bluuebunny/crossref_metadata_2025_split huggingface dataset:
Constitutive NOTCH3 Signaling Promotes the Growth of Basal Breast Cancers
Authors: Choy Lisa , Hagenbeek Thijs J. , Solon Margaret , French Dorothy , Finkle David , Shelton Amy , Venook Rayna , Brauer Matthew J. , Siebel Christian W. 
Published: January 2017

Abstract
Notch ligands signal through one of four receptors on neighboring cells to mediate cell–cell communication and control cell fate, proliferation, and survival. Although aberrant Notch activation has been implicated in numerous malignancies, including breast cancer, the importance of individual receptors in distinct breast cancer subtypes and the mechanisms of receptor activation remain unclear. Using a novel antibody to detect active NOTCH3, we report here that NOTCH3 signals constitutively in a panel of basal breast cancer cell lines and in more than one third of basal tumors. Selective inhibition of individual ligands revealed that this signal does not require canonical ligand induction. A NOTCH3 antagonist antibody inhibited growth of basal lines, whereas a NOTCH3 agonist antibody enhanced the transformed phenotype in vitro and in tumor xenografts. Transcriptomic analyses generated a Notch gene signature that included Notch pathway components, the oncogene c-Myc, and the mammary stem cell regulator Id4. This signature drove clustering of breast cancer cell lines and tumors into the common subtypes and correlated with the basal classification. Our results highlight an unexpected ligand-independent induction mechanism and suggest that constitutive NOTCH3 signaling can drive an oncogenic program in a subset of basal breast cancers. Cancer Res; 77(6); 1439–52. ©2017 AACR.
A Transposon-based Analysis Reveals RASA1 Is Involved in Triple-Negative Breast Cancer
Authors: Suárez-Cabrera Cristian , Quintana Rita M. , Bravo Ana , Casanova M. Llanos , Page Angustias , Alameda Josefa P. , Paramio Jesús M. , Maroto Alicia , Salamanca Javier , Dupuy Adam J. , Ramírez Angel , Navarro Manuel 
Published: January 2017

Abstract
RAS genes are mutated in 20% of human tumors, but these mutations are very rare in breast cancer. Here, we used a mouse model to generate tumors upon activation of a mutagenic T2Onc2 transposon via expression of a transposase driven by the keratin K5 promoter in a p53+/− background. These animals mainly developed mammary tumors, most of which had transposon insertions in one of two RASGAP genes, neurofibromin1 (Nf1) and RAS p21 protein activator (Rasa1). Immunohistochemical analysis of a collection of human breast tumors confirmed that low expression of RASA1 is frequent in basal (triple-negative) and estrogen receptor negative tumors. Bioinformatic analysis of human breast tumors in The Cancer Genome Atlas database showed that although RASA1 mutations are rare, allelic loss is frequent, particularly in basal tumors (80%) and in association with TP53 mutation. Inactivation of RASA1 in MCF10A cells resulted in the appearance of a malignant phenotype in the context of mutated p53. Our results suggest that alterations in the Ras pathway due to the loss of negative regulators of RAS may be a common event in basal breast cancer. Cancer Res; 77(6); 1357–68. ©2017 AACR.
Fibrinolytic Enzyme Cotherapy Improves Tumor Perfusion and Therapeutic Efficacy of Anticancer Nanomedicine
Authors: Kirtane Ameya R. , Sadhukha Tanmoy , Kim Hyunjoon , Khanna Vidhi , Koniar Brenda , Panyam Jayanth 
Published: January 2017

