Abstract B66: The immunoproteasome: A point of convergence between immune response chemokine signaling and metastasis in breast cancer
This study demonstrates a knowledge-based and data-driven approach to discovery of gene modules underlying organotropic metastasis in breast cancer. This network resource will serve as a foundation for future research into both the underlying mechanisms driving organotropic metastasis and the development of subtype-specific therapies.Citation Format: Alison M. Anderson. The immunoproteasome: A point of convergence between immune response chemokine signaling and metastasis in breast cancer. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research; Oct 17-20, 2015; Bellevue, WA. Philad...
Source: Molecular Cancer Research - February 29, 2016 Category: Cancer & Oncology Authors: Anderson, A. M. Tags: Tumor Microenvironment and Immunotherapy: Poster Presentations - Proffered Abstracts Source Type: research

Abstract A66: Comprehensive gene expression analysis of ductal carcinoma in situ (DCIS) progression to invasive breast cancer reveals potential biomarkers
The big challenge in breast cancer is to discriminate which patients with non-invasive disease would benefit from minimal clinical interventions from those who require a more traditional treatment approach, keeping the highest survival rates. Hence, identification of molecular alterations of epithelial cells that take place in earliest stages of ductal carcinoma in situ (DCIS) progression is crucial for understanding the invasion process and for guiding the design of intervention strategies. In order to assess the molecular changes that occur during progression of non-invasive breast cancer we analyzed gene expression of e...
Source: Molecular Cancer Research - February 29, 2016 Category: Cancer & Oncology Authors: Elias, E. V., Castro, N. P. d., Pineda, P. H. B., Abuazar, C. S., Pinilla, M. G., Osorio, C. A., Silva, S. D. d., Napolitano, E. F. e., Brentani, H. P., Carraro, D. M. Tags: Other Topics: Poster Presentations - Proffered Abstracts Source Type: research

Abstract B65: Live-cell imaging of 3D/4D parallel co-cultures of breast carcinoma cells and breast fibroblasts in tissue architecture and microenvironment engineering (TAME) chambers
Interactions among breast carcinoma cells and other cells in the tumor microenvironment, e.g., stromal fibroblasts and immune cells, contribute to malignant progression. We have developed three dimensional (3D) co-culture models and live-cell imaging assays for the analysis of such interactions in real-time, focusing on interactions and associated signaling pathways that might be druggable. Bissell, Brugge and colleagues have elegantly shown that the 3D context of breast cells is essential for their development and neoplastic progression, and the genes down-regulated during acini development in 3D culture are prognostic fo...
Source: Molecular Cancer Research - February 29, 2016 Category: Cancer & Oncology Authors: Ji, K., Zhao, Z., Moin, K., Xu, Y., Sloane, B. F. Tags: Tumor Microenvironment and Immunotherapy: Poster Presentations - Proffered Abstracts Source Type: research

Abstract B64: Macrophage-specific deletion of STAT5 disrupts normal mammary gland development and accelerates mammary tumorigenesis
Fibroblast growth factor receptor 1 (FGFR1) is amplified in 10% of human breast cancers and the ligands for FGFR1 are overexpressed in 60% of triple negative breast cancers. Additionally, amplification of the FGFR1 locus can confer resistance to endocrine-based therapies in patients with estrogen receptor (ER) positive tumors. Previous studies using a mouse model of FGFR1-induced mammary tumorigenesis demonstrated that FGFR1 activation in mammary epithelial cells recruits macrophages to hyperplastic regions where they promote angiogenesis and epithelial cell proliferation. Clinically, patients with increased numbers of tum...
Source: Molecular Cancer Research - February 29, 2016 Category: Cancer & Oncology Authors: Brady, N. J., Farrar, M. A., Schwertfeger, K. L. Tags: Tumor Microenvironment and Immunotherapy: Poster Presentations - Proffered Abstracts Source Type: research

Abstract B63: The utility and mechanistic basis of CTLA-4 and PD-1 immunotherapeutic checkpoint inhibitors in enhancing tumor-specific adaptive responses to effectively treat triple-negative breast cancer
While most breast cancers driven by estrogen-mediated signaling (ER+) or HER2 expression (HER2+) can be effectively treated by agents targeting these pathways, recent deep sequencing efforts have failed to identify widespread targetable drivers in Triple Negative Breast Cancers (TNBCs). Despite a lack of unifying drivers, our lab and others have uncovered that these cancers are highly inflammatory and associated with higher numbers of infiltrating immune cells (including CD8+ T-cells and Foxp3+ T-regulatory cells) , as well as expressing immuno-suppressive molecules (such as PD-L1). We hypothesized that despite TNBC molecu...
Source: Molecular Cancer Research - February 29, 2016 Category: Cancer & Oncology Authors: Crosby, E., Wei, J.-P., Yang, X.-Y., Lei, G., Wang, T., Lyerly, H. K., Hartman, Z. C. Tags: Tumor Microenvironment and Immunotherapy: Poster Presentations - Proffered Abstracts Source Type: research

Abstract A63: Clonal analysis of normal and malignant human mammary epithelial cell responsiveness to radiation
Knowledge gap: Fatal breast cancers are characterized by biological, genomic and extensive treatment heterogeneity. Although many breast cancers can now be cured by established therapies, treatment failure remains a major problem and is difficult to predict. In the current era of "personalized medicine", a possible solution is to develop a large-scale system for quantifying responses to candidate treatments of individual malignant human mammary cells with in vivo clonogenic activity. Such cells can be detected by their ability to produce uniquely barcoded clones of progeny in xenografted immunodeficient mice and ...
Source: Molecular Cancer Research - February 29, 2016 Category: Cancer & Oncology Authors: Balani, S., Kannan, N., Nguyen, L. V., Lefort, S., Pellacani, D., Eaves, C. J. Tags: Other Topics: Poster Presentations - Proffered Abstracts Source Type: research

