Abstract B13: Targeting the TGF-{beta} pathway in breast cancer: Insights from preclinical studies
Overexpression of transforming growth factor-βs (TGF-βs) correlates with metastasis and poor prognosis in many advanced cancers, and TGF-βs have pro-oncogenic effects on nearly every cell type in the ecosystem of advanced tumors. Based on these observations and encouraging results in preclinical models, strategies to block TGF-β signaling are in early phase clinical oncology trials. To date however, preclinical studies supporting the development of anti-TGF-β therapeutics in cancer have focused around a few well-characterized mouse models which do not capture the heterogeneity of the human disease....
Source: Molecular Cancer Research - February 29, 2016 Category: Cancer & Oncology Authors: Yang, Y.-a., Flanders, K., Chen, J.-q., Merchant, A. S., Yang, H., Lee, M. P., Wakefield, L. M. Tags: Targeted Therapies: Poster Presentations - Proffered Abstracts Source Type: research

Abstract B12: Co-targeting PTEN-defined TNBC with p110beta-isoform specific inhibitor and PARP inhibitor BMN 673: A predictive context to sensitize PARP inhibitors in TNBC
Background: TNBC is a highly aggressive form of BRCA-associated BC subtype for which chemotherapy still remains a major form of treatment to which patients initially respond yet a majority of them inevitably relapse. PARP1 has been identified as a target in BRCA-defined cancers and inhibitors of PARP1 has been recently approved by FDA as targeted agents in BRCA-defined cancers. The loss of PTEN is the most common "first event" associated with basal-like subtype (Martins et al., 2012) and this PI3K-pathway activating event (deletion/mutation/loss of PTEN) occurs more frequently (35%) than PIK3CA mutations in this ...
Source: Molecular Cancer Research - February 29, 2016 Category: Cancer & Oncology Authors: Dey, N., Carlson, J. H., De, P., Leyland-Jones, B. Tags: Targeted Therapies: Poster Presentations - Proffered Abstracts Source Type: research

Abstract IA11: Functional and clinical relevance of intratumor heterogeneity in breast cancer
Intratumor heterogeneity is a major obstacle toward understanding and treatment of cancers. We have analyzed cellular genetic and phenotypic heterogeneity in breast tumors using immune-FISH and found that higher pre-treatment genetic diversity predicts therapy resistance and distant metastases are the most diverse. In HER2+ tumors we detected startling heterogeneity for HER2 copy number gain and PIK3CA mutation using STAR-FISH, a novel method we developed, and determined that changes in the topologic distribution of cellular heterogeneity for these genetic alterations during neoadjuvant chemotherapy predicts long-term clin...
Source: Molecular Cancer Research - February 29, 2016 Category: Cancer & Oncology Authors: Polyak, K. Tags: Tumor Heterogeneity (Intratumor and Intertumoral): Oral Presentations - Invited Abstracts Source Type: research

Abstract B11: A dual PI3K/mTOR inhibitor, BEZ235 blocks tumor-induced angiogenesis: Evidence for an effect on the tumor and endothelial compartment
Conclusion: Our data suggest that BEZ235 has potent antiangiogenic activity in three different xenograft models probably via mTOR-HIF1α-VEGF signaling axis.Citation Format: Pradip De, Yuliang Sun, Jennifer H. Carlson, Xiaoqian Lin, Nandini Dey, Brian Leyland-Jones. A dual PI3K/mTOR inhibitor, BEZ235 blocks tumor-induced angiogenesis: Evidence for an effect on the tumor and endothelial compartment. [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 B11. (Source: Molecular Cancer Research)
Source: Molecular Cancer Research - February 29, 2016 Category: Cancer & Oncology Authors: De, P., Sun, Y., Carlson, J. H., Lin, X., Dey, N., Leyland-Jones, B. Tags: Targeted Therapies: Poster Presentations - Proffered Abstracts Source Type: research

Abstract A11: Cyclin A expression and endocrine resistance in an experimental model of murine mammary carcinomas
Most of human breast cancers are aneuploid because of chromosome missegregation occurring during mitosis. Deregulation in the control of cell cycle progression is frequently found in mammary carcinomas and is associated with mitotic spindle checkpoint defects and aneuploidy. The Laboratory of Hormonal Carcinogenesis has developed an experimental model of mammary carcinomas by the administration of medroxyprogesterone acetate (MPA) to BALB/c mice. These tumors are metastatic luminal ductal carcinomas, which express estrogen and progesterone receptors (PR) and show different responses to antiprogestin treatment. An associati...
Source: Molecular Cancer Research - February 29, 2016 Category: Cancer & Oncology Authors: Bilinski, M., Lanari, C., Fabris, V. T. Tags: Animal Models: Poster Presentations - Proffered Abstracts Source Type: research

Abstract IA10: Sox10 regulates stem/progenitor and mesenchymal cell states in mammary epithelial cells
To discover mechanisms that mediate the initiation and progression of aggressive and stem-like breast cancers, we characterized signaling networks that are present in the mammary stem cells responsible for fetal and adult mammary development. These analyses identified a signaling axis between FGF signaling and the transcription factor, Sox10. Here we report that Sox10 is specifically expressed in mammary cells that exhibit the highest levels of stem/progenitor activity. This includes fetal and adult mammary cells in vivo and mammary organoids in vitro. Sox10 is functionally relevant, as its deletion reduces stem/progenitor...
Source: Molecular Cancer Research - February 29, 2016 Category: Cancer & Oncology Authors: Dravis, C., Wahl, G. M. Tags: Differentiation Hierarchy and Cancer: Oral Presentations - Invited Abstracts Source Type: research

