bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A019: IGF-1R protein pathway activation is associated with pathologic complete response to an anti-IGF-1R regimen (paclitaxel, ganitumab, and metformin) in the I-SPY2 neoadjuvant breast cancer trial
Authors: Petricoin Emanuel F. , Wolf Denise M. , Yau Christina , Wulfkuhle Julia , van ‘t Veer Laura , Gallagher Rosa I. , Hirst Gillian L. , Brown-Swigart Lamorna , Esserman Laura J. , Yee Douglas 
Published: February 2024

Abstract
BACKGROUND: The addition of PGM followed by doxorubicin/cyclophosphamide versus control was evaluated as neoadjuvant therapy. Here IGF-1R pathway based protein and phosphoprotein (p) biomarkers were examined for their predictive utility. METHODS: Reverse phase protein array evaluated 102 pretreatment PGM and 169 control HER2- specimens. 32 pre-specified biomarker candidates were examined. A logistic regression model adjusted for hormone receptor (HR) status. The Benjamini-Hochberg (BH) method adjusted for multiple hypothesis testing. ROC analysis identified dichotomizing thresholds for select biomarkers. RESULTS: In the entire PGM population in a model adjusting for HR status, higher levels of pIGF-1R (Y1135/Y1136)/IR (Y1150/Y1151) (OR=2.13 p&lt;0.002; BH p&lt;0.05) and lower levels of p27 T187 (OR= 0.41 p&lt;0.002; BH p&lt;0.05) were significantly associated with pCR. Downstream IGF-1R signaling proteins were nominally associated with pCR (IRS-1 S612, p90 RSK S380, FOXO1 T24/FOXO3a T32). In HR+ tumors (n=58), pIGF-1R retained its significant positive association with pCR (OR=4.08 P&lt;0.002; LR p&lt;0.05), with an AUC of 0.79 [95% CI: 0.56-1]. Using an optimal dichotomizing threshold, 16% (9/58) of HR+HER2- were classified pIGF-1R.IR-High; and 56% (5/9) of these patients achieved pCR vs. 6% (3/49) in the pIGF1R.IR-Low subset. In TN patients (n=44), pIGF-1R did not associate with response. However, lower pp27 remained nominally associated with higher pCR rates for PGM treatment (OR=0.42 p&lt;0.009; BH p&gt;0.05) with an AUC of 0.74 [95% CI: 0.58-0.89]; and when optimally dichotomized, 52% (13/25) of pp27 Low TN patients achieved pCR vs. 12% (2/17) in the pp27 High group. None of these PGM-response-predictive biomarkers associated with response in the control arm. Total receptor levels did not associate with response. CONCLUSION: We are the first to show that pre-treatment levels of IGF-1R protein pathway activation-based signaling phosphoproteins, including levels of pIGF-1R, the drug target for ganitumab, may be predictive biomarkers for drugs targeting this receptor especially in the HR+ subset.
Citation Format: Emanuel F. Petricoin, Denise M. Wolf, Christina Yau, Julia Wulfkuhle, Laura van ‘t Veer, Rosa I. Gallagher, Gillian L. Hirst, Lamorna Brown-Swigart, Laura J. Esserman, Douglas Yee. IGF-1R protein pathway activation is associated with pathologic complete response to an anti-IGF-1R regimen (paclitaxel, ganitumab, and metformin) in the I-SPY2 neoadjuvant breast cancer trial [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Breast Cancer Research; 2023 Oct 19-22; San Diego, California. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_1):Abstract nr A019.
Abstract A044: P2Y2 signaling disruption reduces ATP-dependent calcium elevation and actin localization to promote breast tumor cell dissemination
Authors: Mull Makenzy , Pratt Stephen , Thompson Keyata , Annis David , Ju Julia , Stemberger Megan , Boyman Liron , Vitolo Michele , Lederer W. Jonathan , Martin Stuart 
Published: February 2024