Abstract B62: A novel combination HER2, brachyury, and MUC1 adenovirus based vaccines for a multitargeted immunotherapy approach to treat breast cancer
This study lays the foundation to test whether a multi-targeted immunotherapy employing HER2/neu, MUC1 and Brachyury vaccines can result in greater anti-tumor activity against established tumors as well as prevent the development of metastatic disease in breast cancer patients.Citation Format: Yvette Latchman, Adrian Rice, Joseph Balint, Elizabeth Gabitzsch, Jeffrey Schlom, Frank Jones. A novel combination HER2, brachyury, and MUC1 adenovirus based vaccines for a multitargeted immunotherapy approach to treat breast cancer. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research; Oct...
Source: Molecular Cancer Research - February 29, 2016 Category: Cancer & Oncology Authors: Latchman, Y., Rice, A., Balint, J., Gabitzsch, E., Schlom, J., Jones, F. Tags: Tumor Microenvironment and Immunotherapy: Poster Presentations - Proffered Abstracts Source Type: research

Abstract A61: Cell cycle regulated centrosome orientation during directed migration requires Aurora Kinase A
Cell cycle progression and the acquisition of a migratory phenotype are hallmarks of human carcinoma cells. Here we report a strong correlation between cell cycle progression into G2 phase and an increased migratory velocity for non-malignant, immortalized mammary epithelia nMuMG (Mus musculus mammary gland) cells, or malignant cervical carcinoma HeLa cells, expressing a fluorescent ubiquitin cell cycle indicator and quantified in wound closure assays with high content multi-parameter live cell imaging. Cells at the wound edge exhibited elevated microtubule nucleation capacity at centrosomes, and a reduction of this capaci...
Source: Molecular Cancer Research - February 29, 2016 Category: Cancer & Oncology Authors: Chu, T. L., Won, J., Nemirovsky, O., Fotovati, A., Nielsen, T., Maxwell, C. A. Tags: Other Topics: Poster Presentations - Proffered Abstracts Source Type: research

Abstract B60: The clinical significance and molecular features of the spatial tumor shapes in breast cancers
Conclusion: The present study validates the usefulness of the current tumor size method in determining tumor stages. Furthermore, we show that the tumors with high eccentricity are more likely to have aggressive tumor characteristics. Genes involved in the extracellular matrix remodeling are candidate regulators of the spatial tumor shapes in breast cancer.Citation Format: Hyeong-Gon Moon, Namshin Kim, Minju Lee, HyunHye Moon, Tae-Kyung Yoo, Han-Byoel Lee, Jisun Kim, Dong-Young Noh, Wonshik Han. The clinical significance and molecular features of the spatial tumor shapes in breast cancers. [abstract]. In: Proceedings of th...
Source: Molecular Cancer Research - February 29, 2016 Category: Cancer & Oncology Authors: Moon, H.-G., Kim, N., Lee, M., Moon, H., Yoo, T.-K., Lee, H.-B., Kim, J., Noh, D.-Y., Han, W. Tags: Tumor Microenvironment and Immunotherapy: Poster Presentations - Proffered Abstracts Source Type: research

Abstract A60: DOK1 gene may act as a tumor suppressor in breast cancer
The DOK1 (Downstream of Tyrosine kinase 1) gene is a putative tumor suppressor gene located on human chromosome 2p13 which is frequently rearranged in leukaemia and other human tumours. The DOK1 protein is a member of the Dok protein family comprising seven members. It inhibits MAP kinase activity and displays anti-proliferative activities. The DOK1 gene may act as a tumor suppressor gene in ovarian cancer, Burkitt lymphoma, head and neck cancer (HNC), chronic lymphocytic leukaemia (CLL) and lung cancer by inhibiting cell proliferation. So far there is no study in the literature analyzing the relationship between the DOK1 ...
Source: Molecular Cancer Research - February 29, 2016 Category: Cancer & Oncology Authors: Buyru, N., Tuna, E., Ozdemir, F., Bulut, P., Dalay, N. Tags: Other Topics: Poster Presentations - Proffered Abstracts Source Type: research

Abstract B59: Age and estrogen-dependent inflammation in breast adenocarcinoma and normal breast tissue
Chronic inflammation promotes breast tumor growth and invasion by accelerating angiogenesis and tissue remodeling in the tumor microenvironment. There is a complex relationship between inflammation and estrogen, which drives the growth of 70 percent of breast tumors. Low levels of estrogen exposure stimulate macrophages and other inflammatory cell populations, but very high levels are immune suppressive. Breast tumor incidence is increased by obesity and age, which interact to influence inflammatory cell populations in normal breast tissue. To characterize the impact of these factors on tumors and the tumor microenvironmen...
Source: Molecular Cancer Research - February 29, 2016 Category: Cancer & Oncology Authors: Quigley, D. A., Tahiri, A., Lüders, T., Riis, M. H., Balmain, A., Borresen-Dale, A.-L., Bukholm, I. R., Kristensen, V. Tags: Tumor Microenvironment and Immunotherapy: Poster Presentations - Proffered Abstracts Source Type: research

Abstract A59: Prognostic relevance of PTEN and TP53 deletion in breast cancer
Inactivation of PTEN and TP53 have been suggested to promote unfavorable phenotypes in various cancers, including breast cancer. Chromosomal deletion is one well established mechanism for inactivation of these genes. In breast cancer, deletions of TP53 and PTEN are known to occur, but systematic analyses of its clinical relevance are lacking. We thus analyzed a tissue microarray (TMA) with 2,197 breast cancers by fluorescence in-situ hybridization (FISH) using specific probes against TP53 and PTEN in combination with respective centromere probes. We found, that TP53 deletion (29%/1026 cancers) occur more frequent in breast...
Source: Molecular Cancer Research - February 29, 2016 Category: Cancer & Oncology Authors: Kluth, M., Lebeau, A., Witzel, I., Mahner, S., Woelber, L., Geist, S., Paluchowski, P., Wilke, C., Heilenkoetter, U., Mueller, V., Simon, R., Sauter, G., Terracciano, L., Krech, R., Assen, A. v. d., Burandt, E., Lebok, P. Tags: Other Topics: Poster Presentations - Proffered Abstracts Source Type: research