Abstract B10: mTORC1 directly phosphorylates and activates ER{alpha} upon estrogen stimulation
Approximately 75% of breast cancers are estrogen receptor (ERα) positive, underscoring the dependence of cancer cells on estrogen for growth and survival. Patients treated with endocrine therapy often develop resistance, either de novo or acquired, which is caused by aberrations within the growth factor signaling pathways. The mechanistic target of rapamycin complex 1 (mTORC1) has emerged as a critical node in estrogenic signaling. We have previously shown that mTORC1 can phosphorylate and activate ERα on S167 via its effector the 40S ribosomal S6 kinase 1 (S6K1). Presently, we have uncovered a direct link betw...
Source: Molecular Cancer Research - February 29, 2016 Category: Cancer & Oncology Authors: Alayev, A., Holz, M. K. Tags: Targeted Therapies: Poster Presentations - Proffered Abstracts Source Type: research

Abstract A10: Oncogenomic analysis of IGF-IR driven mammary tumors identifies a potential cell of origin and mechanisms of tumor recurrence
Genetically engineered mice are valuable tools for understanding the genetic events that contribute to breast cancer development and progression. We have previously generated a doxycycline (Dox) inducible model of breast cancer, MTB-IGFIR, in which overexpression of the human type-I IGF receptor (IGF-IR) leads to the rapid induction of ER-mammary tumors with mixed luminal and basal features. Following Dox withdrawal and subsequent transgene downregulation, a subset of tumors escape IGF-IR dependence and spontaneously recur with evidence of an epithelial-mesenchymal transition (EMT). To gain insight into the molecular pathw...
Source: Molecular Cancer Research - February 29, 2016 Category: Cancer & Oncology Authors: Jones, R. A., Campbell, C. I., Watson, K. L., Moorehead, R. A. Tags: Animal Models: Poster Presentations - Proffered Abstracts Source Type: research

Abstract A09: Development of novel breast cancer brain-metastases-derived xenografts and cell lines
Conclusions: We have developed novel PDXs derived from breast cancer brain metastases, which retain their ability to colonize the brain when disseminated in circulation. These novel GFP-luciferase labeled xenografts and cell lines, represent unique tools to study brain metastasis biology and to test novel therapeutic treatments for brain metastasis in clinically relevant models.Citation Format: Colton Hanna, Britta M. Jacobsen, Carol A. Sartorius, Peter Kabos, Kevin Lillehei, David R. Ormond, Michael Graner, Virginia F. Borges, Diana M. Cittelly. Development of novel breast cancer brain-metastases-derived xenografts and ce...
Source: Molecular Cancer Research - February 29, 2016 Category: Cancer & Oncology Authors: Hanna, C., Jacobsen, B. M., Sartorius, C. A., Kabos, P., Lillehei, K., Ormond, D. R., Graner, M., Borges, V. F., Cittelly, D. M. Tags: Animal Models: Poster Presentations - Proffered Abstracts Source Type: research

Abstract IA08: Developmental insights into breast cancer intratumoral heterogeneity
Breast cancer is no longer considered a single disease, but instead is made up of multiple subtypes with genetically and epigenetically heterogeneous tumors composed of numerous clones. Both the hierarchical cancer stem cell and clonal evolution models have been invoked to help explain this intratumoral heterogeneity. Several recent studies have helped define the functional interactions among the different cellular subpopulations necessary for the evolution of this complex ecosystem. These interactions involve paracrine interactions that include locally acting Wnt family members, reminiscent of the signaling pathways impor...
Source: Molecular Cancer Research - February 29, 2016 Category: Cancer & Oncology Authors: Rosen, J. M., Roarty, K., Zhang, M. Tags: Differentiation Hierarchy and Cancer: Oral Presentations - Invited Abstracts Source Type: research

Abstract B08: ESR1 coregulator binding site inhibitors (ECBIs) as novel therapeutics to target hormone therapy-resistant breast cancer
Conclusions: The ECBI is a novel agent that targets ESR1 with a unique mechanism of action. ECBI has distinct pharmacologic advantages of oral bioavailability, in vivo stability, and is associated with minimal systemic side effects. Remarkably, ECBIs block both native and mutant forms of ESR1 and have activity against therapy resistant breast cancer cell proliferation both in vitro and in vivo and against primary human tissues ex vivo. Thus development of ECBI represents a quantum leap in therapies to target ESR1Citation Format: Ratna K. Vadlamudi, Gangadhara Reddy Sareddy, Suryavathi Viswanadhapalli, Tae-Kyung Lee, Shi-Ho...
Source: Molecular Cancer Research - February 29, 2016 Category: Cancer & Oncology Authors: Vadlamudi, R. K., Sareddy, G. R., Viswanadhapalli, S., Lee, T.-K., Ma, S.-H., Lee, W. R., Mann, M., Krishnan, S. R., Gonugunta, V., Strand, D. W., Tekmal, R. R., Ahn, J., Raj, G. V. Tags: Targeted Therapies: Poster Presentations - Proffered Abstracts Source Type: research

Abstract A08: A patient-derived xenograft model to study the effects of postmenopausal obesity on endocrine therapy resistance
Conclusions: We have developed a novel, transplant-competent mouse model of obesity and menopause using a specialized HFD and thermoneutral housing. Using this model, we determined that HFD supports the growth of a previously estrogen-dependent breast cancer PDX after EWD, potentially through increased signaling through HER2 and FGFR pathways. Our mouse model, in combination with PDX breast tumors, will offer novel insights into the relationships between obesity, menopause, and ER+ breast cancer progression.Citation Format: Elizabeth Wellberg, Britta Jacobsen, Peter Kabos, Paul MacLean, Carol Sartorius. A patient-derived x...
Source: Molecular Cancer Research - February 29, 2016 Category: Cancer & Oncology Authors: Wellberg, E., Jacobsen, B., Kabos, P., MacLean, P., Sartorius, C. Tags: Animal Models: Poster Presentations - Proffered Abstracts Source Type: research

