bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B022: The adaptor protein FRS2beta fashions a cytokine-rich inflammatory microenvironment that is associated with DCIS and promotes breast cancer carcinogenesis
Authors: Gotoh Noriko 
Published: December 2022

Abstract
Although it is commonly held that pro-inflammatory changes precede the onset of breast cancer, the underlying mechanisms remain obscure. Here, we report that FRS2beta, an adaptor protein with a highly restricted epithelial expression pattern, mediates the pro-inflammatory changes that alter the stroma in premalignant mammary tissues. We posit that these changes, which include lesions of ductal carcinoma in situ (DCIS), precede disease onset. In the MMTV-ErbB2 mouse model of mammary carcinoma, FRS2beta-deficiency markedly attenuated tumorigenesis. Importantly, tumor cells derived from MMTV-ErbB2 mice failed to generate tumors when grafted in the FRS2beta-deficient premalignant tissues. We found that the co-localization of FRS2beta and the NEMO subunit of the IkappaB kinase (IKK) complex in early endosomes activated nuclear factor-kappaB (NFkappaB), a master regulator of inflammation. Moreover, the inhibition of NFkappaB-induced cytokines CXC chemokine ligand (CXCL)12 and insulin-like growth factor (IGF1) abrogated tumorigenesis. In line with this, human breast cancer tissues that express higher levels of FRS2beta contain more stroma. The elucidation of the FRS2beta-NFkappaB axis uncovers a hitherto unknown molecular link between the pro-inflammatory changes in the DCIS and the disease onset.
Citation Format: Noriko Gotoh. The adaptor protein FRS2beta fashions a cytokine-rich inflammatory microenvironment that is associated with DCIS and promotes breast cancer carcinogenesis [abstract]. In: Proceedings of the AACR Special Conference on Rethinking DCIS: An Opportunity for Prevention?; 2022 Sep 8-11; Philadelphia, PA. Philadelphia (PA): AACR; Can Prev Res 2022;15(12 Suppl_1): Abstract nr B022.
Abstract IA011: Patient-derived organoids as models for breast cancer prevention and interception
Authors: Rosenbluth Jennifer M. 
Published: December 2022

Abstract
Organoid culture technology can be an efficient means for propagating breast tissues from patients, and we have previously generated organoid biobanks derived from normal and malignant human breast samples. Non-cancerous organoids, which are grown in a hydrogel that mimics the basement membrane and are bathed in a cocktail of growth factors, vitamins, and substances that substitute for stroma, grow in a polarized fashion to re-form acinar- and duct-like structures, and differentiate into the major mammary epithelial lineages, and we have found that all the major mammary epithelial lineages can be propagated in vitro. We have utilized mass cytometry and single-cell RNA sequencing to identify specific cell subtypes that are associated with breast cancer risk factors in organoids. In parallel, in malignant organoid cultures we have utilized RNA sequencing and compound screening approaches to identify potential strategies to overcome therapeutic resistance. We now present our initial efforts to establish a DCIS organoid biobank. Similar to the normal breast, organoids can be propagated from DCIS cases that are resistant to endocrine therapy with the goal of identifying strategies to overcome the resistant state.
Citation Format: Jennifer M. Rosenbluth. Patient-derived organoids as models for breast cancer prevention and interception [abstract]. In: Proceedings of the AACR Special Conference on Rethinking DCIS: An Opportunity for Prevention?; 2022 Sep 8-11; Philadelphia, PA. Philadelphia (PA): AACR; Can Prev Res 2022;15(12 Suppl_1): Abstract nr IA011.
Abstract IA013: A single-cell and spatial investigation of tumor and TME for DCIS
Authors: Wei Runmin , He Siyuan , Bai Shanshan , Sei Emi , Hu Min , Nagi Chandandeep , Menegaz Brian , Javaid Huma , Wesseling Jelle , Futreal Andrew , Thompson Alastair , Krishnamurthy Savitri , Navin Nicholas 
Published: December 2022