Abstract
Elevated interstitial fluid pressure and solid stress within tumors contribute to poor intratumoral distribution of nanomedicine. In this study, we hypothesized that the presence of fibrin in tumor extracellular matrix contributes to hindered intratumoral distribution of nanocarriers and that this can be overcome through the use of a fibrinolytic enzyme such as tissue plasminogen activator (tPA). Analysis of fibrin expression in human tumor biopsies showed significant fibrin staining in nearly all tumor types evaluated. However, staining was heterogeneous across and within tumor types. We determined the effect of fibrin on the diffusion, intratumoral distribution, and therapeutic efficacy of nanocarriers. Diffusivity of nanocarriers in fibrin matrices was limited and could be improved significantly by coincubation with tPA. In vivo, coadministration of tPA improved the anticancer efficacy of nanoparticle-encapsulated paclitaxel in subcutaneous syngeneic mouse melanoma and orthotopic xenograft lung cancer models. Furthermore, treatment with tPA led to decompression of blood vessels and improved tumor perfusion. Cotreatment with tPA resulted in greater intratumoral penetration of a model nanocarrier (Doxil), leading to enhanced availability of the drug in the tumor core. Fibrinolytics such as tPA are already approved for other indications. Fibrinolytic cotherapy is therefore a rapidly translatable strategy for improving therapeutic effectiveness of anticancer nanomedicine. Cancer Res; 77(6); 1465–75. ©2017 AACR.
Biomarker-Based PET Imaging of Diffuse Intrinsic Pontine Glioma in Mouse Models
Authors: Kossatz Susanne , Carney Brandon , Schweitzer Melanie , Carlucci Giuseppe , Miloushev Vesselin Z. , Maachani Uday B. , Rajappa Prajwal , Keshari Kayvan R. , Pisapia David , Weber Wolfgang A. , Souweidane Mark M. , Reiner Thomas 
Published: January 2017

Abstract
Diffuse intrinsic pontine glioma (DIPG) is a childhood brainstem tumor with a universally poor prognosis. Here, we characterize a positron emission tomography (PET) probe for imaging DIPG in vivo. In human histological tissues, the probes target, PARP1, was highly expressed in DIPG compared to normal brain. PET imaging allowed for the sensitive detection of DIPG in a genetically engineered mouse model, and probe uptake correlated to histologically determined tumor infiltration. Imaging with the sister fluorescence agent revealed that uptake was confined to proliferating, PARP1-expressing cells. Comparison with other imaging technologies revealed remarkable accuracy of our biomarker approach. We subsequently demonstrated that serial imaging of DIPG in mouse models enables monitoring of tumor growth, as shown in modeling of tumor progression. Overall, this validated method for quantifying DIPG burden would serve useful in monitoring treatment response in early phase clinical trials. Cancer Res; 77(8); 2112–23. ©2017 AACR.
Cancer Risk in Women Treated with Fertility Drugs According to Parity Status—A Registry-based Cohort Study
Authors: Reigstad Marte Myhre , Storeng Ritsa , Myklebust Tor Åge , Oldereid Nan Birgitte , Omland Anne Katerine , Robsahm Trude Eid , Brinton Louise Annette , Vangen Siri , Furu Kari , Larsen Inger Kristin 
Published: January 2017

