bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract P6-10-18: Developing novel lysyl oxidase (LOX) inhibitors to overcome chemotherapy resistance in triple negative breast cancer
Authors: Cetin Metin , Saatci Ozge , Akbulut Ozge , Beneker Chad , Rezaeian Abdol-Hossein , Chernov Mikhail , McInnes Campbell , Sahin Ozgur 
Published: March 2023

Abstract
Triple negative breast cancer (TNBC) is the most aggressive breast cancer subtype. It accounts for ~15% of all breast cancer patients yet is responsible for 30% of breast cancer deaths. TNBC is treated primarily with conventional chemotherapy; however, resistance to therapy is common, leading to high mortality rates. Importantly, the benefit of current therapeutic strategies used in chemoresistant TNBC, i.e., immunotherapy and antibody-drug conjugates, is confined to only a fraction of patients, and survival benefit is limited. Therefore, there is an urgent need to identify novel and effective treatment strategies to overcome chemoresistance. Recently, we identified hypoxia-induced ECM re-modeler, lysyl oxidase (LOX), a member of LOX family, as a key mediator of chemoresistance in TNBC. However, currently available LOX inhibitors are either non-selective and/or show toxicity. Here, we performed a high-throughput cell-based LOX activity screen (HTS) with more than 5,000 molecules selected from a diversified compound library and identified the bi-thiazole derivatives as novel potent LOX inhibitors. Our structure activity relationship (SAR) analysis resulted in two lead compounds 6403, a relatively LOX-specific inhibitor, and 6415, a more LOX/LOXL2 inhibitor. Both compounds reduced collagen cross-linking (canonical function of LOX) and led to chemosensitization in TNBC cell lines and in chemoresistant TNBC PDX organoids. In addition, 6403 and 6415 reduced the TGF-beta induced fibrosis and inhibited migration capacity of the breast cancer cell lines. Importantly, 6403 showed excellent pharmacokinetic profile and did not lead to any observable toxicity in mice. Notably, 6403 overcame doxorubicin resistance in LOX-expressing 4T1 syngeneic model with no apparent toxicity. Furthermore, our novel LOX and LOX/LOXL2 dual inhibitors show superior inhibition of LOX activity compared to the recently developed and clinically tested LOX family or LOXL2/LOXL3 inhibitors. Overall, we identified novel potent LOX inhibitors with no observable toxicity for further preclinical development and future clinical testing to overcome chemoresistance in TNBC.
Citation Format: Metin Cetin, Ozge Saatci, Ozge Akbulut, Chad Beneker, Abdol-Hossein Rezaeian, Mikhail Chernov, Campbell McInnes, Ozgur Sahin. Developing novel lysyl oxidase (LOX) inhibitors to overcome chemotherapy resistance in triple negative breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-10-18.
Abstract P6-10-19: Screening of GPCR-targeting drugs for repositioning in breast cancer
Authors: Abdulkareem Noor , Bhat Raksha , Powell Reid , Chikermane Soumya , Yande Soham , Trinh Lisa , Abdelnasser Hala , Ruiz Alexis , Sobieski Mary , Nguyen Nghi , Johnson Camille , Johnson Michael , Stephan Clifford , Trivedi Meghana 
Published: March 2023

Abstract
Drug repositioning can overcome both substantial costs and the long process of new drug discovery and development in cancer treatment. Some FDA-approved drugs have been found to have the potential to be repositioned as anti-cancer drugs. However, the progress is slow due to only a handful of strategies employed to identify drugs with repositioning potential. In this study, we evaluated GPCR-targeting drugs by high throughput screening (HTS) for their repositioning potential in triple-negative breast cancer (TNBC) and drug-resistant human epidermal growth factor receptor-2-positive (HER2+) breast cancer (BC), due to the dire need to discover novel targets and drugs in these subtypes. We assessed the efficacy and potency of drugs/compounds targeting different GPCRs for the growth rate inhibition in the following models: two TNBC cell lines (MDA-MB-231 and MDA-MB-468) and two HER2+ BC cell lines (BT474 and SKBR3), sensitive or resistant to lapatinib + trastuzumab, an effective combination of anti-HER2 therapies. We identified 7 drugs/compounds as potential hits, out of which 4 were FDA-approved drugs. We focused on beta-adrenergic receptor-targeting nebivolol as a candidate, primarily because of the potential role of these receptors in BC and its excellent long-term safety profile. The effects of nebivolol were validated in an independent assay in all the cell line models. The effects of nebivolol were independent of its activation of β3 receptors and nitric oxide (NO) production. Nebivolol reduced invasion and migration potentials which may suggest its inhibitory role in metastasis. Analysis of the Surveillance, Epidemiology, and End Results (SEER)-Medicare dataset found a reduced but not statistically significant risk of all-cause mortality in the nebivolol group. In-depth future analyses including detailed in vivo studies and real-world data analysis with more patients are needed to investigate further the potential of nebivolol as a repositioned therapy for BC.
