tbuckley/cabot-search huggingface dataset:
Abstract 4634: Breastfeeding and prognosis of breast cancer among Chinese women
Authors: Zefang Ren, Xiang Wang, Luying Tang
Journal: Cancer Research (2020)

Abstract Breastfeeding that linked to breast cancer risk may also influence the prognosis. A few previous studies on this topic have yielded inconsistent results. This study aimed to explore the dose-effect relationship between breastfeeding duration and breast cancer survival among Chinese women. We collected breastfeeding status, first breastfeeding duration (FBD), total breastfeeding duration (TBD) and average breastfeeding duration per child (ABD) from 3110 primary breast cancer patients recruited between October 2008 and June 2016 in Guangzhou, China and followed up until June 30, 2018. Restricted cubic splines and Cox proportional regression models were conducted to estimate the hazard ratios (HRs) and 95% confidence intervals (95% CI) for overall survival (OS) and progression-free survival (PFS) in association with breastfeeding. Long FBD (≥13 months) (HR=1.56 [1.13-2.17]), ABD (≥13 months) (HR=1.43 [1.04-1.96]) and TBD (≥37 months) (HR=1.73 [1.07-2.80]) were found to be associated with an increased risk of progression compared to moderate durations (FBD/ABD of 7-12 months, TBD of 19-36 months). Similar associations were observed for all-cause death. When stratified by ER status, the above effects of long FBD and ABD occurred only among patients with ER-positive tumor and the interactions were significant (FBD: Pinteraction=0.04 and 0.06, ABD: Pinteraction=0.07 and 0.04 for OS and PFS, respectively). Additionally, short FBD (≤6 months) increased the risk of a poor prognosis among young patients (≤45 years) (HR=1.86 [1.04-3.32] and 1.58 [1.06-2.34] for OS and PFS, respectively) but not old women (Pinteraction=0.02 for both OS and PFS). These findings would help clinical counseling and gaining insight into the mechanisms of breast cancer development. Citation Format: Zefang Ren, Xiang Wang, Luying Tang. Breastfeeding and prognosis of breast cancer among Chinese women [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4634.
Abstract 2504: Modeling molecular development of breast cancer in canine mammary tumors
Authors: Kiley Graim, Dmitriy Gorenshteyn, David G. Robinson, Nicholas J. Carriero, James Cahill, Rumela Chakrabarti, Michael H. Goldschmidt, Amy C. Durham, Julien Funk, John D. Storey, Vessela N. Kristensen, Chandra L. Theesfeld, Karin U. Sorenmo, Olga G. Troyanskaya
Journal: Cancer Research (2020)

Abstract Malignancy in cancer is a consequence of the progressive accumulation of mutations in a tumor, with profound implications for drug selection and treatment. However, in human studies, inter-patient variability obscures molecular signatures of tumor progression because patients usually present with a single mammary tumor. In contrast, dogs frequently exhibit multiple naturally occurring mammary tumors in the same individual. Moreover, canine mammary tumors (CMTs) and human breast cancer have similar histopathological profiles and clinical presentation. We leverage the CMT model to elucidate genome-wide molecular changes clinically relevant in human breast cancer, focusing on signals underlying tumor development. We develop a robust, generally applicable, computational analysis framework (FREYA) for analysis of CMTs for comparative oncology. Using FREYA, we RNA profile 89 samples from 16 dogs, and demonstrate that CMTs recapitulate human breast cancer subtypes. We then extract molecular profiles of breast cancer progression at three distinct stages (normal, pre-malignant and malignant) and identify signatures of gene expression reflective of tumor progression. Focusing on the transitions to malignancy, we identify transcriptional patterns and biological pathways specific to malignant tumors and distinct from those characterizing pre-malignant tumors or normal tissue. We find that human breast cancer patients whose tumors exhibit strong CMT malignancy signatures have significantly decreased survival, indicative of the importance of the tumor progression processes identified in CMTs to human breast cancer prognosis. Altogether, our comprehensive genomic characterization demonstrates that CMTs are a powerful translational model of breast cancer, providing insights that inform our understanding of tumor development in humans. To catalyze and support similar analyses and use of the CMT model by other biomedical researchers, we publicly share all of our data and provide FREYA, a robust data processing pipeline and statistical analyses framework, at freya.flatironinstitute.org. Citation Format: Kiley Graim, Dmitriy Gorenshteyn, David G. Robinson, Nicholas J. Carriero, James Cahill, Rumela Chakrabarti, Michael H. Goldschmidt, Amy C. Durham, Julien Funk, John D. Storey, Vessela N. Kristensen, Chandra L. Theesfeld, Karin U. Sorenmo, Olga G. Troyanskaya. Modeling molecular development of breast cancer in canine mammary tumors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2504.
Abstract LB-335: Loss of function of the BRCA1-PALB2-BRCA2 axis accelerates p53-associated tumorigenesis
Authors: Yanying Huo, Amar Mahdi, Pier Selenica, Jorge S S. Reis-Filho, Britta Weigelt, Bing Xia
Journal: Cancer Research (2020)