AbstractBackground: Long-term safety of assisted reproductive techniques (ART) is of interest as their use is increasing. Cancer risk is known to be affected by parity. This study examined the risk of cancer after fertility treatment, stratified by women's parity.Methods: Data were obtained from all women (n = 1,353,724) born in Norway between 1960 and 1996. Drug exposure data (2004–2014) were obtained from the Norwegian Prescription Database (drugs used in ART and clomiphene citrate). The Medical Birth Registry of Norway provided parity status. HRs were calculated for all site cancer, breast, cervical, endometrial, ovarian, colorectal, central nervous system, thyroid cancer, and malignant melanoma.Results: In 12,354,392 person-years of follow-up, 20,128 women were diagnosed with cancer. All-site cancer risk was 1.14 [95% confidence interval (95% CI), 1.03–1.26] and 1.10 (95% CI, 0.98–1.23) after clomiphene citrate and ART exposure, respectively. For ovarian cancer, a stronger association was observed for both exposures in nulliparous (HR, 2.49; 95% CI, 1.30–4.78; and HR, 1.62; 95% CI, 0.78–3.35) versus parous women (HR, 1.37; 95% CI, 0.64–2.96; and HR, 0.87; 95% CI, 0.33–2.27). Elevated risk of endometrial cancers was observed for clomiphene citrate exposure in nulliparous women (HR, 4.49; 95% CI, 2.66–7.60 vs. HR, 1.52; 95% CI, 0.67–3.42). Risk was elevated for breast cancer in parous women exposed to clomiphene citrate (HR, 1.26; 95% CI, 1.03–1.54) for thyroid cancer and among nulliparous women after ART treatment (HR, 2.19; 95% CI, 1.08–4.44).Conclusions: Clomiphene citrate appears associated with increased risk of ovarian and endometrial cancer. Elevations in risks of breast and thyroid cancer were less consistent across type of drug exposure and parity.Impact: Continued monitoring of fertility treatments is warranted. Cancer Epidemiol Biomarkers Prev; 26(6); 953–62. ©2017 AACR.
The Interplay Between Neutrophils and CD8+ T Cells Improves Survival in Human Colorectal Cancer
Authors: Governa Valeria , Trella Emanuele , Mele Valentina , Tornillo Luigi , Amicarella Francesca , Cremonesi Eleonora , Muraro Manuele Giuseppe , Xu Hui , Droeser Raoul , Däster Silvio R. , Bolli Martin , Rosso Raffaele , Oertli Daniel , Eppenberger-Castori Serenella , Terracciano Luigi M. , Iezzi Giandomenica , Spagnoli Giulio C. 
Published: January 2017

AbstractPurpose: Tumor infiltration by different T lymphocyte subsets is known to be associated with favorable prognosis in colorectal cancer. Still debated is the role of innate immune system. We investigated clinical relevance, phenotypes, and functional features of colorectal cancer–infiltrating CD66b+ neutrophils and their crosstalk with CD8+ T cells.Experimental Design: CD66b+ and CD8+ cell infiltration was analyzed by IHC on a tissue microarray including &gt;650 evaluable colorectal cancer samples. Phenotypic profiles of tissue-infiltrating and peripheral blood CD66b+ cells were evaluated by flow cytometry. CD66b+/CD8+ cells crosstalk was investigated by in vitro experiments.Results: CD66b+ cell infiltration in colorectal cancer is significantly associated with increased survival. Interestingly, neutrophils frequently colocalize with CD8+ T cells in colorectal cancer. Functional studies indicate that although neutrophils are devoid of direct antitumor potential, coculture with peripheral blood or tumor-associated neutrophils (TAN) enhances CD8+ T-cell activation, proliferation, and cytokine release induced by suboptimal concentrations of anti-CD3 mAb. Moreover, under optimal activation conditions, CD8+ cell stimulation in the presence of CD66b+ cells results in increasing numbers of cells expressing CD45RO/CD62L “central memory” phenotype. Importantly, combined tumor infiltration by CD66b+ and CD8+ T lymphocytes is associated with significantly better prognosis, as compared with CD8+ T-cell infiltration alone.Conclusions: Neutrophils enhance the responsiveness of CD8+ T cells to T-cell receptor triggering. Accordingly, infiltration by neutrophils enhances the prognostic significance of colorectal cancer infiltration by CD8+ T cells, suggesting that they might effectively promote antitumor immunity. Clin Cancer Res; 23(14); 3847–58. ©2017 AACR.
Bombesin Antagonist-Based Radiotherapy of Prostate Cancer Combined with WST-11 Vascular Targeted Photodynamic Therapy
Authors: Kim Kwanghee , Zhang Hanwen , La Rosa Stephen , Jebiwott Sylvia , Desai Pooja , Kimm Simon , Scherz Avigdor , O'Donoghue Joseph A. , Weber Wolfgang A. , Coleman Jonathan A. 
Published: January 2017