Abstract
Ductal carcinoma in situ (DCIS) is early-stage non-malignant breast cancer that tumor cells are confined to the lumens of ducts. Over 50,000 DCIS patients are diagnosed each year in the United States, however, less than half of DCIS will develop into invasive breast cancer (IBC), suggesting a risk of overtreatment for some DCIS patients. A comprehensive investigation of the molecular mechanisms of DCIS initiation and progression is urgently needed that can facilitate us stratifying the risk of DCIS invasion and design better intervention approaches. In this study, we conducted single-cell RNA-seq and spatial transcriptomics (ST) on DCIS and IBC samples (most estrogen receptor positive). We first inferred copy number aberrations (CNA) in these samples and found that DCIS and IBC shared the most copy number events while only marginal differences were identified. Tumor CNA subclones colocalized in different ductal regions from the ST data. Further, we applied a sample-wise non-negative matrix factorization (NMF) to identify robust gene expression metaprograms across tumor samples. On the ST data, we found these metaprograms also displayed distinct spatial patterns. For non-tumor cells in the TME, we sub-clustering them into cell states and identified that some cell states showed a gradual change along breast cancer initiation and progression. To recapitulate the tumor ecosystems, we also conducted an ecotype analysis in DCIS samples and identified that some ecotypes showed an increasing/decreasing trend in IBC patients. Further, tumor and TME ecotypes also showed spatially colocalizations based on our ST data. In summary, these results demonstrated that genomic signatures could hardly predict the DCIS progression while tumor metaprograms and TME ecotypes might serve as a potential risk stratification approach for DCIS patients.
Citation Format: Runmin Wei, Siyuan He, Shanshan Bai, Emi Sei, Min Hu, Chandandeep Nagi, Brian Menegaz, Huma Javaid, Jelle Wesseling, Andrew Futreal, Alastair Thompson, Savitri Krishnamurthy, Nicholas Navin. A single-cell and spatial investigation of tumor and TME for DCIS [abstract]. In: Proceedings of the AACR Special Conference on Rethinking DCIS: An Opportunity for Prevention?; 2022 Sep 8-11; Philadelphia, PA. Philadelphia (PA): AACR; Can Prev Res 2022;15(12 Suppl_1): Abstract nr IA013.
Abstract IA022: Imaging tools for DCIS: Past, present and future
Authors: Lehman Connie 
Published: December 2022

Abstract
In the past, mammography was considered the imaging test of choice to identify DCIS. More recent studies clarified breast MRI is more sensitive than mammography to identify DCIS overall and higher grade DCIS specifically. Techniques to support Fast or Abbreviated MRI were developed to try to support greater access, lower costs, increased patient acceptance of breast MRI in both the screening and the diagnostic setting. In the future, contrast enhanced mammography may provide greater access to more patients to the benefits of vascular imaging of DCIS, benefits previously limited to contrast enhanced breast MRI. Deep learning models in the domain of Artificial Intelligence may support more accurate triage of DCIS lesions more and less likely to progress, supporting more effective triage of low risk DCIS lesions to surveillance.
Citation Format: Connie Lehman. Imaging tools for DCIS: Past, present and future [abstract]. In: Proceedings of the AACR Special Conference on Rethinking DCIS: An Opportunity for Prevention?; 2022 Sep 8-11; Philadelphia, PA. Philadelphia (PA): AACR; Can Prev Res 2022;15(12 Suppl_1): Abstract nr IA022.
Abstract IA030: Molecular subtypes and spatial heterogeneity in DCIS
Authors: Sørlie Therese 
Published: December 2022

Abstract
The large heterogeneity of DCIS complicates the identification of markers for risk of progression to invasive breast cancer. Molecular and cellular heterogeneity is observed across DCIS, between multiple foci of DCIS within a lesion and within mixed lesions of invasive tumors with DCIS foci. The intrinsic breast cancer subtypes represent fundamental biological properties of the disease and are also found at the DCIS stage. However, their frequency and relevance as prognostic markers in pre-invasive stage is still not clear. Novel technologies for spatial characterization of tumors allow detailed mapping of DCIS and the microenvironment and may give us clues to which DCIS have the propensity to invade surrounding stroma. In the presentation, we will discuss results from our ongoing genomic characterization of DCIS and invasive breast carcinomas that illustrate the need for stratification when searching for prognostic markers. We have found disproportionate distribution and characteristics of the intrinsic subtypes in DCIS compared with invasive breast cancer and the dominance of Luminal A and HER2 subtypes. Bona-fide basal-like tumors may rarely be found at the DCIS stage and HER2-enriched DCIS are associated with specific immune cell profiles.
Citation Format: Therese Sørlie. Molecular subtypes and spatial heterogeneity in DCIS [abstract]. In: Proceedings of the AACR Special Conference on Rethinking DCIS: An Opportunity for Prevention?; 2022 Sep 8-11; Philadelphia, PA. Philadelphia (PA): AACR; Can Prev Res 2022;15(12 Suppl_1): Abstract nr IA030.
Abstract PR001: Spatial proximity between CD8+ T cells and tumor cells correlates with invasive recurrence in DCIS
Authors: Campbell Michael J. , Schindler Nicole , Glencer Alexa , Bolen Jennifer , Mori Hidetoshi , Loveday Tristan , Rothschild Harriet , Hirst Gillian , Vandenberg Scott , Borowsky Alexander , Esserman Laura 
Published: December 2022