Abstract The BRCA1-PALB2-BRCA2 axis plays essential roles in the DNA damage response, thereby suppressing genome instability and cancer development. It is widely held that p53 loss promotes BRCA/PALB2-associated tumorigenesis. Here, through parallel conditional knockout of Brca1, Palb2 and Brca2 along with one allele of Trp53 in mice, and by studying mice with a mutation that disengages the PALB2-BRCA1 interaction in different Trp53 backgrounds, we present evidence that support an alternative view, that is, functional loss of the BRCA1-PALB2-BRCA2 axis accelerates p53-associated tumorigenesis. Our results also demonstrate a functional equivalence of BRCA1, PALB2 and BRCA2 in their basic tumor suppressive activity, an epistasis between PALB2 and BRCA2 in tumor suppression, and likely complementary roles of BRCA1 and the PALB2/BRCA2 complex in maintaining cell fitness. These findings may significantly advance the current understanding of the genetic mechanisms that underlie the development of BRCA/PALB2- and p53-associated cancers. Citation Format: Yanying Huo, Amar Mahdi, Pier Selenica, Jorge S S. Reis-Filho, Britta Weigelt, Bing Xia. Loss of function of the BRCA1-PALB2-BRCA2 axis accelerates p53-associated tumorigenesis [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr LB-335.
Abstract 2083: Alternative splicing regulation by the androgen receptor in prostate cancer cells
Authors: Lucas Germain, Camille Lafront, Jolyane Beaudette, Raghavendra Tejo Karthik Poluri, Cindy Weidmann, Etienne Audet-Walsh
Journal: Cancer Research (2020)

Abstract The androgen receptor (AR) is a transcription factor that drives prostate cancer (PCa) by modulating the expression of thousands of genes to promote proliferation and survival and to reprogram metabolism. However, how AR activation affects alternative splicing is mostly unknown. Our objective was to define its role in the transcriptome-wide regulation of alternative splicing. Three human PCa models–LNCaP, LAPC4, and 22Rv1 cells–were treated with and without androgens, and RNA was purified for deep-sequencing analyses (RNA-seq). Several bio-informatic tools were then used to study alternative splicing. We demonstrate that in the absence of androgens, alternative splicing complexity is similar among AR-positive PCa cells, with 48% of all transcripts having various levels of alternative splicing. We also describe splicing differences among cell lines, such as specific splicing of AR, REST, TSC2, and CTBP1. Interestingly, AR activation changed the alternative splicing of thousands of transcripts in all the cell lines tested. Overlap between AR-sensitive alternative splicing events revealed that genes linked to PCa metabolism are major targets for this specific modulation. These genes encode metabolic enzymes such as the prostate-specific membrane antigen (FOLH1), malate dehydrogenase 1 (MDH1), and malic enzyme 2 (ME2). Enzymatic assays revealed that AR alters their activities without changing their total gene expression levels, demonstrating that AR-driven regulation of alternative splicing has a direct effect on cancer cell metabolism. Overall, our study presents a comprehensive analysis of PCa cell transcriptome and its modulation by AR, revealing cell metabolism as a key target for AR-dependent regulation of alternative splicing. Citation Format: Lucas Germain, Camille Lafront, Jolyane Beaudette, Raghavendra Tejo Karthik Poluri, Cindy Weidmann, Etienne Audet-Walsh. Alternative splicing regulation by the androgen receptor in prostate cancer cells [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2083.
Abstract 107: Data mining analysis of the PP2A-cell cycle axis in breast and prostate cancer patients
Authors: Ylenia Cendon-Florez, Raffaella Pippa, Silvia Boffo, Maria D. Odero, Antonio Giordano
Journal: Cancer Research (2020)