Abstract B58: Inflammatory signaling regulates osteoprotegerin expression in breast cancer cells
Osteoprotegerin (OPG) is a secreted member of the Tumor Necrosis Factor family. In addition to the functional roles of OPG in bone metabolism and apoptosis, there is growing evidence of the tumor promoting role of OPG in breast cancer. We have previously shown OPG can promote the invasion and metastasis of triple negative breast cancer cells. To understand the regulation of OPG, we are investigating the molecular mechanisms that control OPG expression in breast cancer cells.Breast cancer cell lines MDA-MB-231 and MDA-MB-436 (triple negative); SKBR-3 and HCC1954 (Human Epidermal Growth Factor Receptor 2 positive; HER2+); ZR...
Source: Molecular Cancer Research - February 29, 2016 Category: Cancer & Oncology Authors: Chung, S. T. M., Renaud, A., Roseman, K., Yadav, N., Connelly, L. Tags: Tumor Microenvironment and Immunotherapy: Poster Presentations - Proffered Abstracts Source Type: research

Abstract A58: Expression and function of endothelin converting enzyme 1 and endothelin receptors in breast cancer invasion
The endothelin axis, comprised of the active peptides endothelin 1-3 (ET1-3), the endothelin A receptor (ETAR) and endothelin B receptor (ETBR), and endothelin converting enzyme 1 (ECE1) has been studied in numerous cancers. In clinical samples of breast cancer, increased levels of ET1, ECE1, and the endothelin receptors have been reported, and several studies correlate expression of these proteins with poor prognosis. The endothelin pathway is known to induce mitogen activated protein kinase activation, leading to increased survival, proliferation, and migration, but the precise role of ECE1 and the endothelin receptors i...
Source: Molecular Cancer Research - February 29, 2016 Category: Cancer & Oncology Authors: Belles, M. E., Halaka, M., Do, J. M., Majmudar, P., Sidani, R., Stephen, H., Watson, M., Conway, R. E. Tags: Other Topics: Poster Presentations - Proffered Abstracts Source Type: research

Abstract B57: Assessment of gene expression of calcium pumps, channels, and channel regulators in human breast cancer-associated fibroblasts
Fibroblasts represent one of the predominant stromal cell populations present in the breast tumor microenvironment. Cancer-associated fibroblasts found growing in close proximity to the tumor site are thought to influence tumor behavior. While a number of protein and mRNA markers showing differential expression between cancer-associated and non-cancer associated fibroblasts have been proposed, current understanding of the phenotypic differences between these two cell populations remains incomplete. Calcium signaling plays an important role in each of the cancer hallmarks and is altered in a variety of disease states includ...
Source: Molecular Cancer Research - February 29, 2016 Category: Cancer & Oncology Authors: Stewart, T. A., Soon, P. S., Roberts-Thomson, S. J., Monteith, G. R. Tags: Tumor Microenvironment and Immunotherapy: Poster Presentations - Proffered Abstracts Source Type: research

Abstract A57: Evaluation of the pathologic predictors of treatment response to neoadjuvant chemotherapy for invasive lobular breast cancer
Conclusions: Despite a limited sample size, this study shows that pathologic predictors (pleomorphic subtype, Ki-67, and HER2 status) are significant predictors of response to NAC, and may be useful in determining which ILC patients will benefit from NAC. This is an important finding because NAC for non-responders may delay the initiation of surgery and hormonal treatments for ILC.Citation Format: Michaela L. Tsai, Marsha J. Finkelstein, Tamera J. Lillemoe, Barbara Susnik, Erin Grimm, Sung-Hae Kang, Caitlin Kelly, Karen K. Swenson. Evaluation of the pathologic predictors of treatment response to neoadjuvant chemotherapy fo...
Source: Molecular Cancer Research - February 29, 2016 Category: Cancer & Oncology Authors: Tsai, M. L., Finkelstein, M. J., Lillemoe, T. J., Susnik, B., Grimm, E., Kang, S.-H., Kelly, C., Swenson, K. K. Tags: Other Topics: Poster Presentations - Proffered Abstracts Source Type: research

Abstract B56: Prolactin promotes breast cancer to bone metastasis and breast cancer cell-mediated osteoclast differentiation
The hormones prolactin (PRL), estrogen and progesterone have long been studied for their role in the primary breast tumor but not yet in modulating the secondary tumor microenvironment of the bone. Metastasis to the bone is a debilitating aspect of many cancers, including breast cancer, where it is a preferred site of metastasis that results in bone loss. Breast cancer cells release osteolytic factors that induce the breakdown of bone, which releases growth factors and calcium that create a vicious cycle of metastatic tumor growth. Using quantitative immunohistochemistry (AQUA) (n=134), we determined that high PRL-receptor...
Source: Molecular Cancer Research - February 29, 2016 Category: Cancer & Oncology Authors: Forsyth, A., Sutherland, A., Cong, Y., Grant, L., Juan, T.-H., Lee, J. K., Klimowicz, A., Petrillo, S. K., Hu, J., Chan, A., Boutillon, F., Goffin, V., Egan, C., Tang, P. A., Cai, L., Morris, D., Magliocco, A., Shemanko, C. S. Tags: Tumor Microenvironment and Immunotherapy: Poster Presentations - Proffered Abstracts Source Type: research

Abstract A56: Regulation of breast tumor kinase (Brk) expression in triple-negative breast cancer integrates cellular (HIF-2alpha) and hormonal (cortisol) stress signaling
Triple-negative breast cancers (TNBC) have a worse prognosis relative to other breast cancer subtypes, underscoring the urgent need for identification of driver molecules or pathways for targeted therapies. Breast tumor kinase (Brk) is a soluble tyrosine kinase that is aberrantly elevated and active in 86% of breast cancers. Our lab has shown Brk to be a potent driver of basal-type mammary tumors. Mechanisms through which Brk overexpression is acquired in breast cancer cells are largely unknown. We recently reported that Brk is a direct target gene of hypoxia-inducible factor 1 alpha (HIF-1alpha) and HIF-2alpha, activated ...
Source: Molecular Cancer Research - February 29, 2016 Category: Cancer & Oncology Authors: Anderson, T. M. R., Ma, S., Raj, G. V., Lange, C. A. Tags: Other Topics: Poster Presentations - Proffered Abstracts Source Type: research