Abstract B07: Mcl-1-mediated resistance to ABT-263 is combated by mTOR inhibition in luminal breast cancers
In the context of cancer, the intrinsic apoptotic pathway is exploited to favor tumor cell survival through overexpression of anti-apoptotic Bcl-2 family members (Bcl-A1, Bcl-2, Bcl-xL, Bcl-w and Mcl-1). We investigated targeting of anti-apoptotic Bcl-2 proteins in a panel of human luminal breast cancer cell lines. Use of ABT-263, the Bcl-2/Bcl-xL/Bcl-w inhibitor, induced transient tumor cell killing and decreased tumor cell growth in only 1 of 4 cell lines in three dimensional (3D) cultures. Mcl-1 expression and activity were rapidly upregulated upon ABT-263 treatment, highlighting the compensatory nature of Mcl-1. In lum...
Source: Molecular Cancer Research - February 29, 2016 Category: Cancer & Oncology Authors: Williams, M. M., Lee, L., Morrison, M. M., McKernan, C., Sanchez, V., Hicks, D., Stricker, T., Cook, R. S. Tags: Targeted Therapies: Poster Presentations - Proffered Abstracts Source Type: research

Abstract A07: Spontaneous canine mammary cancers: A much-needed model for human basal-like breast cancer and an ideal system to understand myoepithelial cells
Spontaneous canine mammary cancer represents an excellent model of human breast cancer but is greatly understudied. To better utilize this valuable resource, we performed the first comprehensive characterization of the genome, transcriptome and epigenome of 12 canine mammary cancer cases, including 7 simple carcinomas and 4 complex carcinomas (1).Simple carcinomas, which histologically match human breast carcinomas, harbor extensive genomic aberrations, many of which faithfully recapitulate key features of human breast cancer. Notably, these tumors closely cluster with human basal-like breast carcinomas from TCGA (2), but ...
Source: Molecular Cancer Research - February 29, 2016 Category: Cancer & Oncology Authors: Liu, D., Xiong, H., Ellis, A. E., Northrup, N. C., Rodriguez, C. O., O'Regan, R. M., Dalton, S., Zhao, S. Tags: Animal Models: Poster Presentations - Proffered Abstracts Source Type: research

Abstract PR06: Modeling the tumor microenvironment to identify novel loss of function mutations in breast cancer progression
Recent next generation sequencing studies have comprehensively mapped the genetic landscape of breast cancer and revealed that only a small number of genes are recurrently mutated in more than 10% of unselected tumors (i.e. TP53, PIK3CA and GATA3), and that the vast majority of recurrent mutations occur at low frequencies. Although some have been shown to be drivers (i.e. confer a selective advantage), such as oncogenic ERBB2 mutations, there is a myriad of significantly altered lower frequency mutations whose functional impact is unknown.We utilized a functional genomics approach silencing the 200 most frequently mutated ...
Source: Molecular Cancer Research - February 29, 2016 Category: Cancer & Oncology Authors: Peck, B., Maguire, S., Morrison, E., Wai, P., Natrajan, R. Tags: Tumor Heterogeneity (Intratumor and Intertumoral): Oral Presentations - Proffered Abstracts Source Type: research

Abstract IA06: Spatial systems biology of cancer
International efforts have now defined the genomic landscapes of most major human cancer types. The genomic landscape of breast cancer is particularly well described in several recent publications. The high level view of this disease suggests a remarkable level of inter- and intra-tumor heterogeneity, the presence of a few recurrent and many rare genomic aberrations and substantial genomic and epigenomic heterogeneity. The challenge now is to understand how these aberrations and tumor extrinsic influences from the microenvironment collaborate to deregulate aspects of cell differentiation, proliferation, apoptosis, DNA repa...
Source: Molecular Cancer Research - February 29, 2016 Category: Cancer & Oncology Authors: Gray, J. Tags: Genomics - Sporadic and Hereditary: Oral Presentations - Invited Abstracts Source Type: research

Abstract B06: CDK7: A marker of poor prognosis and tractable therapeutic target in triple-negative breast cancer
Triple-negative breast cancer (TNBC) represents a heterogeneous subgroup of breast cancer with substantial genotypic and phenotypic diversity. TNBC patients commonly exhibit poor prognosis and high relapse rates at early stages after conventional treatments. Currently, there is a lack of biomarkers and targeted therapies for the management of TNBC. During tumor development and progression, alterations in cellular behavior are frequently linked with kinase expression and activity. Here, we aimed to identify novel kinase targets that may play a pivotal role in the progression of TNBC and, thus, offer new therapeutic vantage ...
Source: Molecular Cancer Research - February 29, 2016 Category: Cancer & Oncology Authors: Li, B., Chonghaile, T. N., Fan, Y., Klinger, R., O'Connor, A. E., Conroy, E., Tarrant, F., O'Hurley, G., Udupi, G. M., Gaber, A., Chin, S.-F., Bardwell, H. A., Schouten, P. C., Dubois, T., Linn, S., Jirstrom, K., Caldas, C., Bernards, R., O'Connor, D. P., Tags: Targeted Therapies: Poster Presentations - Proffered Abstracts Source Type: research

Abstract A06: The murine ortholog of the human cancer-associated 8q24 gene desert affects mammary tumorigenesis and alters mammary gland development through Myc-mediated global gene expression regulation
The vast majority of breast cancer-associated variants identified by genome-wide association studies (GWAS) are located to non-protein coding genomic regions. Although some have been shown to regulate the expression of specific genes, novel approaches to elucidate the in vivo mechanisms underlying such breast cancer susceptibility loci are needed. The gene desert located on human chromosomal band 8q24, proximal to MYC and PVT1, and distal to FAM84B, harbors 2 common, low-penetrance breast cancer variants. We generated a megadeletion mouse model lacking 430 Kb of sequence orthologous to the breast cancer-associated locus of...
Source: Molecular Cancer Research - February 29, 2016 Category: Cancer & Oncology Authors: Smits, B. M. Tags: Animal Models: Poster Presentations - Proffered Abstracts Source Type: research