Abstract
Purpose: The immune microenvironment in ductal carcinoma in situ (DCIS) and its significance are not well established. In this study, we characterized the immune microenvironment of DCIS to determine if immune cell densities, or their spatial relationships with tumor cells, are predictive of recurrence with invasive breast cancer. Methods: One hundred thirty-two cases of DCIS were included in this study. Seventy (53%) cases were high grade, 72 (54%) were HER2+, and 91 (69%) were HR+. Twenty cases recurred with invasive breast cancer. Immune infiltrates were characterized by multiplex immunofluorescence staining of FFPE sections using two 6-plex panels. Panel IP1.2 included markers for CD3, CD20, Foxp3, pan-cytokeratins, Ki67, and HLADR. Panel IP2.2 included markers for CD3, CD8, CD68, pan-cytokeratins, PD-1, and PD-L1. Staining was performed on a Leica Bond autostainer and images were acquired on a Vectra Polaris imaging system. Image analysis was performed utilizing inForm and QuPath software packages, as well as R scripts. Counts for each cell population were determined and spatial point pattern analyses were performed to quantitate the spatial relationships between tumor cells and various immune cell types. Results: High infiltrates of T cells, CD8+ T cells (Tc), Foxp3+ T cells, and B cells were associated with high grade, hormone receptor (HR) negativity, HER2 positivity, and the presence of comedonecrosis. PD-1+ T cells and PD-1+ Tc were associated with high grade, HR negativity, and HER2 positivity. PD-L1+ immune cells, but not PD-L1+ tumor cells, were also associated with high grade, HR negativity, and HER2 positivity. None of the cell populations were associated with invasive recurrence. However, the spatial proximity of tumor cells with T cells, in particular Tc, was significantly associated with a subsequent invasive event. Patients whose DCIS had a high tumor-to-Tc proximity score (indicating close proximity of tumor and Tc) were less likely to have an invasive recurrence. Conclusion: These findings suggest that the tumor immune microenvironment is an important factor in identifying DCIS cases at risk for invasive recurrence and that manipulating the immune microenvironment may be an efficacious strategy to alter or prevent disease progression.
Citation Format: Michael J. Campbell, Nicole Schindler, Alexa Glencer, Jennifer Bolen, Hidetoshi Mori, Tristan Loveday, Harriet Rothschild, Gillian Hirst, Scott Vandenberg, Alexander Borowsky, Laura Esserman. Spatial proximity between CD8+ T cells and tumor cells correlates with invasive recurrence in DCIS [abstract]. In: Proceedings of the AACR Special Conference on Rethinking DCIS: An Opportunity for Prevention?; 2022 Sep 8-11; Philadelphia, PA. Philadelphia (PA): AACR; Can Prev Res 2022;15(12 Suppl_1): Abstract nr PR001.
Abstract A005: Identification of lipid pharmacodynamic biomarkers in FAP model
Authors: Beach Ryan , Mohammed Altaf , Rosenberg Daniel W. 
Published: December 2022