Abstract B55: Suppression of CD8 T-cell activation by tryptophan catabolism in triple-negative breast cancer
Background: The ability of cancer cells to evade and suppress an antitumor immune response is increasingly recognized as a critical feature of aggressive, metastatic disease. Conversion of the amino acid tryptophan (trp) into the catabolite kynurenine (kyn) and the subsequent secretion of kyn is a current area of interest in the field of antitumor immunity, given that trp depletion is a trigger for T-cell death, and that kyn binds to and activates the aryl-hydrocarbon receptor (AhR) in immune cells, often with immunosuppressive consequences. In a screen to identify mechanisms promoting survival of triple-negative breast ca...
Source: Molecular Cancer Research - February 29, 2016 Category: Cancer & Oncology Authors: Greene, L. I., Bruno, T. C., Rogers, T. J., Slansky, J. E., Borges, V. F., Richer, J. K. Tags: Tumor Microenvironment and Immunotherapy: Poster Presentations - Proffered Abstracts Source Type: research

Abstract A55: Exosome-associated microRNAs as plasma biomarkers for breast cancer
Conclusions: Several microRNAs are selectively enriched in breast cancer exosomes, which can be detected in the plasma of PDX mice and breast cancer patients. MUC1 is a viable membrane protein candidate for selective capture of circulating breast cancer specific exosomes from the plasma. These results suggest that selective capture and molecular analysis of breast cancer specific circulating exosomes is a promising strategy for breast cancer biomarker development.Citation Format: Bethany N. Hannafon, Yvonne D. Trigoso, David H. Lum, Alana L. Welm, William C. Dooley, Wei-Qun Ding. Exosome-associated microRNAs as plasma biom...
Source: Molecular Cancer Research - February 29, 2016 Category: Cancer & Oncology Authors: Hannafon, B. N., Trigoso, Y. D., Lum, D. H., Welm, A. L., Dooley, W. C., Ding, W.-Q. Tags: Other Topics: Poster Presentations - Proffered Abstracts Source Type: research

Abstract B54: Location of tumor burden influences tumor and vascular architecture, necrosis, and nanoparticle delivery
The gene and protein expression profile of a metastatic lesion can vary from the primary tumor. As a result, behavior of a secondary lesion can differ in the context of drug uptake and sensitivity as compared to the parent tumor. A better understanding of phenotypic variations that arise as a result of location of disease burden may be able to shed light on why widely used subcutaneous and orthotopic preclinical models fail to predict clinical success of drug candidates evaluated in the metastatic setting. These data can be used as a guide for preclinical study design in drug discovery. Our objective was to examine metasta...
Source: Molecular Cancer Research - February 29, 2016 Category: Cancer & Oncology Authors: Kalra, J., Baker, J., Kyle, A., Minchinton, A., Bally, M. Tags: Tumor Heterogeneity (Intratumor and Intertumoral): Poster Presentations - Proffered Abstracts Source Type: research

Abstract A54: Met and its ligand HGF predict radiotherapy response in premenopausal breast cancer patients
Post-operative radiotherapy effectively decreases the risk for loco-regional recurrence in breast cancer. However, some patients display signs of radioresistance. There are few biomarkers used in the clinic today to predict response to radiotherapy, and patients continue to receive unnecessary treatment. Studies propose a role for the receptor tyrosine kinase Met and its ligand HGF in radioresistance. Therefore, it was aimed in this study to determine MET and HGF copy numbers, Met and HGF expression, and phosphorylated Met expression in breast cancers to elucidate Met and HGF's role in radiotherapy response. MET and HGF co...
Source: Molecular Cancer Research - February 29, 2016 Category: Cancer & Oncology Authors: Veenstra, C., Perez-Tenorio, G., Nordensköljd, B., Fornander, T., Stal, O. Tags: Other Topics: Poster Presentations - Proffered Abstracts Source Type: research

Abstract B53: Genomic redefinition of Her2+ breast shows role of estrogen and androgen signaling
In conclusion, considering the transcriptional profile of Her2+ breast tumors provides combination strategies and viable treatment options for patients who developed resistance to Her2-targeted treatments, with endocrine therapies for Her2+/ER+ tumors, and antiandrogen strategies for Her2+/AR+ tumors. Furthermore, co-ordinated regulation of Her2 and neighboring genes supports the notion that the effect of the Her2 amplicon may be more than through overexpression of Her2.Citation Format: Anneleen Daemen, Jacob Rinaldi, Gerard Manning. Genomic redefinition of Her2+ breast shows role of estrogen and androgen signaling. [abstr...
Source: Molecular Cancer Research - February 29, 2016 Category: Cancer & Oncology Authors: Daemen, A., Rinaldi, J., Manning, G. Tags: Tumor Heterogeneity (Intratumor and Intertumoral): Poster Presentations - Proffered Abstracts Source Type: research

Abstract A53: An analysis of breast cancer incidence in young women: A single site study
Conclusions: This retrospective study indicates that breast cancer diagnosed in women younger than 45 y.o. is associated with an aggressive clinical and molecular subtype. Delay in diagnosis has been a concern among this age group given the lack of screening guidelines. In our country Georgia screening starts from 40 years. More awareness, screening programs and trainings to both practitioners and young women should be implemented.Note: This abstract was not presented at the conference.Citation Format: Tamta Makharadze. An analysis of breast cancer incidence in young women: A single site study. [abstract]. In: Proceedings ...
Source: Molecular Cancer Research - February 29, 2016 Category: Cancer & Oncology Authors: Makharadze, T. Tags: Other Topics: Poster Presentations - Proffered Abstracts Source Type: research

Abstract B52: Overcoming phenotypic heterogeneity and plasticity in basal-like breast cancer through targeting adaptive pathway use
In this study, we seek to identify such drug combinations through first identifying single agent therapeutics that reduce phenotypic heterogeneity and enrich distinct cell-states with common pathway reliance. To do so, we focus on phenotypic heterogeneity in tumor-cell lineage-state; using immunofluorescent staining against markers of the luminal, basal, and mesenchymal lineages, we combine high-throughput drug screening with high-content imaging and pursue small-molecule inhibitors that reduce phenotypic heterogeneity and promote the accumulation of particular lineage-states in residual cell populations. We observe pronou...
Source: Molecular Cancer Research - February 29, 2016 Category: Cancer & Oncology Authors: Risom, T., Langer, E., Rantala, J., Alvarez, M., Johnson-Camacho, K., Pelz, C., Wang, N., Spellman, P., Califano, A., Gray, J., Sears, R. Tags: Tumor Heterogeneity (Intratumor and Intertumoral): Poster Presentations - Proffered Abstracts Source Type: research