Abstract PR05: The effect of chemotherapy on HER2+ breast cancer heterogeneity measured by STAR-FISH: Detection of PIK3CA mutation and HER2 amplification at single-cell level in situ
Current therapies in HER2-positive breast cancer are effective in only a subset of cases and part of the resistance is attributed to single nucleotide mutation H1047R in PIK3CA. Conventional PIK3CA mutation detection methods require isolation of DNA from the tumor bulk, which requires relatively large amount of tissue and may not detect mutations in rare cancer cells.We developed a novel method, Specific-To-Allele PCR-FISH (STAR-FISH), which allows for in situ detection of point mutation and gene amplification at single cell level. The assay consists of in situ PCR steps with mutation specific primers, followed by hybridiz...
Source: Molecular Cancer Research - February 29, 2016 Category: Cancer & Oncology Authors: Janiszewska, M., Liu, L., Almendro, V., Kuang, Y., Paweletz, C., Weigelt, B., Sakr, R. A., King, T. A., Chandarlapaty, S., Reis-Filho, J. S., Hanker, A. B., Arteaga, C. L., Yeon, P. S., Michor, F., Polyak, K. Tags: Tumor Heterogeneity (Intratumor and Intertumoral): Oral Presentations - Proffered Abstracts Source Type: research

Abstract B05: Self-assembling platinum-acridine loaded carbon nanotubes for triple-negative breast cancer chemotherapy
Triple-negative breast cancer (TNBC) accounts for 10-15% of breast cancers, has the highest levels of recurrence, and the lowest five-year survival of all breast cancer subtypes. TNBC does not express estrogen or progesterone receptors and does not overexpress HER2 receptors. Therefore, TNBC does not benefit from current FDA-approved targeted therapies against HER2 or hormone-positive cancers. Early clinical trials show that TNBC is susceptible to platinum chemotherapy, but dose-limiting toxicities and cross-resistance amongst current FDA-approved platinum agents may limit clinical efficacy. To address this issue, we have ...
Source: Molecular Cancer Research - February 29, 2016 Category: Cancer & Oncology Authors: Fahrenholtz, C. D., Ding, S., Bernish, B. W., Wright, M., Bierbach, U., Singh, R. N. Tags: Targeted Therapies: Poster Presentations - Proffered Abstracts Source Type: research

Abstract A05: The tumor suppressor function of Plk2 in triple-negative breast cancer may be mediated through regulation of Plk1
We reported recently that a loss of Plk2 in the developing mammary gland results in increased proliferation, hyperbranching, misoriented mitotic spindle assembly and defects in polarity (Villegas et al Development 2015). Loss of Plk2 was accompanied by increased expression of Plk1. Genetic rescue experiments, knocking down Plk1 in Plk2 null mouse mammary epithelium, and bimolecular fluorescence complementation assays, using wildtype Plk2 and a kinase dead mutant (KD) of Plk2 as bait, revealed that Plk2 regulates these processes through its direct interaction with Plk1. Our preliminary data suggest that loss of Plk2 results...
Source: Molecular Cancer Research - February 29, 2016 Category: Cancer & Oncology Authors: Acosta, D., Villegas, E., Kabotyanski, E., Montemayor, C., Kurley, S. J., Dominguez-Vidana, R., Shaw, C. A., Westbrook, T. F., Rosen, J. M. Tags: Animal Models: Poster Presentations - Proffered Abstracts Source Type: research

Abstract PR04: Tissue tension promotes mammary stemness and breast cancer aggression
Breast cancers frequently develop treatment resistance that leads to recurrence, dissemination and patient mortality. Among the mechanisms that foster treatment resistance is the ability of tumor cells to undergo an epithelial-to-mesenchymal transition (EMT) and exhibit stem-like behavior. Accumulating evidence now supports the concept that the mechanical properties of the extracellular matrix microenvironment can critically influence developmental cell fate and modify several features of tumor progression. Data from our laboratory using preclinical models and clinical samples suggest that tissue tension and elevated mecha...
Source: Molecular Cancer Research - February 29, 2016 Category: Cancer & Oncology Authors: Northey, J. J., Yui, Y., Mouw, J. K., Lakins, J. N., Weaver, V. M. Tags: Differentiation Hierarchy and Cancer: Oral Presentations - Proffered Abstracts Source Type: research

Abstract B04: Systemic delivery of silver nanoparticles and targeting of the folate receptor alpha for the treatment of triple-negative breast cancer
Triple-negative breast cancer (TNBC) lacks expression of the estrogen and progesterone receptors and does not overexpress the HER-2 receptor. Thus, current targeted therapies are rendered ineffective against this subtype of breast cancer, leaving a gap in treatment options for these patients. The use of nanotechnology has the potential to dramatically enhance the way cancer is diagnosed and treated. However, concerns persist about the toxicity of nanomaterials, which may not degrade, or are only slowly degraded and excreted after long body residence time. For clinical translation to become a reality, the potential risk&nda...
Source: Molecular Cancer Research - February 29, 2016 Category: Cancer & Oncology Authors: Swanner, J. L., Fahrenholtz, C. D., Singh, R. N. Tags: Targeted Therapies: Poster Presentations - Proffered Abstracts Source Type: research

Abstract A04: The role of surgical resection of primary tumor before the appearance of circulating tumor cells based on orthotopic allograft mouse model
Breast cancer causes death not because of the primary tumor in the breast but because of metastases in distant sites that gradually cause organ dysfunction. Circulating tumor cells (CTCs) are cells that have detached from the primary tumor or metastatic tumor site and entered the peripheral circulation. Using CTC-mouse model, we tested the hypothesis that curative resection prior to CTC appearance results in repression of tumor metastasis. In method, we implanted 1 x104 GFP expressing 4T1 cells in 4th or 5th mammary fat pad of 8 week-old BALB/cAnNCrl mice (n=69). Enumeration of CTCs was performed using a FACSCalibur flow c...
Source: Molecular Cancer Research - February 29, 2016 Category: Cancer & Oncology Authors: Lee, H. W., Han, A., Yang, B. S., Park, J. T., Ahn, S. G., Jeong, J. Tags: Animal Models: Poster Presentations - Proffered Abstracts Source Type: research