Abstract
The tumor microenvironment and wound healing after injury both contain extremely high concentrations of the extracellular signaling molecule, adenosine triphosphate (ATP) compared to normal tissue. P2Y2 receptor, an ATP-activated purinergic receptor, is typically associated with pulmonary, endothelial, and neural cell signaling. Here we report the importance of ATP-dependent P2Y2 signaling in breast epithelial cells and how it is altered in metastatic breast cancer. In response to ATP activation, P2Y2 receptor signaling causes an increase of intracellular calcium (Ca2+) in non-tumorigenic breast epithelial cells, while their tumorigenic and metastatic counterparts have significantly reduced Ca2+ responses. The non-tumorigenic cells respond to increased Ca2+ with actin polymerization and localization to cell edges, while the metastatic cells remained unaffected. The increase in intracellular Ca2+ after ATP stimulation was blunted using a P2Y2 antagonist, which also prevented actin mobilization and caused cell dissemination from spheroids in non-tumorigenic breast epithelial cells. Furthermore, the lack of Ca2+ concentration changes and actin mobilization in the metastatic breast cancer cells could be due to reduced P2Y2 expression, which correlates with poorer overall survival in breast cancer patients. This study elucidates rapid changes that occur after elevated intracellular Ca2+ in breast epithelial cells and how metastatic cancer cells have adapted to evade this cellular response.
Citation Format: Makenzy Mull, Stephen Pratt, Keyata Thompson, David Annis, Julia Ju, Megan Stemberger, Liron Boyman, Michele Vitolo, W. Jonathan Lederer, Stuart Martin. P2Y2 signaling disruption reduces ATP-dependent calcium elevation and actin localization to promote breast tumor cell dissemination [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Breast Cancer Research; 2023 Oct 19-22; San Diego, California. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_1):Abstract nr A044.
Abstract A079: Loss of BPTF restores estrogen-regulated programs and suppress metastatic development of mammary tumors
Authors: Chen Chen , Ciccone Michael F. , Trousdell Marygrace c. , Chatterjee Deeptiman , Zhao Yixin , Lewis Steven M. , Anandan Dhivya , Wilkinson John E. , Pomerantz William C. K. , Siepel Adam , dos Santos Camila O. 
Published: February 2024

Abstract
Chromatin remodeling controls transcriptional programs that drive mammary epithelial lineage commitment and cellular differentiation. This process is also important for the regulation of highly dynamic cellular states during mammary tumorigenesis, and perturbing the chromatin landscape of cancer cells can halt cellular and molecular mechanisms of mammary cancer development and progression. However, this paradigm assumes that all cancer cells that develop in the mammary tissue bear the same chromatin dependencies, and rely on similar programs throughout cancer progression. Here, we show that molecular dependencies regulated by the epigenetic factor BPTF control tumor development and progression across distinct mammary cancer cell states. With the utilization of classical models of mammary tumorigenesis, single cell transcriptional profiling, and organoid cultures, we demonstrate that BPTF loss results in the development of mammary tumors with a longer latency of ER•+ expression and tamoxifen sensitivity and the inhibition of lung metastasis development. While gain of ER• expression was associated with gain of luminal markers in Krt5+ BPTF KO mammary epithelial cells (MECs), metastasis-like signatures were significantly perturbed in cells with defined luminal fate. In addition, we detected a partial rescue of metastatic features via the activation of transcriptional programs controlled by TGF-•, thus indicating that BPTF sits atop a canonical metastatic pathway. Collectively, our studies illustrate how BPTF-specific chromatin remodeling inhibition induces phenotypes that differentially affect tumor development and progression, while allowing for the development of a murine model of ER•+ mammary tumorigenesis.
Citation Format: Chen Chen, Michael F. Ciccone, Marygrace c. Trousdell, Deeptiman Chatterjee, Yixin Zhao, Steven M. Lewis, Dhivya Anandan, John E. Wilkinson, William C. K. Pomerantz, Adam Siepel, Camila O. dos Santos. Loss of BPTF restores estrogen-regulated programs and suppress metastatic development of mammary tumors [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Breast Cancer Research; 2023 Oct 19-22; San Diego, California. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_1):Abstract nr A079.
Abstract B009: TWEAK/Fn14 signalling driven super-enhancer reprogramming promotes pro-metastatic metabolic rewiring in Triple-Negative Breast Cancer
Authors: Li Yinghui , Sim Nicholas , Carter Jean-Michel , Deka Kamalakshi , Tan Benita Kiat Tee , Sim Yirong , Tan Suet-Mien 
Published: February 2024