Citation Format: Noor Abdulkareem, Raksha Bhat, Reid Powell, Soumya Chikermane, Soham Yande, Lisa Trinh, Hala Abdelnasser, Alexis Ruiz, Mary Sobieski, Nghi Nguyen, Camille Johnson, Michael Johnson, Clifford Stephan, Meghana Trivedi. Screening of GPCR-targeting drugs for repositioning in breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-10-19.
Abstract P6-11-05: Carnitine palmitoyltransferase 1A (CPT1A) mediates therapeutic response to endocrine therapy in estrogen receptor positive breast cancer
Authors: Hussein Shaimaa , Gatza Michael L. , Ganesan Shridar 
Published: March 2023

Abstract
Breast cancer (BC) is the most commonly diagnosed cancer and second leading cause of cancer-related deaths in women in the United States, with more than 70% of the cases are hormone receptor positive (HR+) disease. Endocrine based therapies (ET) are successfully used, however, 30-50% will acquire ET resistance leading to tumor progression. Since the mechanism of acquired resistance remains unknown for ~60% of patients, identifying novel mechanisms of resistance is essential. We recently reported that carnitine palmitoyltransferase 1A (CPT1A), the rate limiting enzyme in fatty acid oxidation, is overexpressed in aggressive HR+ tumors, including ET resistant patients. We propose that CPT1A level and activity changes the tumor microenvironment to enhance tumorigenesis and contribute to ET resistance. To determine the mechanism by which CPT1A is promoting cell proliferation, tumor microenvironment, cellular signaling and ET resistance, we used a series of in vitro studies incorporating a panel of either endogenously or experimentally derived CPT1A-low and CPT1A-high controls, HR+ breast cancer cell lines as well as their ET resistant counterparts. We determined that CPT1A is upregulated in cell lines that acquire ET resistance. Our analyses demonstrated that levels of CPT1A can affect tumor formation ability in both CPT1A-high and adjacent CPT1A-low tumor cells with concurrent changes in both intra- and inter-cellular signaling which may be essential to promote tumor progression and mediate therapeutic response. This represents a promising step in understanding the mechanisms that promote tumorigenesis and ET resistance in HR+ breast cancer.
Citation Format: Shaimaa Hussein, Michael L. Gatza, Shridar Ganesan. Carnitine palmitoyltransferase 1A (CPT1A) mediates therapeutic response to endocrine therapy in estrogen receptor positive breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-11-05.