Abstract Breast and prostate cancer are aggressive hormone-dependent diseases that affect thousands of people every year. Despite advances in early detection and the understanding of the molecular bases of both cancers' biology, resistance to therapy frequently occurs. Thus, the identification of novel therapeutic targets and pathways that contribute to breast and prostate cancer lethality is necessary for improving clinical outcomes. Here, we analyzed the gene expression of known inhibitors of the protein phosphatase 2A (PP2A) in both cancer patient samples. Our analysis disclosed a general over-expression of all PP2A negative regulators. Additionally, SET, CIP2A, ANP32E and TIPRL genes are frequently co-expressed, and their expression positively correlates with the ones of the main cyclins and CDKs, suggesting the existence of a feed-forward loop that might contribute to the cancer progression via PP2A inactivation. Overall, our study indicates the existence of a strategic and targetable axis between PP2A inhibitors (SET, CIP2A, ANP32E and TIPRL) and cell cycle regulators (Cyclin A, Cyclin E, Cyclin B and CDK1) and provides a valuable rationale for using a personalized combinational therapy approach to improve breast and prostate cancer patient survival. Keywords: Breast cancer, Prostate Cancer, PP2A, cell cycle Citation Format: Ylenia Cendon-Florez, Raffaella Pippa, Silvia Boffo, Maria D. Odero, Antonio Giordano. Data mining analysis of the PP2A-cell cycle axis in breast and prostate cancer patients [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 107.
Abstract 1936: Immunoproteasome inhibitors for the treatment of ALL
Authors: Tyler W. Jenkins, Sondra Downey-Kopyscinski, William C. Colley, Jennifer L. Fields, Steven N. Fiering, Alexei F. Kisselev
Journal: Cancer Research (2020)

Abstract The t(4;11)(q21;q23) chromosomal translocation that creates MLL-AF4 fusion protein confers a poor prognosis protein in infant acute lymphoblastic leukemia (ALL). This translocation also sensitizes cells to proteasome inhibitors bortezomib and carfilzomib, which are approved by the FDA for the treatment of multiple myeloma. Clinical activity of bortezomib in combination with standard chemotherapy has been documented in several clinical trials of ALL patients, and a case of a single-agent activity against relapsed leukemia driven by MLL-AF4 translocation has been described. However, toxicities of bortezomib and carfilzomib may be unacceptable to pediatric patients. We found that the overwhelming majority of proteasomes in this subtype of ALL are lymphoid tissue specific immunoproteasomes. Cells with MLL-AF4 translocations were sensitive to pharmacologically relevant concentrations of specific immunoproteasome inhibitor ONX-0914. Furthermore, ONX-0914 dramatically delayed growth of orthotopic xenograft tumors in mice. Thus, immunoproteasomes are therapeutic targets in ALL; replacing bortezomib and carfilzomib with immunoproteasome inhibitors in ALL should reduce toxicities associated with inhibition of the proteasomes in non-lymphoid tissues. Citation Format: Tyler W. Jenkins, Sondra Downey-Kopyscinski, William C. Colley, Jennifer L. Fields, Steven N. Fiering, Alexei F. Kisselev. Immunoproteasome inhibitors for the treatment of ALL [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1936.
Abstract 1908: Kinome rewiring upon acquisition of resistance to PI3K inhibitors in ER+ breast cancer
Authors: Jacqueline Reedy Griffin, Nicole Traphagen, Arminja Kettenbach, Todd Miller
Journal: Cancer Research (2020)