Abstract A52: The microRNA control of 17{beta}-hydroxysteroid dehydrogenase type 1 and 2 in breast cancer
Conclusion: These findings are the first which start to map out the microRNA regulation of 17β-HSD type 1 and 2 in breast cancer, and this may be one important mechanism by which their expression levels are regulated in the pathogenesis of breast cancer.Citation Format: Erik Hilborn, Olle Stal, Agneta Jansson. The microRNA control of 17β-hydroxysteroid dehydrogenase type 1 and 2 in breast cancer. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research; Oct 17-20, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(2_Suppl):Abstract nr A52. (Source: Molecular Cancer Research)
Source: Molecular Cancer Research - February 29, 2016 Category: Cancer & Oncology Authors: Hilborn, E., Stal, O., Jansson, A. Tags: Other Topics: Poster Presentations - Proffered Abstracts Source Type: research

Abstract B51: Modeling the intrinsic and extrinsic influences on breast cancer phenotypic heterogeneity using mouse models and three-dimensional bioprinting
Breast cancer cells exhibit intertumoral and intratumoral heterogeneity due to both tumor cell intrinsic and extrinsic influence. We have been modeling phenotypic heterogeneity in breast cancer using multiple model systems to interrogate the causes of this heterogeneity as well as its effects on therapeutic resistance. Toward this end, we generated a novel, genetically-engineered mouse model of triple negative breast cancer driven by loss of PTEN in combination with low-level deregulated c-Myc expression. Expression of deregulated Myc significantly accelerates tumorigenesis in this model. Histologic and global gene express...
Source: Molecular Cancer Research - February 29, 2016 Category: Cancer & Oncology Authors: Langer, E. M., Wang, X., Liang, J., Allen-Petersen, B. L., Kendsersky, N. D., Risom, T., Pelz, C., Sears, R. C. Tags: Tumor Heterogeneity (Intratumor and Intertumoral): Poster Presentations - Proffered Abstracts Source Type: research

Abstract A51: Investigation of the DEK oncogene as a blood biomarker for breast cancer
Breast cancer (BC) is one of the leading causes of death for women in the United States. This is due, in part, because women wait too long to get a diagnosis or the disease returns, sometimes years later, due to ineffective treatment. Therefore, it is critically important to identify biomarkers that can better inform clinicians while providing a screening test more amenable to patients than mammograms. We are investigating the feasibility of using DEK protein levels in patient plasma as a biomarker for disease stage and prognosis. DEK is a chromatin-organizing protein that functions in DNA replication and repair, transcrip...
Source: Molecular Cancer Research - February 29, 2016 Category: Cancer & Oncology Authors: Sendilnathan, A., Charif, M., Shaughnessy, E., Lewis, J. D., Radhakrishnan, N., Lower, E., Lanigan, C., Kumar, H., Wise-Draper, T. M., Vinnedge, L. P. Tags: New Omics in Breast Cancer: Poster Presentations - Proffered Abstracts Source Type: research

Abstract A50: Nonredundant functions of splicing factors in breast-cancer initiation and metastasis
Alternative splicing is a key control point in gene expression, whose misregulation contributes to cancer malignancy. Although certain splicing factors (SFs) and their targets are altered in human tumors, the functional significance of these alterations remains unclear. We previously demonstrated that the splicing factor SRSF1 is upregulated in human breast tumors and promotes transformation in vivo and in vitro. SRSF1 is a prototypical member of the SR protein family, composed of 12 structurally related proteins. However, little is known about differences and redundancies in their splicing targets and biological functions...
Source: Molecular Cancer Research - February 29, 2016 Category: Cancer & Oncology Authors: Anczukow, O., Das, S., Lin, K.-T., Wu, J., Akerman, M., Muthuswamy, S. K., Krainer, A. R. Tags: New Omics in Breast Cancer: Poster Presentations - Proffered Abstracts Source Type: research

Abstract A49: Building a comprehensive view of tumor biology in breast cancer by combining NanoString's Prosigna assay with the Pancancer Pathways, Immune Profiling, and Progression Panels
In this study, we show that the NanoString PanCancer Pathways, Immune Profiling and Progression panels reveal associations between intrinsic breast cancer subtype and specific pathway dysregulation as well as related changes in the immune landscape of the tumor. We demonstrate that a comprehensive view of the biology of a tumor can be readily obtained with the NanoString platform and the PanCancer Panels.Citation Format: Lucas Dennis, Patrick Danaher, Maribeth Eagan, Andrew White, Nathan Elliot, Namratha Ram, Gayathri Balasundaram, Arthur Jeiranian, Seely Kaufmann, Rich Boykin, Lindy Irving, Wesley Buckingham, Sean Ferree,...
Source: Molecular Cancer Research - February 29, 2016 Category: Cancer & Oncology Authors: Dennis, L., Danaher, P., Eagan, M., White, A., Elliot, N., Ram, N., Balasundaram, G., Jeiranian, A., Kaufmann, S., Boykin, R., Irving, L., Buckingham, W., Ferree, S., Bailey, C., Beechem, J. Tags: New Omics in Breast Cancer: Poster Presentations - Proffered Abstracts Source Type: research

Abstract B48: Intratumor ploidy heterogeneity as a chemoresistance mechanism in triple-negative breastcancer
In this study, we isolated and functionally characterized the diploid and polyploid sub-populations derived from TNBC cell lines. DNA ploidy was assessed in Hoechst 33342 stained cells using flow cytometry. Cells with greater than 4N DNA content were considered as polyploid. Next, we analyzed cell proliferation in HCC1937 cells using CFSE and DNA labeling. Live-cell imaging was performed on flow-sorted diploid and polyploid cells using IncuCyte Zoom to monitor cell proliferation in the absence and presence of mitotic inhibitor (docetaxel).Results: DNA ploidy analysis identified presence of polyploid cells in HCC1395 and HC...
Source: Molecular Cancer Research - February 29, 2016 Category: Cancer & Oncology Authors: Gyanchandani, R., Lee, A. Tags: Tumor Heterogeneity (Intratumor and Intertumoral): Poster Presentations - Proffered Abstracts Source Type: research