Abstract
Familial Adenomatous Polyposis (FAP) is a genetic disorder characterized by the development of numerous polyps in the colon, that unless removed by colectomy, inevitably progress to colorectal cancer (CRC). Although there is currently no FDA-approved treatment to delay colectomy, a common target for chemoprevention is cyclooxygenase-2 (COX-2). Non-steroidal anti-inflammatory drugs (NSAIDs) and omega-3 fatty acids are known to alter COX metabolism and affect downstream eicosanoids involved in CRC progression. In this study, we examined the chemopreventive efficacy of the NSAID naproxen alone, or in combination with TP-252, a novel, chemically-stable analogue of the omega-3 fatty acid, eicosapentaenoic acid (EPA), in the intestinal tumorigenesis Apcam1137 PIRC rat model. Over the course of this 20-week study, rats were fed a modified AIN-93G diet supplemented with 200 ppm naproxen, alone or in combination with TP-252 (1.5%, or 3% by weight). Rats treated with 200 ppm naproxen had 66% (p &lt; 0.0001) fewer colon tumors than controls (AIN-93G) and an 81% (p &lt; 0.0001) reduction in tumor size. However, when Naproxen was combined with high-dose TP-252 (3%), tumor number and size were reduced by 95% (p &lt; 0.0001) and 98% (p &lt; 0.0001) respectively, when compared to controls. Since the primary mechanisms of action for naproxen and EPA target COX metabolic activity, we performed a comprehensive lipidomic analysis on colon tissue and plasma to determine lipidomic changes associated with drug treatment. Increased formation of several EPA-derived eicosanoids, including 9-HEPE, 12-HEPE, 18-HEPE, and resolvin E2, whose mucosal levels correlated with both reduced tumor number and volume, were observed.
These metabolites were also concomitantly elevated in the plasma of treated animals, representing potential pharmacodynamic (PD) biomarkers of CRC prevention. Future studies will decipher potential mechanisms that underlie these EPA-derived PD biomarkers and their role in tumor suppression. (Supported by the NCI Prevent Program 75N91019D00019, Task Order 75N91019F00132).
Citation Format: Ryan Beach, Altaf Mohammed, Daniel W. Rosenberg. Identification of lipid pharmacodynamic biomarkers in FAP model [abstract]. In: Proceedings of the Second Biennial NCI Meeting: Translational Advances in Cancer Prevention Agent Development (TACPAD); 2022 Sep 7-9. Philadelphia (PA): AACR; Can Prev Res 2022;15(12 Suppl_2): Abstract nr A005.
Abstract A006: Shared gene expression and immune pathway changes associated with progression from nevi to melanoma
Authors: Borden Elizabeth S. , Adams Anngela C. , Buetow Kenneth H. , Wilson Melissa A. , Bauman Julie E. , Curiel-Lewandrowski Clara , Chow H.-H. Sherry , LaFleur Bonnie J. , Hastings Karen Taraszka 
Published: December 2022

Abstract
There is a need to identify biomarkers of melanoma progression to assist the development of chemoprevention strategies to lower melanoma incidence. In this study, we assessed the feasibility of creating a molecular signature for melanomagenesis using three publicly available RNA sequencing and microarray expression datasets. We performed differential expression and regularized regression analyses across nevi and melanoma samples to identify consistent genes associated with melanomagenesis. The regularized regression models demonstrated that a small number of genes could successfully distinguish between nevi and melanoma, providing evidence for the feasibility of creating a molecular signature. Differential expression analysis identified consistent upregulation of C1QB, CXCL9, CXCL10, DFNA5 (GSDME), FCGR1B, and PRAME in melanoma and consistent downregulation of SCGB1D2 in melanoma compared to nevi. Additionally, each of these genes demonstrated a linear association with the progression from benign nevi to dysplastic nevi, to radial growth phase melanoma to vertical growth phase melanoma, providing additional evidence for their role in melanomagenesis. Subsequent pathway analysis demonstrated significant enrichment of immune-related pathways among the differentially expressed genes. Overall, this study 1) demonstrates the feasibility of creating a gene signature for melanomagenesis and 2) highlights genes and pathways of interest for melanoma progression. We are in the process of generating a new dataset with benign nevi, dysplastic nevi, and melanoma with which to build and validate a molecular signature of melanoma.
Citation Format: Elizabeth S. Borden, Anngela C. Adams, Kenneth H. Buetow, Melissa A. Wilson, Julie E. Bauman, Clara Curiel-Lewandrowski, H.-H. Sherry Chow, Bonnie J. LaFleur, Karen Taraszka Hastings. Shared gene expression and immune pathway changes associated with progression from nevi to melanoma [abstract]. In: Proceedings of the Second Biennial NCI Meeting: Translational Advances in Cancer Prevention Agent Development (TACPAD); 2022 Sep 7-9. Philadelphia (PA): AACR; Can Prev Res 2022;15(12 Suppl_2): Abstract nr A006.
Abstract A009: Effects of commonly prescribed β-blockers on tobacco carcinogen induced reactive oxygen species in human non-tumorigenic lung epithelial cells
Authors: Lee Jenny , Shahid Ayaz , Huang Ying 
Published: December 2022