Abstract PR03: GLUT1 is required for induction of mammary tumorigenesis by activated ErbB2/HER2/Neu
Alterations in tumor cell metabolism have been investigated for decades, and include changes in glucose utilization, as well as changes in mitochondrial and fatty acid metabolism; however, it is unclear at what point during the process of tumorigenesis these metabolic changes occur. We hypothesized that elevated glucose uptake represents the first metabolic adaptation to transformation, and thus may be a target for the prevention of breast cancer. The GLUT1 transporter is expressed in breast cancer cells and is responsible for the majority of their glucose uptake. Not surprisingly, breast cancer patients with high levels o...
Source: Molecular Cancer Research - February 29, 2016 Category: Cancer & Oncology Authors: Wellberg, E. A., D'Allessandro, A., Lewis, A. S., Terrell, K., Abel, E. D., Muller, W. A., Hansen, K. A., Anderson, S. M. Tags: Animal Models: Oral Presentations - Proffered Abstracts Source Type: research

Abstract B03: A small-molecule antagonist of CX3CR1 impairs homing and colonization of breast cancer cells in the skeleton
Therapeutic approaches aimed to prevent breast cancer cells from spreading to distant sites are commonly neglected, based on the indication that dissemination from primary tumors can occur early. However, mounting evidence indicates that cancer cells recirculating from established bone lesions could further seed and colonize both skeleton and soft-tissue organs, thus precipitating metastatic dissemination and accelerating disease progression. We have previously shown that breast circulating tumor cells (CTCs) rely on the chemokine receptor CX3CR1 for lodging to the skeleton. Here, we show that this receptor is overexpresse...
Source: Molecular Cancer Research - February 29, 2016 Category: Cancer & Oncology Authors: Shen, F., Zhang, Y., Jernigan, D., Yan, J., Garcia, F., Meucci, O., Salvino, J., Fatatis, A. Tags: Targeted Therapies: Poster Presentations - Proffered Abstracts Source Type: research

Abstract PR02: The spliceosome is a therapeutic vulnerability in MYC-driven breast cancer
c-MYC (MYC) hyperactivation is one of the most common drivers of human breast cancer and correlates with poor prognosis. Despite intensive study, the MYC oncogene remains recalcitrant to therapeutic inhibition. Like other classic oncogenes, hyperactivation of MYC leads to collateral stresses onto breast cancer cells, suggesting that tumors harbor unique vulnerabilities arising from oncogenic activation of MYC. Herein, we discover the spliceosome as a new target of oncogenic stress in MYC-driven cancers. We demonstrate that core components of the spliceosome and its catalytic activity are required to tolerate oncogenic MYC....
Source: Molecular Cancer Research - February 29, 2016 Category: Cancer & Oncology Authors: Hsu, T., Simon, L., Neill, N., marcotte, r., Sayad, A., Karlin, K., Lagisetti, C., Cooper, T., Webb, T., Neel, B., Shaw, C., Westbrook, T. Tags: Targeted Therapies: Oral Presentations - Proffered Abstracts Source Type: research

Abstract B02: Complex molecular-scale dynamics of HER2 receptor transport in live SKBR3 breast cancer cells revealed by nanoscale quantum dot imaging
Conclusions: In contrast to the simple diffusive motions previously reported for members of major classes of receptors (e.g. GPCRs, tyrosine kinase receptors), our sensitive measurements of HER2 receptor motion demonstrate complex molecular dynamics in both unstimulated and stimulated cells. Ligand stimulation induces changes in cell morphology such as membrane ruffling and protrusion growth that accompany changes in HER2 mobility and range of motion. The diversity of receptor dynamics suggest a heterogeneous environment in which HER2 engages. Future experiments include understanding the dynamic interplay between HER2 with...
Source: Molecular Cancer Research - February 29, 2016 Category: Cancer & Oncology Authors: Lam, W. Y., Wang, Y., Olah, M. J., Lidke, K. A., Bruchez, M., Gray, J., Vu, T. Q. Tags: Other Topics: Poster Presentations - Proffered Abstracts Source Type: research

Abstract A02: Stat3 plays a critical role in the establishment of immunosuppressive tumor microenvironment: Implications for tumor immunsurviellance and metastatic progression
Immune surveillance is thought to play a critical role in promoting the elimination of developing malignant lesions through activation of immune response. However, cancer cells eventually acquire the ability to escape immune surveillance by favoring recruitment of immune cell types that exert an inflammatory and immunosuppressive state. Despite the importance of immune surveillance, the molecular mechanisms that promote escape from immune remains poorly defined. Here we demonstrate that expression of the Stat3 transcription factor in the tumor epithelial is involved in promoting an immunosuppressive tumor microenvironment....
Source: Molecular Cancer Research - February 29, 2016 Category: Cancer & Oncology Authors: Jones, L. M., Broz, M., Ranger, J., Ursini-Siegel, J., Krummel, M., Muller, W. J. Tags: Animal Models: Poster Presentations - Proffered Abstracts Source Type: research

Abstract PR01: Understanding the role of BCL11A in triple-negative breast cancer
This study highlights the potential for targeting BCL11A as an approach for TNBC-targeted therapy. To this end we are currently using the Crispr/Cas9 system to generate endogenous reporter cell lines for high-throughput drug screens to identify potential inhibitors of BCL11A.Citation Format: Kyren Lazarus, Carlos Caldas, Pentao Liu, Walid T. Khaled. Understanding the role of BCL11A in triple-negative 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 PR01. (Source...
Source: Molecular Cancer Research - February 29, 2016 Category: Cancer & Oncology Authors: Lazarus, K., Caldas, C., Liu, P., Khaled, W. T. Tags: Differentiation Hierarchy and Cancer: Oral Presentations - Proffered Abstracts Source Type: research