Abstract A48: Role of premature mRNA cleavage and alternative polyadenylation in driving breast cancer
We report the identification of a truncated tumor suppressor, MAGI3, at both the mRNA and protein levels from the MDA-MB-231 breast cancer cell line. Using 3' rapid amplification of cDNA ends (RACE), we have determined that the truncated transcript arises due to premature cleavage and APA at a cryptic intronic PAS. We have previously demonstrated genetically and biochemically that MAGI3 functions as a mammary tumor suppressor by antagonizing the oncoprotein and Hippo pathway effector, YAP, via a physical sequestration mechanism. Importantly, here we find that the truncated gene product encoded by this aberrant MAGI3 transc...
Source: Molecular Cancer Research - February 29, 2016 Category: Cancer & Oncology Authors: Ni, T. K., Kuperwasser, C. Tags: New Omics in Breast Cancer: Poster Presentations - Proffered Abstracts Source Type: research

Abstract A47: Membrane translocation of GLUT1 induced by TP53 mutation is positively correlated with increased glucose uptake in patients with breast cancer
Conclusion: We showed that TP53 mutation promotes GLUT1 translocation to membrane, which consequently induces glucose influx in patients with breast cancer. In terms of glucose metabolism, P53 mutation caused the increase of glucose uptake within tumor and adversely affect survival in breast cancer.Citation Format: Sung Gwe Ahn, Hak Woo Lee, Airi Han, Jeong Joon. Membrane translocation of GLUT1 induced by TP53 mutation is positively correlated with increased glucose uptake in patients with breast cancer. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research; Oct 17-20, 2015; Belle...
Source: Molecular Cancer Research - February 29, 2016 Category: Cancer & Oncology Authors: Ahn, S. G., Lee, H. W., Han, A., Joon, J. Tags: New Omics in Breast Cancer: Poster Presentations - Proffered Abstracts Source Type: research

Abstract B46: EMT-inducing transcription factors Twist1, Snail1 and Six1 increase metastasis of neighboring tumor cells via induction of Hedgehog-Gli signaling
Breast cancer is the second leading cause of cancer related deaths in women and more than 90% of these deaths result from metastatic disease rather than from the primary tumor burden. Recent studies have shown that intratumoral heterogeneity exists, and can affect chemotherapeutic and as well as metastatic outcome. To determine if crosstalk between metastatic and non-metastatic breast cancer cells can occur in the earlier stages of metastasis, where an epithelial-to-mesenchymal transition (EMT) is thought to occur in a small population of cells within a tumor, allowing them to metastasize, we examined whether different EMT...
Source: Molecular Cancer Research - February 29, 2016 Category: Cancer & Oncology Authors: Neelakantan, D., Zhou, H., Cabrera, J., Ford, H. Tags: Tumor Heterogeneity (Intratumor and Intertumoral): Poster Presentations - Proffered Abstracts Source Type: research

Abstract B45: De novo generation of highly aggressive human breast tumors by rapid serial passaging of oncogene-transduced starting populations of purified normal cells
Human breast cancers are clonal outgrowths that have diversified genetically and biologically by the time they are clinically evident. However, early events that predicate malignant transformation of normal human mammary epithelial cells and the importance of the specific cell type to first be altered has remained elusive. We have developed an in vivo system that allows analysis of the initial steps of tumorigenesis from defined subsets of normal human mammary cells within 8 weeks using a single (KRASG12D) or multiple oncogenes. Using a protocol in which we first isolate biologically, transcriptionally and phenotypically d...
Source: Molecular Cancer Research - February 29, 2016 Category: Cancer & Oncology Authors: Lefort, S., Pellacani, D., Nguyen, L., Eaves, C. J. Tags: Tumor Heterogeneity (Intratumor and Intertumoral): Poster Presentations - Proffered Abstracts Source Type: research

Abstract A45: Breast tumor metabolism
Proliferative cells have an increased need for macromolecular precursors required to sustain proliferation. Therefore, alteration of metabolic pathway flux and metabolite consumption is a hallmark of the transformed state. We have begun to investigate the specific metabolic pathway rewiring that occurs in the transformation of human breast cells, and the different metabolic phenotypes exhibited in breast cancers of specific molecular subtypes. These efforts have focused on the contribution of proper amino acid management in supporting breast tumor metabolism. For example, we have observed that ER-negative breast cancers ex...
Source: Molecular Cancer Research - February 29, 2016 Category: Cancer & Oncology Authors: Possemato, R. Tags: New Omics in Breast Cancer: Poster Presentations - Proffered Abstracts Source Type: research

Abstract B44: Clinical relevance of androgen and estrogen receptors in patients with ductal carcinoma in situ of the breast treated with surgery and radiotherapy
Conclusions: In agreement with our previous work on a series of DCIS patients treated with surgery alone, the preliminary results from the present study highlight the important role of AR and of the AR/ER ratio as prognostic indicators of relapse in patients treated with surgery and radiotherapy. Our findings also suggest that the treatment used was not capable of controlling disease or of eliminating the risk of recurrence. New avenues for tailored therapy must be sought.Citation Format: Sara Bravaccini, Sara Ravaioli, Maria Maddalena Tumedei, Rosella Silvestrini, Flavia Foca, Ilaria Massa, Roberta Maltoni, Andrea Rocca, ...
Source: Molecular Cancer Research - February 29, 2016 Category: Cancer & Oncology Authors: Bravaccini, S., Ravaioli, S., Tumedei, M. M., Silvestrini, R., Foca, F., Massa, I., Maltoni, R., Rocca, A., Folli, S., Buggi, F., Curcio, A., Puccetti, M., Serra, L., Pietri, E., Andreis, D., Farolfi, A., Amadori, D. Tags: Tumor Heterogeneity (Intratumor and Intertumoral): Poster Presentations - Proffered Abstracts Source Type: research