Abstract
Triple Negative Breast Cancer (TNBC) is the most aggressive breast cancer subtype suffering from a lack of targeted treatment options. There is a high priority to identify effective molecular markers or driver factors specific to TNBC patients for targeted therapies. The Tumour necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK)/Fibroblast growth factor-inducible 14 (Fn14) pathway is one such signalling cascade implicated in the pathogenesis of TNBC and other solid tumours. However, the clinical significance and biological roles of deregulated TWEAK/Fn14 signalling in regulating the epigenetic plasticity and transcriptome of TNBCs remain elusive. In this study, we performed integrative transcriptomic and epigenomic analyses of TNBC cell lines and patient samples to characterise the gene regulatory roles of TWEAK/Fn14 pathway in remodelling the super-enhancer (SE) landscape of TNBC tumours. Here, we show that Fn14 is specifically overexpressed in TNBC patients and associated with poor survival. We demonstrate that constitutive Fn14 signalling rewires the transcriptomic and epigenomic landscape of TNBC, leading to enhanced tumour growth and metastasis. We further illustrate that such mechanisms activate TNBC-specific super enhancers (SE) to drive the transcriptional activation of cancer dependency genes via chromatin looping. In particular, we uncover the SE-driven upregulation of NAMPT, which promotes NAD+ and ATP metabolic reprogramming critical for filopodia formation and metastasis. Collectively, our study details the complex mechanistic link between TWEAK/Fn14 signalling and TNBC metastasis, which reveals several vulnerabilities which could be pursued for the targeted treatment of TNBC patients.
Citation Format: Yinghui Li, Nicholas Sim, Jean-Michel Carter, Kamalakshi Deka, Benita Kiat Tee Tan, Yirong Sim, Suet-Mien Tan. TWEAK/Fn14 signalling driven super-enhancer reprogramming promotes pro-metastatic metabolic rewiring in Triple-Negative Breast Cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Breast Cancer Research; 2023 Oct 19-22; San Diego, California. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_1):Abstract nr B009.
Abstract B014: Bioinformatic and in-vitro analyses identify cAMP/PKA/CREB signaling as a major molecular alteration in invasive lobular breast cancer
Authors: Wedn Abdalla , Puthanmadhom-Narayanan Susrutha , Lee Adrian , Oesterreich Steffi 
Published: February 2024

Abstract
Invasive lobular cancer (ILC) is the second most common subtype of breast cancers after invasive carcinoma of no special type (NST) but associated with worse outcomes. Despite the known molecular differences between ILC and NST, ILC treatment is the same as stage matched NST making the development of ILC targeted therapies an urgent need. Therefore, this study was conducted to identify novel molecular alterations in ILC that could be exploited for therapeutic purposes. Differential gene expression and Geneset Enrichment and Variation analyses were performed on RNA-seq data from three large public breast cancer databases – the Sweden Cancerome Analysis Network-Breast (SCAN-B), The Cancer Genome Atlas (TCGA) and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC). Pathways enriched in overlapping differentially expressed genes from these datasets were clustered using Jaccard index to identify novel pathways related to ILC. The cAMP/PKA/CREB signaling was studied in ILC, ILC-like and NST cell lines and patient-derived organoids (POD) using Forskolin, an activator of the pathway. Clinicopathological features of patients with ILC and NST in SCAN-B were similar to prior population-based studies. There was a consistent pattern of up-regulation of cAMP/PKA/CREB related signaling in ILC compared to NST tumors in SCAN-B, TCGA and METABRIC. Treatment with forskolin resulted in a greater increase in phospho-CREB in ILC cell lines and organoids compared to NST. CRISPR deletion of CDH1 in NST cell lines did not alter response of cells to forskolin as measured by phospho-CREB. Co-immunofluorescence supported the enhanced nuclear localization and subsequent phosphorylation of CREB at Serine 133 in ILC cell lines. Forskolin treatment caused growth inhibition in ILC and NST cells, with ILC cell lines being more sensitive to forskolin-mediated growth inhibition. Collectively the data indicate that the cAMP/PKA/CREB signaling is higher in ILC than NST tumors. This was consistent across three separate cancer datasets and was validated in cell lines and organoids. Loss of CDH1 is not sufficient to mediate this phenotype in lobular tumors. Future studies should investigate the mechanisms for differential cAMP/PKA/CREB signaling in ILC and NST and investigate the potential for therapeutic targeting especially in patients with ILC.
Citation Format: Abdalla Wedn, Susrutha Puthanmadhom-Narayanan, Adrian Lee, Steffi Oesterreich. Bioinformatic and in-vitro analyses identify cAMP/PKA/CREB signaling as a major molecular alteration in invasive lobular breast cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Breast Cancer Research; 2023 Oct 19-22; San Diego, California. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_1):Abstract nr B014.
Abstract B028: Investigating immune activity caused by a novel anti-cancer cell penetrating peptide
Authors: Hecksel Ryan , Escoto Angelica , Schroeder Joyce 
Published: February 2024