Abstract Hyperactivation of the phosphatidylinositol-3 kinase (PI3K) pathway is a critical step in oncogenesis and plays a role in the development of treatment resistance in estrogen receptor-positive (ER+) breast cancer. Targeted inhibition of PI3K (PI3Ki) was recently approved in combination with endocrine therapy for advanced ER+ breast cancer. As most tumor-targeted therapies are encumbered by the development of secondary resistance, there remains a need to identify novel therapeutic strategies to prevent and overcome PI3Ki resistance. We treated mice bearing anti-estrogen-resistant ER+ breast cancer xenografts with the anti-estrogen fulvestrant +/- the pan-PI3Ki GDC-0941. The drug combination induced partial regression of tumors, followed by regrowth despite continued drug treatment. We harvested tumors before, during, and after acquisition of resistance to the drug combination and performed quantitative phosphoproteomic profiling. Using LC-MS/MS, we identified 203 phosphopeptides and 227 unique phosphorylation sites in the drug-resistant tumors, with clusters of 87 upregulated and 116 downregulated phosphopeptides. The NetPhorest analysis platform predicted hyperactivation of 6 kinases and hypoactivation of 16 kinases in drug-resistant tumors. Notably, two hyperactive kinases, MAPK1 and HIPK2, were predicted to target substrates MARKS (at Ser27 in the calcium binding domain) and NS1BP (at Ser322 in the homeodomain kelch repeat). MARCKS is a filamentous actin cross-linking protein, while the kelch repeats of NS1BP are known to associate with F-actin to stabilize actin filaments. In addition, the most significant predicted kinase among the cluster of 116 downregulated phosphopetides in the drug-resistant tumors was “PKCiota”, predicted to target PARD3 at Ser852. Previous work showed that PARD3 is central for the formation of tight junctions. These data collectively suggest a dynamic role of kinase-substrate interactions involved in resistance to combined anti-estrogen/PI3Ki treatment, including filamentation actin formation and stabilization, as well as the deregulation of tight junction formation. Citation Format: Jacqueline Reedy Griffin, Nicole Traphagen, Arminja Kettenbach, Todd Miller. Kinome rewiring upon acquisition of resistance to PI3K inhibitors in ER+ breast cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1908.
Abstract 3828: Tumor promoting effects of sulforaphane on diethylnitrosamine-induced murine hepatocarcinogenesis
Authors: Jie Zheng, Do-Hee Kim, Xi Zhu Fang, Seong Hoon Kim, Soma Saeidi, Su-Jung Kim, Young-Joon Surh
Journal: Cancer Research (2020)

Abstract Nuclear factor erythroid 2-related factor 2 (NRF2) is a key transcription factor involved in protection against initiation of carcinogenesis in normal cells. Notably, recent studies have demonstrated that mutation of the gene encoding this transcription factor causes its overactivation in various types of human malignancies. The aberrant activation of NRF2 is considered to accelerate the proliferation and progression of cancer cells. However, the exact function of NRF2 in the stage of pre-malignancy remains still largely unresolved. The differential effects of NRF2 on multi-stage carcinogenesis have raised a concern about the validity of NRF2 activators for chemoprevention. In the present study, a well-known NRF2 activating chemopreventive phytochemical, sulforaphane (SFN), was daily injected intraperitonally (25 mg/kg) for 3 months to male C57BL/6 mice at 6 months after single intraperitoneal administration of a hepatocarcinogen, diethylnitrosamine (DEN). The relative fold changes of liver weight, tumor growth, and the number and the size of hepatomas measured at 9 months after DEN administration were significantly higher in SFN-treated mice than that in vehicle-treated mice. Moreover, the expression of NRF2, its target protein NAD(P)H:quinone oxidoreductase 1 (NQO1), and the cell proliferation marker proliferating cell nuclear antigen (PCNA) and the DNA damage marker gamma-histone 2A family member X (γH2AX) was markedly elevated in SFN-treated mice compared with that in vehicle-treated mice as assessed by the Western blot assay. Immunohistochemistry and Immunofluorescence staining data further verified higher expression of NRF2 and PCNA in SFN-treated mice. These results suggest that once HCC is initiated, SFN stimulates the progression of DEN-induced HCC via activation of NRF2, rather than exerting a cancer chemopreventive effect. RNA sequencing analysis with liver tumors from DEN-treated mice revealed the B-raf V637E mutation (4/7). We speculate that mutation of B-raf proto-oncogene may contribute, at least in part, to activation of oncogenic NRF2 in DEN-induced murine carcinogenesis. The effects of SFN on DEN-induced mutation spectrum is under investigation. This study was supported by the Global Core Research Center (GCRC) Grant (No. 2011-003-0001) from the National Research Foundation (NRF) of Republic of Korea. Citation Format: Jie Zheng, Do-Hee Kim, Xi Zhu Fang, Seong Hoon Kim, Soma Saeidi, Su-Jung Kim, Young-Joon Surh. Tumor promoting effects of sulforaphane on diethylnitrosamine-induced murine hepatocarcinogenesis [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3828.
Abstract 1719: Drug-loaded porphyrin nanoparticles as a platform for targeted and photodynamic combination therapy
Authors: Justin M. Cheung, Hanan Baker, Daniel Li, Daniel Stor, Daniel A. Heller
Journal: Cancer Research (2020)