Abstract A44: Clinical significance of ESR1 mutations by cell-free DNA in recurrent/metastatic breast cancer
Purpose: We aimed to develop a droplet digital Polymerase Chain Reaction (ddPCR)-based method for the sensitive detection of estrogen receptor (ER) α (ESR1) mutations of tumor tissues and the corresponding cell-free DNA (cfDNA) in recurrent/ metastatic breast cancer.Experimental Design: We investigated a total of 325 tumor specimens (270 primary breast cancer specimens and 55 ER-positive recurrent/metastatic tumor specimens, in which 33 recurrent/ metastatic tumor specimens had the corresponding plasma). We investigated the quantification of rare ESR1 mutations, four representative types, Y537S, Y537N, Y537C, and D53...
Source: Molecular Cancer Research - February 29, 2016 Category: Cancer & Oncology Authors: Takeshita, T., Yamamoto, Y., Yamamoto-Ibusuki, M., Inao, T., Sueta, A., Fujiwara, S., Iwase, H. Tags: Monitoring Metastasis and CTCs: Poster Presentations - Proffered Abstracts Source Type: research

Abstract B43: APOBEC3B upregulation by the PKC-NF{kappa}B pathway in breast cancer
Overexpression of the antiviral DNA cytosine deaminase APOBEC3B has been linked to somatic mutagenesis in breast and other cancer. Human papillomavirus (HPV) infection accounts for APOBEC3B upregulation in cervical and head/neck cancers. However, the responsible mechanisms are unclear for non-viral malignancies such as breast cancer. Here, we demonstrate APOBEC3B upregulation through the PKC-NFB pathway. PKC activation by the diacylglycerol mimic PMA causes specific and dose-responsive increases in APOBEC3B mRNA, protein, and activity levels, which are strongly suppressed by PKC and NFB inhibition. Induction correlates wit...
Source: Molecular Cancer Research - February 29, 2016 Category: Cancer & Oncology Authors: Leonard, B., McCann, J., Starrett, G., Kosyakovsky, L., Amy, M., Burns, M., McDougle, R., Parker, P., Brown, W., Harris, R. Tags: Tumor Heterogeneity (Intratumor and Intertumoral): Poster Presentations - Proffered Abstracts Source Type: research

Abstract A43: Context-dependent growth effects of progestins in estrogen receptor-positive breast cancer patient-derived xenografts (PDX)
Conclusion: Progestins have mixed effects on breast cancer PDX tumor growth. Tumors that have high ER and PR and are highly estrogen-dependent are more likely to exhibit strong growth inhibition by progestins (both P4 and MPA). Tumors with mixed luminal/basal phenotype that have less ER and PR and are moderately estrogen-dependent are less likely to be progestin-inhibited. In tumors with low ER and PR but high AR content MPA can act as an AR agonist to stimulate growth. Tumor-specific downstream estrogen-dependent pathways such as Notch may indicate whether progestins are therapeutic. Additional tumors are needed to confir...
Source: Molecular Cancer Research - February 29, 2016 Category: Cancer & Oncology Authors: Finlay-Schultz, J., Brechbuhl, H. M., Rosen, R. B., Gillen, A. E., Jacobsen, B. M., Kabos, P., Sartorius, C. A. Tags: Luminal Breast Cancer: Poster Presentations - Proffered Abstracts Source Type: research

Abstract B42: Ibrutinib in combination with durvalumab (MEDI4736) in patients with relapsed or refractory HER2-positive or triple-negative breast cancer: A phase 1b/2 multicenter study
Purpose: HER2+ and triple-negative (TN) breast cancers (BC) are associated with an aggressive course and poor prognosis, with currently available treatments yielding low response rates and decreased progression-free survival (PFS) due to a high relapse rate, rapid disease progression, and development of resistance. Hence, novel agents with efficacy and a tolerable safety profile are needed for this challenging patient (pt) population. Ibrutinib is a first-in-class, oral inhibitor of Bruton's tyrosine kinase (BTK), which is a crucial signaling molecule in the B-cell receptor pathway. It has demonstrated robust clinical acti...
Source: Molecular Cancer Research - February 29, 2016 Category: Cancer & Oncology Authors: Rasco, D. W., Borazanci, E., Guiterrez, M., Hong, D., Tawashi, A., Lin, J., Dimery, I. W., Fosdale, M. Tags: Trials in Progress: Poster Presentations - Proffered Abstracts Source Type: research

Abstract A42: Inhibition of the invasive component of mucinous breast cancers by targeting c-kit
Conclusions: Targeting c-kit may represent a new type of therapy for some mucinous breast cancers. This is the first study to examine estrogen regulated genes in a model of mucinous breast cancer, allowing identification of genetic pathways that cause more indolent pure mucinous tumors to switch to aggressive mixed mucinous tumors.Citation Format: J. Chuck Harrell, Megan J. Blatner, Britta M. Jacobsen. Inhibition of the invasive component of mucinous breast cancers by targeting c-kit. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research; Oct 17-20, 2015; Bellevue, WA. Philadelphi...
Source: Molecular Cancer Research - February 29, 2016 Category: Cancer & Oncology Authors: Harrell, J. C., Blatner, M. J., Jacobsen, B. M. Tags: Luminal Breast Cancer: Poster Presentations - Proffered Abstracts Source Type: research

Abstract B41: HGFL-Ron signaling enhances breast cancer stem cell populations
The Ron receptor tyrosine kinase is overexpressed in a high fraction of human breast cancers (BCs). Ron and its ligand, the Hepatocyte Growth Factor-Like protein (HGFL), play important roles during BC initiation, progression, and therapeutic resistance, with overexpression of this signaling cascade associated with increased BC metastasis and poor prognosis in humans. Reports demonstrate that a small subpopulation of cancer cells, called the breast cancer stem cells (BCSCs), are essential for the development and maintenance of BC, leading to tumor formation and recurrence. Despite the role of HGFL-Ron signaling as a key reg...
Source: Molecular Cancer Research - February 29, 2016 Category: Cancer & Oncology Authors: Ruiz-Torres, S. J., Waltz, S. E. Tags: Targeted Therapies: Poster Presentations - Proffered Abstracts Source Type: research