Abstract
Activating the immune system against cancerous cells represents a promising therapy against multiple cancer types, particularly breast cancer. The epidermal growth factor receptor (EGFR) represents an emerging target in immunotherapy. A novel anti-cancer cell penetrating peptide was recently discovered to affect immune recruitment and potentially function in a murine model of breast cancer. This peptide, termed cSNX1.3, is a targeted therapy to block the nuclear localization of the epidermal growth factor receptor (EGFR), a phenomenon thought to occur primarily in cancerous cells. This suggests that nuclear localized EGFR may play a role in suppressing an anti-cancer immune response. To gain a better understanding of this in vivo data, we used in vitro immune cell co-culture techniques, migration assays, and other techniques to investigate immune recruitment and function after cancer cells are treated with this novel peptide therapy. In addition, we are investigating the mechanism of cSNX1.3 mediated cell death to determine if it can induce immunogenic cell death. To determine if nuclear EGFR plays a role in immune cell suppression, we are using a CRISPR/Cas9 strategy to mutate the nuclear localization sequence. This will provide a valuable tool to better understand the seemingly cancer-specific trafficking phenomenon. Together, this work will expand our understanding of therapy induced immune cell recruitment and trafficking.
Citation Format: Ryan Hecksel, Angelica Escoto, Joyce Schroeder. Investigating immune activity caused by a novel anti-cancer cell penetrating peptide [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Breast Cancer Research; 2023 Oct 19-22; San Diego, California. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_1):Abstract nr B028.
Abstract B045: Novel Small Molecule Inhibitors Targeting Proinflammatory Cytokines in Metastatic Breast Cancer
Authors: Wolf Cody L , Pruett Clyde , Lighter Darren , McGrath Cooper , Feci Andrea , Tuccinardi Joseph , Dinca Simion , Tawara Ken , King Matthew , Warner Lisa , Warner Don , Jorcyk Cheryl L. 
Published: February 2024

Abstract
Breast cancer is currently the most commonly diagnosed and second leading cause of cancer-related deaths among women in the Unites States. For the past several years, research has focused on the role of inflammatory cytokines such as interleukin-6 (IL-6) and their role in cancer. Increasing evidence suggests that breast cancer patients with high levels of proinflammatory modulators have an overall worse prognosis. Research performed by our lab and others has also shown that oncostatin M (OSM) promotes breast cancer progression and metastasis by inducing circulating tumor cell (CTC) numbers, and metastasis to distant sites in vivo. While efforts have been made to develop FDA approved therapeutics for OSM, previous studies have all utilized monoclonal antibodies and none have survived clinical trials. For the first time, our research group has developed a stepwise approach towards designing and testing novel small molecule inhibitors (SMIs) against OSM. To determine viable candidates, in silico computational screening of compound libraries towards OSM revealed top potential compounds that interact with the receptor binding region and inhibit biological function. These top candidate inhibitors were then analyzed for direct interaction with cytokines using fluorescent quenching and chemical shift perturbation NMR (CSP-NMR). In vitro efficacy of each SMI was then analyzed by measuring inhibition of all signaling cascades activated by OSM using enzyme-linked immunosorbent assays (ELISA) and immunoblot assays. From these in silico and in vitro methods, SMIs were then structurally modified with effective functional groups to increase efficacy of binding interaction and reduce toxicity for living systems. Finally, our most promising small molecule inhibitor that has been sufficiently tested for efficacy was examined in vivo utilizing a novel estrogen receptor-positive (ER+) mouse model of metastatic breast cancer, and treatment with our SMI proved to decrease tumor burden and metastasis, particularly to the lung when compared to vehicle control. In conclusion, our lab has generated the first ever SMI aimed to inhibit OSM-mediated cancer progression. Our continued efforts aim to develop a novel FDA approved therapeutic to improve outcomes for breast cancer patients.
Citation Format: Cody L Wolf, Clyde Pruett, Darren Lighter, Cooper McGrath, Andrea Feci, Joseph Tuccinardi, Simion Dinca, Ken Tawara, Matthew King, Lisa Warner, Don Warner, Cheryl L. Jorcyk. Novel Small Molecule Inhibitors Targeting Proinflammatory Cytokines in Metastatic Breast Cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Breast Cancer Research; 2023 Oct 19-22; San Diego, California. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_1):Abstract nr B045.
Abstract B053: The role of whole genome doubling in immune escape in TNBC
Authors: Foidart Pierre , Li Zheqi , Seehawer Marco , Nishida Jun , Rojas Ernesto , Bui Triet , Yan Pengze , Goyette Marie-Anne , Stevens Laura , Huang Xiao-Yun , Anand Jayati , Nanjangud Gouri , Xie Yingtian , Qiu Xintao , Cejas Paloma , Long Henry , Polyak Kornelia 
Published: February 2024