Abstract
Purpose: DOTA-AR, a bombesin-antagonist peptide, has potential clinical application for targeted imaging and therapy in gastrin-releasing peptide receptor (GRPr)–positive malignancies when conjugated with a radioisotope such as 90Y. This therapeutic potential is limited by the fast washout of the conjugates from the target tumors. WST-11 (Weizmann STeba-11 drug; a negatively charged water-soluble palladium-bacteriochlorophyll derivative, Tookad Soluble) vascular targeted photodynamic therapy (VTP) is a local ablation approach recently approved for use in early-stage prostate cancer. It generates reactive oxygen/nitrogen species within tumor blood vessels, resulting in their instantaneous destruction followed by rapid tumor necrosis. We hypothesize that the instantaneous arrest of tumor vasculature may provide a means to trap radiopharmaceuticals within the tumor, thereby improving the efficacy of targeted radiotherapy.
Experimental Design: GRPr-positive prostate cancer xenografts (PC-3 and VCaP) were treated with 90Y-DOTA-AR with or without VTP. The uptake of radioisotopes was monitored by Cherenkov luminescence imaging (CLI). The therapeutic efficacy of the combined VTP and 90Y-DOTA-AR in PC-3 xenografts was assessed.
Results: CLI of 90Y-DOTA-AR demonstrated longer retention of radiotracer within the VTP-treated PC-3 xenografts compared with the non–VTP-treated ones (P &lt; 0.05) at all time points (24–144 hours) after 90Y-DOTA-AR injection. A similar pattern of retention was observed in VCaP xenografts. When 90Y-DOTA-AR administration was combined with VTP, tumor growth delay was significantly longer than for the control or the monotherapy groups.
Conclusions: Tumor vascular arrest by VTP improves 90Y-DOTA-AR retention in the tumor microenvironment thereby enhancing therapeutic efficacy. Clin Cancer Res; 23(13); 3343–51. ©2017 AACR.
Tumor-induced Stromal STAT1 Accelerates Breast Cancer via Deregulating Tissue Homeostasis
Authors: Zellmer Victoria R. , Schnepp Patricia M. , Fracci Sarah L. , Tan Xuejuan , Howe Erin N. , Zhang Siyuan 
Published: January 2017

Abstract
The tumor microenvironment (TME), the dynamic tissue space in which the tumor exists, plays a significant role in tumor initiation, and is a key contributor in cancer progression; however, little is known about tumor-induced changes in the adjacent tissue stroma. Herein, tumor-induced changes in the TME were explored at the morphologic and molecular level to further understand cancer progression. Tumor-adjacent mammary glands (TAG) displayed altered branching morphology, expansion of myofibroblasts, and increased mammosphere formation, broadly suggesting a tumor-induced field effect. FACS analysis of TAGs demonstrated an increased number of Lin−CD24+/CD49+ enriched mammary gland stem cells (MaSC), suggesting deregulated tissue homeostasis in TAGs. Comparative transcriptome analysis of TAGs and contralateral control glands coupled with meta-analysis on differentially expressed genes with two breast cancer stromal patient microarray datasets identified shared upregulation of STAT1. Knockdown of STAT1 in cancer-associated fibroblast (CAF) cocultured with human breast cancer cells altered cancer cell proliferation, indicating a role for STAT1 as a stromal contributor of tumorigenesis. Furthermore, depletion of STAT1 in CAFs significantly reduced periductal reactive fibrosis and delayed early breast cancer progression in vivo. Finally, cotreatment with fludarabine, a FDA-approved STAT1 activation inhibitor and DNA synthesis inhibitor, in combination with doxorubicin, showed enhanced therapeutic efficacy in treating mouse mammary gland tumors. Taken together, these results demonstrate that stromal STAT1 expression promotes tumor progression and is a potential therapeutic target for breast cancer.
Implications: Tumors induce stromal STAT1-dependent cytokine secretion that promotes tumor cell proliferation and can be targeted using clinically-approved inhibitors of STAT1. Mol Cancer Res; 15(5); 585–97. ©2017 AACR.
Metabolic Reprogramming by Folate Restriction Leads to a Less Aggressive Cancer Phenotype
Authors: Ashkavand Zahra , O'Flanagan Ciara , Hennig Mirko , Du Xiuxia , Hursting Stephen D. , Krupenko Sergey A. 
Published: January 2017

