER interactions with essential transcriptional coactivators represents an effective approach to suppress ER driven breast cancer. To this end we have identified the HER4 intracellular domain (4ICD) as a potent estrogen receptor coactivator modulating estrogen induced gene expression and mediating estrogen stimulated proliferation of breast tumor cells. In multiple clinical studies, HER4 expression is significantly associated with ER positive tumors with up to 90% of ER positive breast tumors coexpressing HER4. These clinical observations imply a strong tumor cell selection for HER4 and ER coexpression. Estrogen stimulation of the ER and HER4 positive MCF-7 breast tumor cell line results in proteolytic processing of HER4 to release 4ICD. Significantly, estrogen stimulates nuclear translocation and binding of the 4ICD/ER complex to promoters containing estrogen response elements. Here we performed microarray gene expression analysis comparing MCF-7 cells with endogenous HER4 expression to MCF-7 cells where HER4 was stably suppressed. We found that estrogen significantly stimulated expression (2 fold and above) of 786 genes and 399 (51%) of these genes also required HER4 expression. Furthermore, chromatin immunoprecipitation (ChIP) analysis of two ER-inducible genes, progesterone receptor (PgR) and stromal-derived factor 1 (SDF-1) shows that 4ICD binds to PgR and SDF-1 gene promoters suggesting that it is required for efficient promoter binding of ER to certain ER-mediated genes. These results clearly indicate that 4ICD is an important ER coactivator that enhances ER promoter interactions. Finally, we have evidence that HER4/4ICD is required for estrogen stimulated tumor cell proliferation raising the possibility that disrupting the interaction between 4ICD and ER would represent a novel therapeutic approach to suppress breast tumorigenesis. In the future, we propose to identify additional transcription factors recruited with the ER/4ICD genomic complex.
Citation Format: Wen Han, Frank Jones. The HER4 intracellular domain (4ICD) functions as a potent estrogen receptor coactivator mediating estrogen stimulated proliferation of breast tumor 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 A132.
Abstract A133: The DNA cytosine deaminase APOBEC3B drives mutagenesis in breast cancer
Authors: Harris Reuben 
Published: May 2015

Abstract
A typical breast cancer accumulates hundreds to thousands of somatic mutations. Breast cancer mutation spectra are often dominated by C-to-T transition mutations, which occur in a mostly dispersed manner but can also occur in localized clusters called kataegis. Several lines of evidence indicate that the innate immune DNA cytosine deaminase APOBEC3B is the primary cause of these mutations. First, APOBEC3B mRNA is up-regulated in the majority of primary breast tumors and breast cancer cell lines. Second, endogenous APOBEC3B protein is predominantly nuclear and the only detectable source of DNA C-to-U editing activity in breast cancer cell line extracts. Third, APOBEC3B knockdown causes a corresponding decrease in genomic uracil concentrations, mutation frequencies, and C-to-T mutation levels in breast cancer cell lines. Fourth, the biochemical signature of APOBEC3B is over-represented in breast cancer mutation spectra. Fifth, breast carcinomas that express high levels of APOBEC3B have twice as many mutations as those expressing low levels. Finally, high levels of APOBEC3B associate with more aggressive disease including shorter durations of survival. All of these data are consistent with a model in which APOBEC3B-catalyzed DNA cytosine deamination provides a chronic source of DNA damage and mutagenesis in breast carcinomas that may help to explain how some tumors evolve rapidly and manifest gross heterogeneity.
Citation Format: Reuben Harris. The DNA cytosine deaminase APOBEC3B drives mutagenesis 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 A133.
Abstract A136: Deconstructing stemness from the fetal mammary perspective
Authors: Spike Benjamin T. , Engle Danielle D. , Lin Jennifer C. , Kelber Jonathan A. , La Justin , Cheung Samantha K. , Booker Evan , Rodewald Rose , Dravis Christopher , Gray Peter C. , Wahl Geoffrey M. 
Published: May 2015

Abstract
Somatic stem cells govern the development, maintenance and regeneration of tissues, and their dysregulation is associated with diverse pathologies including cancer. Given the significance of these cells both biologically and therapeutically, it is critical to elucidate the signaling mechanisms that dictate their behavior. Our recent work on the fetal mammary gland has dissected complementary roles for the stem cell compartment and stromal cues in fetal mammary stem cell function. We also identified significant similarities between the gene expression profiles of some of the most aggressive and untreatable forms of human breast cancer and those of the mouse fetal stem cell enriched mammary epithelial and stromal fractions. These similarities suggest that stem cell regulatory mechanisms operative during organogenesis, including those specified by the stromal niche, may serve as novel therapeutic targets in these cancers.
We also discovered significant gene expression heterogeneity within the fetal stem cell compartment when analyzed at single cell resolution. While such heterogeneity likely reflects the natural diversity of stem and non-stem cell states comprising the system, it confounds the interpretation of expression profiles from mixed populations and the delineation of stem cell specific and niche specific molecular components. Our current objective is to utilize genome wide single cell RNA-Sequencing to hasten the identification of functionally relevant, stem cell specific regulators and markers in the context of this multi-cellular/multi-signal system. Among other candidates, we have identified the Cripto/GRP78 signaling axis as a critical regulator of mammary stem cell activity, and have developed novel molecular genetic tools to temporally control the activity of candidate stem cell regulators in vivo in normal and neoplastic contexts. Integration of these tools promises to deliver a new molecular understanding of stem cell biology in the mammary gland and other systems and of stem cell-like cancer cells.
Citation Format: Benjamin T. Spike, Danielle D. Engle, Jennifer C. Lin, Jonathan A. Kelber, Justin La, Samantha K. Cheung, Evan Booker, Rose Rodewald, Christopher Dravis, Peter C. Gray, Geoffrey M. Wahl. Deconstructing stemness from the fetal mammary perspective. [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 A136.
Abstract B056: p70S6K activity drives local relapse in breast cancer
Authors: Segatto Ilenia , Berton Stefania , Sonego Maura , Massarut Samuele , Perin Tiziana , Baldassarre Gustavo , Belletti Barbara 
Published: May 2015