Abstract
Triple-negative breast cancers (TNBC) account for 10-15% of all breast cancers. The combination of chemotherapy and immune checkpoint inhibitor (ICI) therapy is now a standard in stage II-III TNBC while this regimen is used only in a subset of advanced TNBC tumors with high expression of PD-L1. Whole exome sequencing of solid tumors (other than breast cancer) in clinical trials investigating ICI determined that tumors which undergone a WGD (whole genome doubling) are more sensitive to immune checkpoints inhibitors, but the underlying mechanisms have not been defined. WGD occurs in 44% of breast cancers and it has been associated with advanced stage, poor survival, and higher risk of resistance to chemotherapies and targeted therapies. However, its role in response to ICI treatment in TNBC has not been investigated. To investigate the functional relevance of WGD in therapeutic responses in TNBC, we generated isogenic cell line pairs (3 murine and 1 human) that are diploid/euploid (WGD-) or tetraploid (WGD+) using somatic cell fusion. To explore the impact of WGD on tumor growth, we injected parental (WGD-) and fusion (WGD+) cells into mammary fat pads of syngeneic immunocompetent or immunocompromised (NSG) mice. We found that while there was no difference in growth between parental (WGD-) and fusion (WGD+) cells in immune deficient mice, in immunocompetent mice tumors derived from fusion (WGD+) cells grew significantly faster compared to parental (WGD-). We have been analyzing differences between parantel and fusion cell-derived tumos using FACS, immunofluorescence, and single cell RNA-seq (scRNA-seq) and found significant immune-related differences implying a more immune suppressive environment in fusion tumors. These data suggest that WGD in TNBC may be a predictor of response to ICI therapies.
Citation Format: Pierre Foidart, Zheqi Li, Marco Seehawer, Jun Nishida, Ernesto Rojas, Triet Bui, Pengze Yan, Marie-Anne Goyette, Laura Stevens, Xiao-Yun Huang, Jayati Anand, Gouri Nanjangud, Yingtian Xie, Xintao Qiu, Paloma Cejas, Henry Long, Kornelia Polyak. The role of whole genome doubling in immune escape in TNBC [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Breast Cancer Research; 2023 Oct 19-22; San Diego, California. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_1):Abstract nr B053.
Abstract B070: Myc synthetic lethality as a therapeutic strategy for resistance: Insights into the targetability of mitochondrial complex I in Myc-high TNBC
Authors: Hiltunen Antti O , Id Linda J , Klefström Juha 
Published: February 2024

Abstract
Patients with advanced triple-negative breast cancer (TNBC) frequently develop chemoresistance, emphasizing an urgent need for novel therapeutic strategies able to eradicate treatment resistant tumor cells. Recent studies have highlighted MYC as a common oncogenic alteration and a driver of stem-like TNBC phenotype, which commonly features high mitochondrial respiratory activity instated through OXPHOS system and chemoresistance. Interestingly, emerging evidence suggests that residual tumors from chemo treatment remain susceptible to OXPHOS inhibition through inhibition of respiratory complex I. Our previous studies have revealed a specific MYC-dependent and tumor suppressive synthetic lethal action for combination of metformin and BH3 mimetics in cells, ex vivo and in vivo models of aggressive breast cancer (PMID: 30728358). Metformin is a systemic and local metabolic modulator, which acts as a weak complex I inhibitor and promoter of AMPK activation. Here, we have explored the role of MYC in OXPHOS regulation, to address the question if metformin specifically and lethally targets MYC-modulated OXPHOS in MYC-high TNBC. We found that a selective c-MYC inhibitor (EN4) leads to a significant decrease in complex I activity despite only a modest drop in complex I mass in endogenously MYC-high TNBC cell lines. Conversely, engineered MYC overexpression in these cells upregulated complex I activity. Our current work explores transcriptomic, proteomic, and functional approaches to the mechanisms through which MYC regulates complex I activity, structure, and dynamics, ultimately hoping to define a biological rationale for therapeutic targeting of OXPHOS in Myc-high TNBC.
Citation Format: Antti O Hiltunen, Linda J Id, Juha Klefström. Myc synthetic lethality as a therapeutic strategy for resistance: Insights into the targetability of mitochondrial complex I in Myc-high TNBC [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Breast Cancer Research; 2023 Oct 19-22; San Diego, California. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_1):Abstract nr B070.