Abstract
Folate coenzymes are involved in biochemical reactions of one-carbon transfer, and deficiency of this vitamin impairs cellular proliferation, migration, and survival in many cell types. Here, the effect of folate restriction on mammary cancer was evaluated using three distinct breast cancer subtypes differing in their aggressiveness and metastatic potential: noninvasive basal-like (E-Wnt), invasive but minimally metastatic claudin-low (M-Wnt), and highly metastatic claudin-low (metM-Wntliver) cell lines, each derived from the same pool of MMTV-Wnt-1 transgenic mouse mammary tumors. NMR-based metabolomics was used to quantitate 41 major metabolites in cells grown in folate-free medium versus standard medium. Each cell line demonstrated metabolic reprogramming when grown in folate-free medium. In E-Wnt, M-Wnt, and metM-Wntliver cells, 12, 29, and 25 metabolites, respectively, were significantly different (P &lt; 0.05 and at least 1.5-fold change). The levels of eight metabolites (aspartate, ATP, creatine, creatine phosphate, formate, serine, taurine and β-alanine) were changed in each folate-restricted cell line. Increased glucose, decreased lactate, and inhibition of glycolysis, cellular proliferation, migration, and invasion occurred in M-Wnt and metM-Wntliver cells (but not E-Wnt cells) grown in folate-free versus standard medium. These effects were accompanied by altered levels of several folate-metabolizing enzymes, indicating that the observed metabolic reprogramming may result from both decreased folate availability and altered folate metabolism. These findings reveal that folate restriction results in metabolic and bioenergetic changes and a less aggressive cancer cell phenotype.
Implications: Metabolic reprogramming driven by folate restriction represents a therapeutic target for reducing the burden of breast cancer. Mol Cancer Res; 15(2); 189–200. ©2016 AACR.
Enhancer Remodeling during Adaptive Bypass to MEK Inhibition Is Attenuated by Pharmacologic Targeting of the P-TEFb Complex
Authors: Zawistowski Jon S. , Bevill Samantha M. , Goulet Daniel R. , Stuhlmiller Timothy J. , Beltran Adriana S. , Olivares-Quintero Jose F. , Singh Darshan , Sciaky Noah , Parker Joel S. , Rashid Naim U. , Chen Xin , Duncan James S. , Whittle Martin C. , Angus Steven P. , Velarde Sara Hanna , Golitz Brian T. , He Xiaping , Santos Charlene , Darr David B. , Gallagher Kristalyn , Graves Lee M. , Perou Charles M. , Carey Lisa A. , Earp H. Shelton , Johnson Gary L. 
Published: January 2017

Abstract
Targeting the dysregulated BRAF–MEK–ERK pathway in cancer has increasingly emerged in clinical trial design. Despite clinical responses in specific cancers using inhibitors targeting BRAF and MEK, resistance develops often involving nongenomic adaptive bypass mechanisms. Inhibition of MEK1/2 by trametinib in patients with triple-negative breast cancer (TNBC) induced dramatic transcriptional responses, including upregulation of receptor tyrosine kinases (RTK) comparing tumor samples before and after one week of treatment. In preclinical models, MEK inhibition induced genome-wide enhancer formation involving the seeding of BRD4, MED1, H3K27 acetylation, and p300 that drives transcriptional adaptation. Inhibition of the P-TEFb–associated proteins BRD4 and CBP/p300 arrested enhancer seeding and RTK upregulation. BRD4 bromodomain inhibitors overcame trametinib resistance, producing sustained growth inhibition in cells, xenografts, and syngeneic mouse TNBC models. Pharmacologic targeting of P-TEFb members in conjunction with MEK inhibition by trametinib is an effective strategy to durably inhibit epigenomic remodeling required for adaptive resistance.
Significance: Widespread transcriptional adaptation to pharmacologic MEK inhibition was observed in TNBC patient tumors. In preclinical models, MEK inhibition induces dramatic genome-wide modulation of chromatin, in the form of de novo enhancer formation and enhancer remodeling. Pharmacologic targeting of P-TEFb complex members at enhancers is an effective strategy to durably inhibit such adaptation. Cancer Discov; 7(3); 302–21. ©2017 AACR.
This article is highlighted in the In This Issue feature, p. 235
Myeloid STAT3 Promotes Lung Tumorigenesis by Transforming Tumor Immunosurveillance into Tumor-Promoting Inflammation
Authors: Zhou Jingjiao , Qu Zhaoxia , Sun Fan , Han Lei , Li Liwen , Yan Shapei , Stabile Laura P. , Chen Lin-Feng , Siegfried Jill M. , Xiao Gutian 
Published: January 2017