Abstract IA01: Potential applications of genomics in patients with metastatic breast cancer
Genomic studies have shown that breast cancer includes large number of genomic segments. From this observation has arisen the concept that sequencing could be used to select breast cancer patients for new therapies. There are at least six applications of genomic tests to individualize therapy in breast cancer. In the present document and presentation, we will only focus on metastatic breast cancers.First, genomic tests can be used to identify oncogenic drivers at the individual level. There are seven genomic alterations that are currently the focus on genomic-driven drug development. This includes AKT1 mutations, ERBB2 mut...
Source: Molecular Cancer Research - February 29, 2016 Category: Cancer & Oncology Authors: Andre, F. Tags: Keynote Lecture: Oral Presentations - Invited Abstracts Source Type: research

Abstract B01: B cell lymphoma 9 mediates a cross talk between the canonical Wnt and EGFR signaling in breast cancer
Conclusion: BCL9 is a molecular driver of DCIS invasive progression. The molecular mechanism for BCL9's role in breast cancer progression is through the enhancement in the canonical Wnt and EGFR signaling.Citation Format: Hanan Elsarraj, Hong Yan, Jennifer Knapp, Anna Tsimelzon, Shixia Huang, Andrew Godwin, Sue Hilsenbeck, Dean Edwards, Fariba Behbod. B cell lymphoma 9 mediates a cross talk between the canonical Wnt and EGFR signaling 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...
Source: Molecular Cancer Research - February 29, 2016 Category: Cancer & Oncology Authors: Elsarraj, H., Yan, H., Knapp, J., Tsimelzon, A., Huang, S., Godwin, A., Hilsenbeck, S., Edwards, D., Behbod, F. Tags: Other Topics: Poster Presentations - Proffered Abstracts Source Type: research

Kindlin-2 and Prostate Cancer Chemoresistance
This study investigated the role of Kindlin-2 (FERMT2/K2), a member of the Kindlin family of FERM domain proteins and key regulators of the adhesive functions mediated by integrin, in the sensitization of mCRPC to chemotherapeutics. Loss of K2, which is overexpressed in prostate cancer cells derived from mCRPC tumors, compared with those cells derived from androgen-dependent tumors, significantly enhanced apoptosis and cell death of docetaxel-treated PC3 cells. Furthermore, it was determined that K2-mediated sensitization to docetaxel treatment is the result of inhibition of β1-integrin signaling. Finally, miR-138 spe...
Source: Molecular Cancer Research - February 14, 2016 Category: Cancer & Oncology Authors: Sossey-Alaoui, K., Plow, E. F. Tags: Signal Transduction Source Type: research

MNKs and Pancreatic Cancer Progression
In this report, it is demonstrated that PDAC cells grown in collagen exhibit increased activation of the MAPK-interacting protein kinases (MNK) that mediate eIF4E phosphorylation. Pharmacologic and genetic targeting of MNKs reverse epithelial–mesenchymal transition (EMT), decrease cell migration, and reduce protein expression of the EMT-regulator ZEB1 without affecting ZEB1 mRNA levels. Paradoxically, targeting eIF4E, the best-characterized effector of MNKs, increases ZEB1 mRNA expression through repression of ZEB1-targeting miRNAs, miR-200c and miR-141. In contrast, targeting the MNK effector hnRNPA1, which can func...
Source: Molecular Cancer Research - February 14, 2016 Category: Cancer & Oncology Authors: Kumar, K., Chow, C. R., Ebine, K., Arslan, A. D., Kwok, B., Bentrem, D. J., Eckerdt, F. D., Platanias, L. C., Munshi, H. G. Tags: Oncogenes and Tumor Suppressors Source Type: research

MAP2K1 Outlier Dependencies in Cancer Cell Lines
The identification of somatic genetic alterations that confer sensitivity to pharmacologic inhibitors has led to new cancer therapies. To identify mutations that confer an exceptional dependency, shRNA-based loss-of-function data were analyzed from a dataset of numerous cell lines to reveal genes that are essential in a small subset of cancer cell lines. Once these cell lines were determined, detailed genomic characterization from these cell lines was utilized to ascertain the genomic aberrations that led to this extreme dependency. This method, in a large subset of lung cancer cell lines, yielded a single lung adenocarcin...
Source: Molecular Cancer Research - February 14, 2016 Category: Cancer & Oncology Authors: Gannon, H. S., Kaplan, N., Tsherniak, A., Vazquez, F., Weir, B. A., Hahn, W. C., Meyerson, M. Tags: Oncogenes and Tumor Suppressors Source Type: research

DPYD Is a Driver and Switch of Pyrimidine Metabolism in Human Cancer
New strategies are needed to diagnose and target human melanoma. To this end, genomic analyses was performed to assess somatic mutations and gene expression signatures using a large cohort of human skin cutaneous melanoma (SKCM) patients from The Cancer Genome Atlas (TCGA) project to identify critical differences between primary and metastatic tumors. Interestingly, pyrimidine metabolism is one of the major pathways to be significantly enriched and deregulated at the transcriptional level in melanoma progression. In addition, dihydropyrimidine dehydrogenase (DPYD) and other important pyrimidine-related genes: DPYS, AK9, CA...
Source: Molecular Cancer Research - February 14, 2016 Category: Cancer & Oncology Authors: Edwards, L., Gupta, R., Filipp, F. V. Tags: Genomics Source Type: research

Mre11 Complex Hypomorphism and ATM Deficiency
The Mre11 complex (Mre11, Rad50, and Nbs1) occupies a central node of the DNA damage response (DDR) network and is required for ATM activation in response to DNA damage. Hypomorphic alleles of MRE11 and NBS1 confer embryonic lethality in ATM-deficient mice, indicating that the complex exerts ATM-independent functions that are essential when ATM is absent. To delineate those functions, a conditional ATM allele (ATMflox) was crossed to hypomorphic NBS1 mutants (Nbs1B/B mice). Nbs1B/B Atm–/– hematopoietic cells derived by crossing to vavcre were viable in vivo. Nbs1B/B Atm–/– VAV mice exhibited a prono...
Source: Molecular Cancer Research - February 14, 2016 Category: Cancer & Oncology Authors: Balestrini, A., Nicolas, L., Yang-lott, K., Guryanova, O. A., Levine, R. L., Bassing, C. H., Chaudhuri, J., Petrini, J. H. J. Tags: DNA Damage and Repair Source Type: research