Abstract P6-11-11: Breast cancer stem cell marker, CD24 regulates metabolic reprogramming in triple negative breast cancer
Authors: Murthy Divya , Dutta Debasmita , Yang Sukjin , Park Junhyoung , Kaipparettu Benny 
Published: March 2023

Abstract
Breast cancer stem cell (BCSC) is a subset of cancer cells that can dictate the tumor initiation, metastatic progression, and therapeutic resistance in BC. The eradication of this unusual population is emerging as a new paradigm in cancer treatment. Molecularly, CD24 negativity in conjunction with high expression of CD44 is considered a hallmark for the BCSCs. While extensive studies have been performed to delineate the role of CD44 in BCSCs, the regulation of CD24 and its functional role have not been fully understood. In this study, we investigated the regulatory mechanisms responsible for low CD24 expression in BCSCs and their functional relevance in BCSCs. Analysis of DNA from tumor tissues and blood from BC patients as well as BCSCs sorted from BC cell lines suggest that CD24 is epigenetically regulated via DNMT-1/HDAC1-dependent increased methylation of CpG islands in the CD24 proximal promoter region. To understand the role of CD24 in triple-negative BC (TNBC), an aggressive subgroup of BC, we knocked down (CD24-KD) and overexpressed (CD24-OE) CD24 in metastatic TNBC cells. While CD24-KD resulted in increased proliferation and stemness, CD24-OE diminished the proliferative and stem-like potential. To further identify the signaling cascade underpinning these effects, we performed phospho-proteome analysis using Reverse Phase Protein Array (RPPA). Remarkably, we observed an enhanced activation of AMPK and NF-kB signaling cascades, and reduced PDGFRβ signaling upon depletion of CD24. As signaling cascades are intricately linked to cellular metabolism, we performed a metabolomic analysis of CD24-KD and CD24-OE cells. Our comprehensive analysis revealed heightened activation of mitochondrial fatty acid β-oxidation (FAO) in CD24-KD and increased glutamine metabolism in CD24-OE cells. In coherence with these findings, we observed significant regulation of genes related to fatty acid metabolism in the TNBC patient cohort expressing low levels of CD24. Consistently, the CD24-KD cells demonstrated increased sensitivity towards FAO inhibitors while CD24-OE cells were more sensitive to glutamine metabolism inhibitors. In vivo studies to further understand the translational significance of this metabolic axis is underway. Taken together, our study demonstrates, for the first time, that CD24 presents a novel metabolic vulnerability that can target BCSCs to gain a therapeutic advantage in the treatment of drug-resistant TNBC patients.
Citation Format: Divya Murthy, Debasmita Dutta, Sukjin Yang, Junhyoung Park, Benny Kaipparettu. Breast cancer stem cell marker, CD24 regulates metabolic reprogramming in triple negative breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-11-11.
Abstract P6-14-15: PD-L1 expression regulated by JAK/STAT signaling pathway contributes to cell migration and invasion in breast cancer
Authors: Chen Junqing 
Published: March 2023

Abstract
Background: Programmed death-ligand 1 (PD-L1) implicated in tumor immune evasion and predictive biomarker in immunotherapy is widely recognized, however, the role of PD-L1 in modulating tumor invasion remains largely unexplored. PD-L1 expression on tumor tissue is usually limited by the invasiveness, tumor heterogeneity as well as insufficient tumor tissue samples, while PD-L1 expression on circulating tumor cells (CTCs) might overcome the limitation. In the present study, we aimed to investigate the role and mechanism of PD-L1 in regulating the migration and invasion of breast cancer cells and to evaluate PD-L1 expression on CTCs in metastatic breast cancer patients. Methods: The expression level of PD-L1 in MCF-7 cells and MDA-MB-231 cells was assessed by quantitative real-time RT-PCR and Western Blot. Gain-of-function and loss-of-function study on cell migration and invasion abilities were carried out by overexpression of PD-L1 or silencing PD-L1. PD-L1 expression on CTCs in thirty-six metastatic breast cancer patients were detected. A novel staining procedure which included fluorescent glucose analog staining for CTC enumeration and immunostaining targeting CD45, vimentin and PD-L1 were analyzed. Survival curves were estimated by the Kaplan-Meier method and the log-rank test was used to compare between groups. All tests were two-sided, and p values were considered significant at the 0.05 level. Results: Compared with MCF-7 cells, PD-L1 mRNA and PD-L1 protein expression were significantly increased in MDA-MB-231 cells. Down-regulation of PD-L1 expression in MDA-MB-231 cells inhibited the migration and invasion of MDA-MB-231 cells, while overexpression of PD-L1 in MCF-7 cells increased the migration and invasion of MCF-7 cells. In addition, we found that PD-L1 expression was regulated by JAK/STAT signaling pathway. PD-L1 expression on CTCs in metastatic breast cancer patients was associated with triple negative breast cancers subtype (P=0.013). High expression of PD-L1 on CTCs in metastatic breast cancer patients was correlated to poor overall survival (HR=3.165, 95%CI: 1.121-8.938, P=0.029). Conclusion: Our results indicate that high expression of PD-L1 contributes to cell migration and invasion in breast cancer cell possibly partially through JAK/STAT signaling pathway. The PD-L1 expression on CTCs might serve as a promising non-invasive prognostic biomarker in patients with metastatic breast cancer.
Citation Format: Junqing Chen. PD-L1 expression regulated by JAK/STAT signaling pathway contributes to cell migration and invasion in breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-14-15.