Abstract
One of the most fundamental and challenging questions in the cancer field is how immunity in patients with cancer is transformed from tumor immunosurveillance to tumor-promoting inflammation. Here, we identify the transcription factor STAT3 as the culprit responsible for this pathogenic event in lung cancer development. We found that antitumor type 1 CD4+ T-helper (Th1) cells and CD8+ T cells were directly counter balanced in lung cancer development with tumor-promoting myeloid-derived suppressor cells (MDSCs) and suppressive macrophages, and that activation of STAT3 in MDSCs and macrophages promoted tumorigenesis through pulmonary recruitment and increased resistance of suppressive cells to CD8+ T cells, enhancement of cytotoxicity toward CD4+ and CD8+ T cells, induction of regulatory T cell (Treg), inhibition of dendritic cells (DC), and polarization of macrophages toward the M2 phenotype. The deletion of myeloid STAT3 boosted antitumor immunity and suppressed lung tumorigenesis. These findings increase our understanding of immune programming in lung tumorigenesis and provide a mechanistic basis for developing STAT3-based immunotherapy against this and other solid tumors. Cancer Immunol Res; 5(3); 257–68. ©2017 AACR.
Lower Extremity Peripheral Artery Disease and Quality of Life Among Older Individuals in the Community
Authors: Wu Aozhou , Coresh Josef , Selvin Elizabeth , Tanaka Hirofumi , Heiss Gerardo , Hirsch Alan T. , Jaar Bernard G. , Matsushita Kunihiro 
Published: January 2017

Background

Evidence regarding the association of lower extremity peripheral arterial disease with quality of life (
QOL
) is mainly from selected clinical populations or relatively small clinical cohorts. Thus, we investigated this association in community‐derived populations.

Methods and Results

Using data of 5115 participants aged 66 to 90 years from visit 5 (2011‐2013) of the Atherosclerosis Risk in Communities Study, we quantified the associations of ankle‐brachial index (
ABI
) with several
QOL
parameters, including 12‐item Short‐Form Health Survey (
SF
‐12), after accounting for potential confounders using linear and logistic regression models. Peripheral arterial disease defined by an
ABI
<0.90 (n=402), was independently associated with a low
SF
‐12 Physical Component Summary score (−3.26 [95%
CI
−5.60 to −0.92]), compared to the
ABI
reference 1.10 to 1.19 (n=1900) but not with the Mental Component Summary score (−0.07 [−2.21 to 2.06]). A low
ABI
was significantly associated with poorer status of all
SF
‐12 physical domains (physical functioning, role‐physical, bodily pain, and general health) but only vitality out of 4 mental domains. Similarly, low
ABI
values were more consistently associated with other physically related
QOL
parameters (leisure‐time exercise/activity/walking) than mentally related parameters (significant depressive symptoms and hopeless feeling). Lower physical
QOL
was observed even in individuals with borderline low
ABI
(0.90 to 0.99; n=426).

Conclusions

Low
ABI
(even borderline) was independently associated with poor
QOL
, especially for physical components, in community‐dwelling older adults.
QOL
is a critical element for older adults, and thus, further studies are warranted to assess whether peripheral arterial disease‐specific management can improve
QOL
in older populations.