Abstract Many traditional nanoparticle delivery mechanisms require the use of an inert vehicle to deliver single therapeutic payloads. Here, we describe a novel, dual-therapeutic, self-assembled nanoparticle class wherein both the payload and encapsulating vehicle may potentiate anti-neoplastic effects. The nanoparticles consist of photoactive porphyrin dyes encapsulating small molecule drugs. We screened 9 porphyrins with 27 small molecules for the formation of porphyrin-drug nanoparticles; a total of 243 nanoparticle candidates, of which 25 formed nanoparticles as dictated by pre-determined cutoffs for size, polydispersity, and porphyrin/drug concentrations. Logistic regression based on formation data and molecular descriptors suggested that the presence of electronegative groups positively influenced nanoparticle formation. Chemical inhibition of various uptake pathways in endothelial cells indicated that the uptake of these porphyrin-drug nanoparticles is largely mediated by clathrin and macropinocytosis. Stability testing demonstrated that porphyrin-drug nanoparticles remained stable at 37°C for at least 6 hrs. This work outlines the synthesis and characterization of a new class of porphyrin nanoparticles with the capacity to deliver targeted therapy. Furthermore, the simplicity of the self-assembly process highlights the potential for this novel nanoparticle paradigm to be easily tested in disease models. Citation Format: Justin M. Cheung, Hanan Baker, Daniel Li, Daniel Stor, Daniel A. Heller. Drug-loaded porphyrin nanoparticles as a platform for targeted and photodynamic combination therapy [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1719.
Abstract 3859: CXCL17 modulates macrophage polarization and immune cell infiltrate in cutaneous squamous cell carcinoma
Authors: Alok R. Khandelwal, Ameesha A. Paralikar, Rafay Q. Soleja, Zachary B. Temple, Madison M. Robert, Maksudul Alam, Cherie-Ann O. Nathan
Journal: Cancer Research (2020)

Abstract Cutaneous squamous cell carcinoma (cSCC), a keratinocyte-derived invasive and metastatic tumor of the skin, is the second most common form of skin cancer. Exposure to UltraViolet B (UVB) radiation represent a unique risk factors for cSCC development, and the immune system plays a key role in modulating the response. Immunosuppressed patients are at a considerably increased risk for cSCC-induced morbidity and mortality due to its enhanced recurrence and metastatic potential. Novel mechanism-based therapeutics are needed to prevent UVB-induced cSCC. Chemokines are a group of small chemotactic cytokines that can exert extensive and complex effects on cancer via interaction with their receptors. Chemokine (C-X-C motif) ligand 17 (CXCL17) is the latest member of the chemokine family, and recent studies have identified both a causative and suppressive role of CXCL17 and its cognate receptor GPR35 in tumorigenesis. The purpose of the study was to investigate the role of CXCL17 in modulating tumor immune cell infiltrate with primary focus on macrophages. Further, the effect of CXCL17 on macrophage polarization and function was also assessed. Treatment of RAW 264.7 and bone marrow-derived macrophages (BDMC) with CXCL17 increased chemotaxis and polarized the cells towards an M2 phenotype with significant increase in transcriptional levels of Arginase, Fizz and Ym2. Interestingly, CXCL17 also increased transcript level of TNF-alpha in both RAW and BDMC's suggesting a “mixed” M1/M2 phenotype population that may potentially maintain a certain degree of flexibility and adaptability in facilitating tumor survival and resistance to biologic therapies. This “mixed” phenotype is also expected to promote a variety of pro-tumor functions. To further translate our in vitro studies in an in vivo mouse syngeneic cSCC model, SCCB cells were deleted for CXCL17 and injected into the flank of FVB mice. Tumors were collected and subjected to flow cytometry analysis for tumor cell infiltrate. Deletion of CXCL17 significantly decreased macrophage infiltration at the tumor site. Further, decrease in CXCL17 was associated with a reduction in immunosuppressive cells such as Tregs and MDSC suggesting a role for CXCL17 in tumor immune evasion. Our studies underscore the importance of CXCL17 signaling in cSCC and provide a novel target for the treatment of non-melanoma skin cancer. Citation Format: Alok R. Khandelwal, Ameesha A. Paralikar, Rafay Q. Soleja, Zachary B. Temple, Madison M. Robert, Maksudul Alam, Cherie-Ann O. Nathan. CXCL17 modulates macrophage polarization and immune cell infiltrate in cutaneous squamous cell carcinoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3859.