Abstract A41: Hormonal-receptor positive breast cancer: IL-6 augments invasion and lymph node metastasis via stimulating cathepsin B expression
Hormonal-receptor positive (HRP) breast cancer patients with positive metastatic axillary lymph nodes (LNs) are characterized by poor prognosis and increase the mortality rate. The mechanisms by which cancer cells invade lymph node have not been fully explored yet. Studies showed that the expression of interleukin-6 (IL-6) cytokine and the proteolytic enzyme cathepsin B (CTSB) are associated with breast cancer poor prognosis. In the present study, we tested the effect of different concentration of IL-6 on invasiveness capacity of HRP breast cancer cell lines MCF-7 cells using in vitro invasion chamber assay. Moreover, we i...
Source: Molecular Cancer Research - February 29, 2016 Category: Cancer & Oncology Authors: Hassan, A. O., Ibrahim, S. A., El-Ghonaimy, E. A., Hassan, H., El-Mamlouk, T., El-Shinawi, M., Mohamed, M. M. Tags: Luminal Breast Cancer: Poster Presentations - Proffered Abstracts Source Type: research

Abstract B40: Transcription factor Snail mediates EMT by altering vesicular trafficking protein Rab25
Epithelial cells maintain intercellular communication directly by cell-cell, cell-ECM interaction and indirectly by paracrine secretion of extracellular messengers either as free molecules or via exosomes. The vesicular trafficking machinery is an integral part of such communication, paralleling digital cables that transmit the information bytes to the correct hub. During the process of EMT, derailing of the trafficking machinery leads to a systemic breakdown of intra and inter-cellular communication pathways. The purpose of the current study is to elucidate the functional role of Rab25, a key member of the vesicular traff...
Source: Molecular Cancer Research - February 29, 2016 Category: Cancer & Oncology Authors: Mitra, S., Federico, L., Mills, G. B. Tags: Targeted Therapies: Poster Presentations - Proffered Abstracts Source Type: research

Abstract A40: ESR1 gene alterations in the metastatic breast cancer with resistance to aromatase inhibitor
Background: Estrogen receptor (ER) positive breast cancer can be treated by endocrine therapy; however a certain population of ER-positive patients becomes resistant to endocrine therapy after long-term estrogen deprivation treatment. ESR1 gene alterations, mutations, translocation and amplification, have been reported as one of the reasons.Patients and Methods: We successfully obtained metastatic tissue samples from 30 patients with resistance to aromatase inhibitor (AI), and 7 patients with resistance to ethinylestradiol (EE2). ER and PgR expression by immunohistochemistry, and ESR1 gene amplification using FISH and copy...
Source: Molecular Cancer Research - February 29, 2016 Category: Cancer & Oncology Authors: Iwase, H., Takeshita, T., Yamamoto-Ibusuki, M., Inao, T., sueta, A., Fujiwara, S. Tags: Luminal Breast Cancer: Poster Presentations - Proffered Abstracts Source Type: research

Abstract B39: A novel analytical approach to accurately assess in vitro drug responses for breast cancer therapy
The measurement of drug dose-response is the cornerstone of pre-clinical assessments of novel therapeutics. High-throughput studies have attempted to identify intrinsic drivers of drug sensitivity by measuring the response of hundreds of cell lines to hundreds of drugs and it has been proposed to use the drug response of primary human tumor cells as a way to personalize therapy for individual patients.The commonly used metrics to parameterize drug response (IC50, Emax, or AUC) are based on assessing the cell count of a treated condition relative to an untreated control. Yet all of these metrics suffer from a fundamental fl...
Source: Molecular Cancer Research - February 29, 2016 Category: Cancer & Oncology Authors: Niepel, M., Hafner, M., Sorger, P. K. Tags: Targeted Therapies: Poster Presentations - Proffered Abstracts Source Type: research

Abstract A39: A role for src kinase in estrogen receptor-positive breast cancer
Estrogen (E2) stimulation promotes proliferation in estrogen receptor-positive (ER+) breast cancer, which accounts for 60-75% of all breast cancer. E2 signals through the ER via three pathways: the classical genomic pathway involving transcriptional activation of the ER, crosstalk between ER and other transcription factors, and "non-genomic" signaling cascades, which do not involve the transcriptional activity of the ER. This "non-genomic" pathway likely involves Src family kinases (SFKs) and has been implicated in cell cycle progression in fibroblasts engineered to express the ER (Castoria 1999). While...
Source: Molecular Cancer Research - February 29, 2016 Category: Cancer & Oncology Authors: Abdullah, C., Korkaya, H., Courtneidge, S. A. Tags: Luminal Breast Cancer: Poster Presentations - Proffered Abstracts Source Type: research

Abstract A38: Effects on epigenomic, transcriptomic, and genomic landscape of neoadjuvant tamoxifen in estrogen receptor alpha breast cancer
We examined the subset of tamoxifen treated patients (n=28). All tumors were HER2-negative. ERα/PR showed no significant difference between pre- and post-treatment levels. Tumor cell proliferation was significantly lower in post-treatment samples (Ki67 gene expression P
Source: Molecular Cancer Research - February 29, 2016 Category: Cancer & Oncology Authors: Severson, T. M., Nevedomskaya, E., Peeters, J., Rossum, A. v., Kuilman, T., Krijgsman, O., Koornstra, R., Peeper, D., Wesseling, J., Simon, I. M., Wessels, L., Zwart, W., Linn, S. C. Tags: Luminal Breast Cancer: Poster Presentations - Proffered Abstracts Source Type: research

Abstract B37: Overcoming resistance to chemotherapy using ZNF217 as a predictive marker and therapeutic target of breast cancer
This study directly influenced the design of the Phase II clinical trials with triciribine and paclitaxel in metastatic breast cancer patients. In addition, our animal models of chemoresistance after Zfp217 overexpression will be used to study the mechanisms of therapeutic resistance by the expansion of a progenitor cell population.Citation Format: Christopher Suarez, Joseph Sparano, Sunil S. Badve, Laurie E. Littlepage. Overcoming resistance to chemotherapy using ZNF217 as a predictive marker and therapeutic target of breast cancer. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Re...
Source: Molecular Cancer Research - February 29, 2016 Category: Cancer & Oncology Authors: Suarez, C., Sparano, J., Badve, S. S., Littlepage, L. E. Tags: Targeted Therapies: Poster Presentations - Proffered Abstracts Source Type: research