Cancer Metabolism in DNA Repair
Conventional wisdom ascribes metabolic reprogramming in cancer to meeting increased demands for intermediates to support rapid proliferation. Prior models have proposed benefits toward cell survival, immortality, and stress resistance, although the recent discovery of oncometabolites has shifted attention to chromatin targets affecting gene expression. To explore further effects of cancer metabolism and epigenetic deregulation, DNA repair kinetics were examined in cells treated with metabolic intermediates, oncometabolites, and/or metabolic inhibitors by tracking resolution of double-strand breaks (DSB) in irradiated MCF7 ...
Source: Molecular Cancer Research - February 14, 2016 Category: Cancer & Oncology Authors: Efimova, E. V., Takahashi, S., Shamsi, N. A., Wu, D., Labay, E., Ulanovskaya, O. A., Weichselbaum, R. R., Kozmin, S. A., Kron, S. J. Tags: DNA Damage and Repair Source Type: research

Direct EZH2-E2F1 Collaboration in Gene Regulation in Cancer
Overexpression of EZH2 is frequently linked to the advanced and metastatic stage of cancers. The mechanisms of its oncogenic function can be context specific, and may vary depending on the protein complexes that EZH2 interacts with. To identify novel transcriptional collaborators of EZH2 in cancers, a computational approach was developed that integrates protein–DNA binding data, cell perturbation gene expression data, and compendiums of tumor expression profiles. This holistic approach identified E2F1, a known mediator of the Rb tumor suppressor, as a transcriptional collaborator of EZH2 in castration-resistant prost...
Source: Molecular Cancer Research - February 14, 2016 Category: Cancer & Oncology Authors: Xu, H., Xu, K., He, H. H., Zang, C., Chen, C.-H., Chen, Y., Qin, Q., Wang, S., Wang, C., Hu, S., Li, F., Long, H., Brown, M., Liu, X. S. Tags: Chromatin, Epigenetics, and RNA Regulation Source Type: research

FOXO1 Determines PR Isoform Transactivation in Ovarian Cancer Cells
This study indicates FOXO1 as a critical component for progesterone signaling to promote cellular senescence and reveals a novel mechanism for transcription factor control of hormone sensitivity. Mol Cancer Res; 14(2); 141–62. ©2015 AACR. (Source: Molecular Cancer Research)
Source: Molecular Cancer Research - February 14, 2016 Category: Cancer & Oncology Authors: Diep, C. H., Knutson, T. P., Lange, C. A. Tags: Cell Cycle and Senescence Source Type: research

Hippo/YAP in Cell Cycle and Cancer
The control of cell division is essential for normal development and the maintenance of cellular homeostasis. Abnormal cell proliferation is associated with multiple pathological states, including cancer. Although the Hippo/YAP signaling pathway was initially thought to control organ size and growth, increasing evidence indicates that this pathway also plays a major role in the control of proliferation independent of organ size control. In particular, accumulating evidence indicates that the Hippo/YAP signaling pathway functionally interacts with multiple other cellular pathways and serves as a central node in the regulati...
Source: Molecular Cancer Research - February 14, 2016 Category: Cancer & Oncology Authors: Ehmer, U., Sage, J. Tags: Review Source Type: research

Selected Articles from This Issue
(Source: Molecular Cancer Research)
Source: Molecular Cancer Research - February 14, 2016 Category: Cancer & Oncology Tags: Highlights Source Type: research

Abstract A92: Aminomethylphosphonic acid inhibits human prostate xenograft tumor growth through interfering glycine synthesis in the cancer cells
Rapidly proliferating cancer cells consume more glycine than rapidly proliferating normal cells, which offers an opportunity to target glycine metabolism in the cancer cells while avoiding causing severe side effects in the normal cells. Two-thirds of glycine consumed is synthesized intracellularly, e.g., through conversion of serine into glycine by serine hydroxymethyltransferase (SHMT). Aminomethylphosphonic acid (AMPA, C3H3NO5P) is an analog to glycine, which inhibits SHMT enzyme activity, thus blocking conversion of serine into glycine. Our previous in-vitro studies have shown that AMPA inhibited cell growth in six can...
Source: Molecular Cancer Research - January 15, 2016 Category: Cancer & Oncology Authors: Parajuli, K. R., Zhang, Q., Liu, S., You, Z. Tags: Therapeutic Targets From Cancer: Poster Presentations - Proffered Abstracts Source Type: research

Abstract A91: Over-the-counter melatonin supplementation in human subjects: A potentially novel chronotherapeutic approach targeting the Warburg effect and fatty acid metabolism in breast cancer therapy/prevention
Melatonin, a circadian anti-cancer hormone produced by the pineal gland during darkness at night suppresses the Warburg effect, linoleic acid (LA) uptake/metabolism and tumor cell proliferation in both estrogen receptor (ERα+) and ERα- in tissue-isolated human breast cancer xenografts. The nighttime circadian melatonin signal regulates circadian rhythms in tumor glucose and fatty acid metabolism as well as related signaling pathways that are important in controlling cell proliferative and survival mechanisms. Over-the-counter (OTC) melatonin supplements are used by millions of individuals to treat insomnia and/...
Source: Molecular Cancer Research - January 15, 2016 Category: Cancer & Oncology Authors: Blask, D. E., Dauchy, R. T., Dauchy, E. M., Hill, S. M., Mao, L., Wren, M. M., Meyaski-Schluter, M. M. C., Yuan, L. Tags: Therapeutic Targets From Cancer: Poster Presentations - Proffered Abstracts Source Type: research