Abstract PD1-08: PAM50 and 21-gene recurrence scores in younger and Black women with breast cancer
Authors: Vohra Sanah , Van Alsten Sarah , Ivory Joannie M. , Hamilton Alina , Gao Xiaohua , Kirk Erin , Nsonwu-Farley Joseph , Butler Ebonee , Taffe Brianna , Perou Charles M. , Carey Lisa , Troester Melissa 
Published: March 2023

Abstract
Background: Black and younger women have poorer breast cancer outcomes. Using a diverse population-based study, we examined the role of biology as measured by genomic assays in outcome disparity among clinically HR+/HER2- women. Methods: Data and biospecimens from the Carolina Breast Cancer Study (CBCS, including 2,103 non-metastatic, invasive breast cancers) were used to perform RNA-based classification according to molecular subtype and research versions of known prognostic assays, the 21-gene Recurrence Score (RS) and the PAM50-based Risk of Recurrence (ROR-PT) score. Prevalence odds ratios (PORs) and 95% confidence intervals (CIs) for subtype by race and age were estimated. Results: Black women had higher frequency of Luminal B [POR (95% CI): 2.08 (1.60, 2.71)], HER2-enriched [POR (95% CI): 2.01 (1.45, 2.79)], and Basal-like tumors [POR (95% CI): 3.51 (2.81, 4.40)] compared to non-Black women. Similarly, younger (&lt; 50 years) women had higher frequency of Luminal B [POR (95% CI): 1.57 (1.21, 2.04)], HER2-enriched [POR (95% CI): 2.03 (1.46, 2.82)], and Basal-like tumors [POR (95% CI): 2.40 (1.92, 3.01)]. Additionally, within clinically-defined HR+/HER2- tumors, Black women had higher frequency of high ROR-PT among younger women [POR (95% CI): 2.88 (1.19, 6.97)], but this association was attenuated among older women [POR (95% CI): 1.99 (0.84, 4.71)]. Race was not significantly associated with the 21-gene RS among younger or older women. Conclusion: While Black and younger women with clinically-defined HR+/HER2- often have higher burden of non-Luminal/high genomic risk tumors, PAM50 and 21-gene assays show different demographic patterns and heterogeneity within age- and race-defined groups, underscoring the value of genomic testing in understanding outcome disparities.
Citation Format: Sanah Vohra, Sarah Van Alsten, Joannie M. Ivory, Alina Hamilton, Xiaohua Gao, Erin Kirk, Joseph Nsonwu-Farley, Ebonee Butler, Brianna Taffe, Charles M. Perou, Lisa Carey, Melissa Troester. PAM50 and 21-gene recurrence scores in younger and Black women with breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD1-08.
Abstract PD12-07: PD12-07 The effect of BMI on the pathological response after neoadjuvant systemic therapy in breast cancer patients: a nationwide retrospective study
Authors: Jansen Britt , Gielen Anke , Agteroff Mariette , van Maaren Marissa , Beijer Sandra , Moossdorff Martine , Smidt Marjolein , Postma Emily 
Published: March 2023

Abstract
Background: Neoadjuvant systemic therapy is increasingly applied in breast cancer patients to improve surgical and oncological outcomes. There is only limited data from clinical practice on the relevance of body mass index (BMI) on the pathologic complete response (pCR) rate following neoadjuvant systemic treatment (NST). We aimed to retrospectively analyze the impact of BMI on pCR after NST for Dutch breast cancer patients.
Methods: Patients diagnosed with invasive breast cancer between 2019 and 2021 who were treated with NST followed by a surgical procedure, were selected from the Netherlands Cancer Registry (NCR). Patients were divided into three groups based on BMI: patients with underweight/normal weight (BMI&lt; 25 kg/m2), patients with overweight (BMI 25-29.9 kg/m2) and patients with obesity (BMI&gt;30 kg/m2). Patients with unknown BMI, ER/PR/HER2 or pCR status were excluded for analysis. The primary outcome was pCR after NST. The association between BMI and pCR was estimated using logistic regression models with the expression of odds ratios (ORs).