Abstract
For early breast cancer (EBC) patients local relapse represents what mostly influences disease outcome. Notably, 90% of local recurrences occur at or close to the same quadrant of the primary cancer. Surgery itself and the consequent process of wound healing have been proposed to stimulate local recurrences via pathway(s) still to be clarified. Our previous studies implicated p70S6K pathway in breast cancer cell response to post-surgical inflammation, supporting the hypothesis that it may be crucial also for breast cancer recurrence.
We designed an in vivo experimental model resembling the course of human BC, in which MDA-MB-231 breast cancer cells were bilaterally injected in nude mice mammary fat pads and, when primary tumors were grown, masses were surgically removed under anesthesia. After recovering, mice were followed up to detect appearance of local relapse. Using this model, we dissected the role of p70S6K during breast cancer growth and recurrence by modulating its activity using both genetic and pharmacologic approaches.
Our results showed that p70S6K positively contributed to proliferation and survival programs in breast cancer cell lines. In vivo, the analysis of the impact of p70S6K on primary tumor growth highlighted that a robust p70S6K signaling was required for the initiation of the tumor masses. But, more importantly, interfering with p70S6K activity strongly impaired local relapse. A three-day schedule of peri-operative treatment using specific pharmacological inhibition of p70S6K1 was sufficient to reduce by 83% the rate of local recurrence. We showed that inhibition of p70S6K activity induced apoptosis in cells challenged to survive in a hostile environment, supporting the idea that p70S6K signaling is necessary for the survival of isolated cancer cells in breast microenvironment, following surgery. The significance of our results was confirmed in human EBC specimens, proving that p70S6K activity is robustly induced by surgery, also in human patients.
Taken together, our results provide a biological rationale for peri-operative treatment targeting p70S6K pathway, directed to compensating the harmful consequences of surgery and to restraining local recurrence in early breast cancer patients.
Citation Format: Ilenia Segatto, Stefania Berton, Maura Sonego, Samuele Massarut, Tiziana Perin, Gustavo Baldassarre, Barbara Belletti. p70S6K activity drives local relapse 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 B056.
Abstract B063: Tumor targeting and diagnostic applications of glycosylated nanotubes
Authors: Singh Ravi N. 
Published: May 2015

Abstract
The goal of this research is to develop a new agent based on multiwalled carbon nanotubes (MWCNT) for the diagnosis and monitoring of advanced breast cancer. MWCNT consist of sheets of graphene carbon rolled into multiwalled tubes and possess many properties that make them extremely useful in biomedical applications, including targeted molecular imaging. Foremost is their ability to deliver large numbers of imaging agents per each targeted molecular recognition event, which can improve the sensitivity of imaging; secondly, they can deliver several different types of imaging agents (such as magnetic resonance imaging or photoacoustic agents) to perform multimodality imaging; thirdly, they can be used for therapeutic applications including chemotherapeutic drug or gene delivery, and as mediators for photothermal cancer therapy. As early and accurate diagnosis is still the most effective approach to treating cancer, improvements in the use of imaging technology to detect and monitor cancer will have a dramatic effect on human health. Breast cancer cells have alterations in the normal metabolism of the sugar, glucose, and exhibit increased glucose uptake and decreased glucose clearance. The hypothesis to be tested is that MWCNTs targeted to glucose transporters will be taken up by cancer cells with high efficiency, and that such MWCNT can be engineered to be effective cancer diagnostic agents. To this end, we have chemically engineered MWCNTs to display deoxyglucose on their surface, which rendered them water soluble, and targets them to cancer cells. It is anticipated that this agent will serve as the basis for a multimodal platform for future combined cancer therapy and diagnostic applications. We now report on our initial findings with this agent, and describe: 1) a new, glycosylated MWCNT which can be traced by radiolabelling; 2) data on clinically-relevant issues relating to blood compatibility, and preclinical data on toxicity (clot formation), biodistribution, blood, urinary, and fecal clearance of intravenously injected glycosylated MWCNT, all of which will be essential for any future translational applications; 3) a new nanomedical platform technology, developed specifically to target and diagnose invasive breast cancer, but with broad applicability to many types of cancer.
Citation Format: Ravi N. Singh. Tumor targeting and diagnostic applications of glycosylated nanotubes. [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 B063.