Abstract
Lung cancer is a detrimental disease to humans and tobacco smoking causes more than 80% of lung cancer deaths. Chemoprevention is currently the major strategy to prevent smoking related lung cancer deaths. Key components that contribute to tobacco carcinogenicity are benzo(a)pyrene [B(a)P] and its diol epoxide metabolite BPDE. The goal of this study is to evaluate the level of reactive oxygen species (ROS), a mediator for cellular DNA damage leading to cancer, when pre-treated with the β-blockers carvedilol and nebivolol, and the antioxidant resveratrol.
B(a)P and BPDE were used to induce ROS in human lung epithelial cells (BEAS-2B). The non- fluorescent and non-polar 2’,7- dichlorofluorescein diacetate (DCFH-DA) probe was added to the cells. DCFH-DA was converted to DCFH in the cells by hydrolyzation of DCFH. ROS then induced the conversation of DCFH into 2,7-dichlorofluorescein (DCF). Florescence of DCF was measured by flow cytometry to detect ROS level.
B(a)P at concentrations 10 and 100 μM failed to induce ROS while BPDE successfully induced ROS dose-dependently during our pilot study. As a result, different concentrations of BPDE(2 μM and 4 μM) were used to induce ROS. When BEAS-2B was pre-treated with resveratrol (50 μM), ROS was reduced by 42% compared to the cells treated with 2 μM BPDE alone. Additionally, there was a decrease in ROS when pre-treated with nebivolol and carvedilol (5 μM). Nebivolol reduced 52% and 64% of the ROS induced by BPDE 2 μM and 4 μM, respectively. Carvedilol reduced 31% and 10% of the ROS induced by BPDE 2 μM and 4 μM, respectively.
These results suggest that some commonly used anti-hypertensive agents, such as the β-blockers , may block or reduce tobacco carcinogen induced ROS and thus can be used as chemopreventive agents for lung cancer.
Citation Format: Jenny Lee, Ayaz Shahid, Ying Huang. Effects of commonly prescribed β-blockers on tobacco carcinogen induced reactive oxygen species in human non-tumorigenic lung epithelial cells [abstract]. In: Proceedings of the Second Biennial NCI Meeting: Translational Advances in Cancer Prevention Agent Development (TACPAD); 2022 Sep 7-9. Philadelphia (PA): AACR; Can Prev Res 2022;15(12 Suppl_2): Abstract nr A009.
Abstract A010: Chemopreventive effects of carvedilol and nebivolol in benzo(a)pyrene-induced transformation of non-tumorous human bronchial epithelial cell
Authors: Lin Carol 
Published: December 2022

Abstract
Lung cancer is among the most common cancers worldwide. The primary risk factor for the development of lung cancer is cigarette smoking and there are a large amount of studies has confirmed the association between smoking and lung cancer. Chemopreventive drug would be beneficial among patients who are in high risk due to chronic exposure to carcinogens. In the previous study of chemopreventive activity of carvedilol, it significantly delayed and reduced skin squamous cell carcinoma development. The aim of the present study was to explore the role of carvedilol and nebivolol in benzo(a)pyrene induced transformation of the non-tumorous human bronchial epithelial cells. To evaluate the effects of carvedilol and nebivolol on chemopreventive activity against BPDE-induced lung carcinogenesis, anchorage-independent growth assay in soft agar was used to determine the degree of malignant transformation of BEAS-2b cells. Before the investigation of carvedilol and nebivolol, the appropriate drug concentration aiming minimum cytotoxicity on normal BEAS-2b cells were determined by MTT assay. The MTT assay was used to measure cellular metabolic activity as an indicator of cytotoxicity. Carvedilol at 10 μM or lower and Nebivolol at 1 μM or lower did not cause significant cytotoxicity. In non-tumorigenic human bronchial epithelial cell culture BEAS-2B vitro assays, carvedilol and nebivolol exert a protective effect against BPDE-indued transformation at non-toxic concentrations in a dose dependent manner. As shown in the figure below, Nebivolol (1 μM and 0.5 μM) and Carvedilol (1 μM and 0.5 μM) both significantly attenuated colony formation compared with BPDE control. However, the anti-transformation mechanism is unknown, further studies of carvedilol and nebivolol are needed to investigate their chemoprevention activity.
Citation Format: Carol Lin. Chemopreventive effects of carvedilol and nebivolol in benzo(a)pyrene-induced transformation of non-tumorous human bronchial epithelial cell [abstract]. In: Proceedings of the Second Biennial NCI Meeting: Translational Advances in Cancer Prevention Agent Development (TACPAD); 2022 Sep 7-9. Philadelphia (PA): AACR; Can Prev Res 2022;15(12 Suppl_2): Abstract nr A010.