Results: After applying in- and exclusion criteria, 4430 patients were included for analysis, statified into four molecular breast cancer subtypes; HR+/HER2- (n=2256), HR+/HER2- (n=722), HR-/HER2+ (n=405) and HR-/HER2- (n=1047). The predictors age, differentiation grade, histological type, clinical tumor (cT) and nodal (cN) stage and molecular breast cancer subtype were found siginificant for achieving pCR after NST. Multivariabele regression analysis identified differentiation grade, cT and cN stage and molecular subtype as independent predictors for pCR after NST. There was no association between pCR and (continuous or categorical) BMI. Above mentioned analyses performed by stratification according to molecular breast cancer subtype, also showed no statistically meaningful association between BMI and pCR.
Conclusion: In this nationwide retrospective cohort study, evaluating 3340 patients with invasive breast cancer, we found no evidence of BMI being a predictive factor for achieving pCR following NST in neither the whole cohort, nor stratified according to molecular breast cancer subtype.
Table 1. Multivariable regression analysis of the total cohort
Citation Format: Britt Jansen, Anke Gielen, Mariette Agteroff, Marissa van Maaren, Sandra Beijer, Martine Moossdorff, Marjolein Smidt, Emily Postma. PD12-07 The effect of BMI on the pathological response after neoadjuvant systemic therapy in breast cancer patients: a nationwide retrospective study [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD12-07.
Abstract PD15-03: PD15-03 Incorporation of Repeated Core Needle Biopsy and Targeted Fine Needle Aspiration to Optimize Axillary Surgery After Neoadjuvant Chemotherapy in Node-positive Breast Cancer: A Prospective Feasibility Study
Authors: Wu Siyu , Li Jianwei , Zhang Ying , Hu Na , Liu Guangyu 
Published: March 2023

Abstract
Background: It is of substantial importance to tailor axillary surgery after neoadjuvant chemotherapy (NAC) based on tumor biology and response to treatment. This study aimed to determine the accuracy of repeated core needle biopsy (RCNB) in breast to predict nodal response after NAC.
Methods: Eligible patients with clip insertment into pathologically-proven positive node underwent RCNB during NAC. Targeted fine needle aspiration (TFNA) of clipped lymph node (CLN) was performed in a subset of patients after NAC. All patients ultimately underwent axillary surgery. RCNB and TFNA results were compared with surgical pathology.
Results: Data from 189 eligible patients were analyzed. The overall axillary pCR was 57.1%. The false-negative rate (FNR) of RCNB across the whole cohort was 12.1% (95% CI, 5.3%–18.9%), and exploratory subgroup analysis revealed an excellent ability to predict the presence of residual nodal disease in estrogen receptor-positive breast cancer with a low FNR of 1.6% (95% CI, 0.0%–4.9%) (Table 1). Adopting a strategy where only patients with negative RCNB undergo targeted axillary dissection (TAD) would potentially reduce the FNR of TAD from 9.3% to 2.3%. Furthermore, combination of RCNB and TFNA demonstrated a FNR of 2.2% (95% CI, 0.0%–6.6%), and negative predictive value of 94.1% (95% CI, 81.6%–100.0%) (N = 87) (Table 2). The proposed algorithm based on RCNB and TFNA is helpful in optimizing axillary surgery by avoiding 25 unnecessary attempts as well as 2 false-negative cases in TAD and conferring 10 patients omission of axillary surgery.
Conclusions: Combination of RCNB and TFNA allows for an accurate assessment of nodal response after NAC. These results may facilitate reliable identification of suitable candidates for de-escalation or elimination in axillary surgery.
Table 1: Overall Cohort Diagnostic Accuracy of Repeated Core Needle Biopsy to Predict Nodal Response (N = 189) Abbreviations: ER, estrogen receptor; HER2, human epidermal factor receptor 2; NPV, negative predictive value; PPV, positive predictive value.
Table 2. Diagnostic Accuracy of Repeated Core Needle Biopsy in Breast, Targeted Fine Needle Aspiration and the Combination in Cohort 2 (N = 87) Abbreviations: NPV, negative predictive value; PPV, positive predictive value; RCNB, repeated core needle biopsy; TFNA, targeted fine needle aspiration.
Citation Format: Siyu Wu, Jianwei Li, Ying Zhang, Na Hu, Guangyu Liu. PD15-03 Incorporation of Repeated Core Needle Biopsy and Targeted Fine Needle Aspiration to Optimize Axillary Surgery After Neoadjuvant Chemotherapy in Node-positive Breast Cancer: A Prospective Feasibility Study [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD15-03.