Abstract A90: Dichloroacetate can overcome drug resistance via decreased ABC drug transporter expression and PDK2 inhibition
We examined DCA's effects in doxorubicin (DOX)-resistant MDA-MB-231 and MCF7 cells (made by continuous exposure to increasing DOX concentrations for one month) and their DOX-sensitive counterparts by neutral red cell viability assay. Intracellular drug uptake was measured by flow cytometry and expression of PDKs and drug transporters was measured by western blotting.Results: DCA treatment (1mM for 48hrs) significantly (p
Source: Molecular Cancer Research - January 15, 2016 Category: Cancer & Oncology Authors: Achuthan, S., Callaghan, R., Blackburn, A. C. Tags: Therapeutic Targets From Cancer: Poster Presentations - Proffered Abstracts Source Type: research

Abstract A89: Glycolytic cancer cell metabolism suppressed by transplantation of exogenous normal mitochondria into human breast cancer cells
Most cancer cells switch metabolism from mitochondria-based glucose oxidation to cytoplasmic glycolysis even under normoxia (the Warburg effect). The effect promotes tumorigenesis, cancer growth, invasion and drug resistance. We hypothesize that introduction of normal mitochondria into cancer cells might suppress the Warburg effect. Normal human (MCF-12A) and mouse (EpH4-Ev) mammary epithelia, and human breast cancer (MCF-7) and mouse mammary adenocarcinoma (4T1) cell lines were used in this study. We found that isolated fluorescent probe-stained mitochondria of MCF-12A or EpH4-Ev could enter into cancer cells when co-cult...
Source: Molecular Cancer Research - January 15, 2016 Category: Cancer & Oncology Authors: Elliott, R. L., Jiang, X.-P., Head, J. F. Tags: Therapeutic Targets From Cancer: Poster Presentations - Proffered Abstracts Source Type: research

Abstract A88: Openers of voltage dependent anion channels are anti-Warburg agents that enhance mitochondrial metabolism, decrease glycolysis, activate JNK and induce ROS-dependent killing of cancer cells
Background: Warburg metabolism is characterized by enhanced aerobic glycolysis and suppressed mitochondrial metabolism. Voltage dependent anion channels (VDAC) located in the mitochondrial outer membrane control flux of metabolites into mitochondria. Free α,β-tubulin closes VDAC in planar lipid bilayers (Rostovtseva et al., PNAS 105:18746), and high free tubulin in cancer cells decreases mitochondrial membrane potential () by limiting ingress of respiratory substrates and ATP that support formation (Maldonado et al., Cancer Res. 70:10192). The small molecule erastin opens VDAC by antagonizing the inhibitory effe...
Source: Molecular Cancer Research - January 15, 2016 Category: Cancer & Oncology Authors: DeHart, D. N., Gooz, M., Lemasters, J. J., Lemasters, J. J., Maldonado, E. N. Tags: Therapeutic Targets From Cancer: Poster Presentations - Proffered Abstracts Source Type: research

Abstract A87: Targeting the mitochondrial quality control machinery in acute myeloid leukemia
Recently, we demonstrated that a subset of AML cells and stem cells have metabolic vulnerabilities in the mitochondria and oxidative phosphorylation (OXPHOS) chain that could impact on the ability of AML and AML stem cells to handle increased electron flux in the respiratory chain (Sriskanthadevan et al., Blood, 2015). To identify additional vulnerabilities in the mitochondria of AML cells and AML stem cells, we analyzed RNA expression levels of a panel of mitochondrial quality control proteins using the nCounter Analysis System (Nanostring technologies) in bulk as well as the progenitor enriched fraction of AML patients a...
Source: Molecular Cancer Research - January 15, 2016 Category: Cancer & Oncology Authors: Jeyaraju, D. V., Voisin, V., Ramakrishnan, A., Hurren, R., Maclean, N., Gronda, M., Minden, M., Bader, G., Schimmer, A. D. Tags: Therapeutic Targets From Cancer: Poster Presentations - Proffered Abstracts Source Type: research

Abstract A86: LRP16, interacting with PKR, prolongs NF-kappaB activation and drives colorectal cancer tumorigenesis
NF-kappaB frequently activated in colorectal cancer (CRC) is linked to rapid malignant progression of CRC and is also crucial for the maintenance of homeostasis and therapy resistance. However, the underlying mechanisms how NF-kappaB activation and the crosstalk of NF-kappaB with other transcription factors are controlled in CRC remain incompletely understood. Here, we show that LRP16 physically interacts with double-stranded RNA-dependent protein kinase (PKR) functions as a signal transducer in signaling pathways activated by different stimuli by a variety of effectors, including NF-kappaB. Overexpression of LRP16 confers...
Source: Molecular Cancer Research - January 15, 2016 Category: Cancer & Oncology Authors: Li, X., Wu, Z., Han, W. Tags: Therapeutic Targets From Cancer: Poster Presentations - Proffered Abstracts Source Type: research

Abstract A85: Concurrent targeting of glutamine and asparagine metabolism produces synergistic inhibition of tumor cell proliferation
One of the best characterized examples of metabolic changes occurring in a wide range of cancer cells is dependence on the non-essential amino acid glutamine. We identified requirements for several other non-essential amino acids, including asparagine, across a panel of glutamine-dependent and –independent breast and lung cancer cell lines. Glutamine and asparagine metabolism are tightly linked. Therefore, we hypothesized that concurrent targeting of the metabolism of these two non-essential amino acids could cooperatively interfere with tumor cell growth. Treatment with a glutaminase inhibitor, BPTES, and concurrent...
Source: Molecular Cancer Research - January 15, 2016 Category: Cancer & Oncology Authors: Schramm, C. L., Xie, Z., Kindt, E., Li, W., Wang, F., Fantin, V. R. Tags: Therapeutic Targets From Cancer: Poster Presentations - Proffered Abstracts Source Type: research