bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract P3-06-03: NR2F1 is a barrier to dissemination of early-evolved mammary cancer cells
Authors: Rodriguez-Tirado Carolina , Kale Nupura , Carlini Maria Jose , Shrivastava Nitisha , Rodrigues Alcina , Khalil Bassem , Bravo-Cordero Jose Javier , Alexander Melissa , Ji Jiayi , Sosa Maria Soledad 
Published: March 2022

Abstract
Pre-malignant cells disseminate during very early and sometimes asymptomatic stages of tumor progression. Once settled in permissive environments at secondary organs, they can act as a source for metastasis (e.g. in breast, pancreatic, colon, melanoma and lung carcinomas), thus emerging as important players in future prognosis. Granted that biological barriers to tumorigenesis exist, there must also be limiting steps to early dissemination in pre-malignant cells, all of which remain largely unknown. We report that the orphan nuclear receptor NR2F1/COUP-TF1, downstream of Her2 signaling via p38alpha serves as a barrier to early dissemination in pre-malignant breast cells. Our work shows that NR2F1 expression is positively regulated by p38α-MAPK pathway and inhibited by HER2 oncogenic signaling pathway. Furthermore, NR2F1 downregulation in human and murine pre-malignant cell lines led to a partial epithelial-to-mesenchymal transition characterized by decreased E-cadherin expression and β-catenin membrane localization, disorganized laminin 5 deposition, and increased expression of CK14, TWIST1, ZEB1 and PRRX1, thus explaining an increased motility and dissemination of early cells upon loss of NR2F1. Interestingly, NR2F1 lost also maintained epithelial markers (like CK18), suggesting an hybrid luminal-mesenchymal phenotype that could favor cellular plasticity to adapt to distant sites. We also showed that NR2F1 blocked b-catenin nuclear localization via a WNT-dependent pathway. Significantly, downregulation of NR2F1 increased the in vivo dissemination potential of pre-malignant cells to lungs in a HER2-dependent manner. Lastly, Nr2f1 expression was downregulated in non-invasive DCIS biopsies when compared to benign adjacent tissue, and its expression was inversely correlated to Prrx1 levels. The inverse correlation between Nr2f1 and Prrx1 levels was lost in genetically evolved primary tumors, which suggests that a unique inhibitory mechanism of dissemination dominates at early stages of tumor progression. Overall, our data suggest the existence of an inhibitory mechanism of dissemination regulated by NR2F1 downstream of HER2 signaling in premalignant breast cells and propose that therapeutic strategies that aim to maintain NR2F1 expression could reduce dissemination of premalignant cells and delay relapses.
Citation Format: Carolina Rodriguez-Tirado, Nupura Kale, Maria Jose Carlini, Nitisha Shrivastava, Alcina Rodrigues, Bassem Khalil, Jose Javier Bravo-Cordero, Melissa Alexander, Jiayi Ji, Maria Soledad Sosa. NR2F1 is a barrier to dissemination of early-evolved mammary cancer cells [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P3-06-03.
Abstract P3-10-02: Enhanced miR-579-3p by anti-estrogen treatment may affect capecitabine response in hormone receptor positive metastatic breast cancer
Authors: Lee Jieun , Joe Seung Yeon , Lee Ji-Sun , Kim Dong-Min , Lee Ahwon 
Published: March 2022

Abstract
Purpose Capecitabine is one of a treatment option in anthracycline and taxane pre-treated metastatic breast cancer (MBC) patients. We have performed miRNA microarray of durable and poor responders to capcitabine, and compared with cell line miRNA expression profile (MCF-7, tamoxifen-resistant MCF-7 [MCF-TAM] cell line treated with 5-FU. Methods Between Jan 2006 to Jan 2021, 66 patients treated with capecitabine after anthracycline and taxane failure were enrolled. Twenty-three archival tumor tissues (11 durables and 12 poor responders, each) were collected and went through nCounter miRNA expression assay. MCF-7, tamoxifen resistant MCF-7 (MCF-TAM) cell line was treated with tamoxifen or 5-FU for proliferation assay and also went through nCounter miRNA expression assay. Results HR positive patients who received anti-estrogen treatment before capecitabine showed longer PFS (median 7.7 vs. 4.03 months, P=0.006). MCF-7 treated with tamoxifen and 5-FU showed decreased proliferation compared to 5-FU treated MCF-7. There was significant difference of miR-579-3p expression between durable and poor responders (log2FC -3.02, P=0.004). Tamoxifen-treated MCF-7 cell line showed upregulation of miR-579-3p compared to MCF-7. Tamoxifen + 5-FU treated MCF-7 cell line showed decreased expression of miR-579-3p compared to 5-FU treated MCF-7 cell line. MCF-7 cell line was treated with 5-FU and miR-579-3p. Compared to 5-FU only treated cell line, 5-FU + miR-579-3p treated cell line showed trends for decreased cell proliferation, suggesting that miR-579-3p may have chemo-sensitizing role during systemic chemotherapy. Based on miRNA database, authors hypothesized that MDM2 may be target protein of miR-579-3p and planning to perform further analysis. Conclusions Anti-estrogen treatment before capecitabine administration was associated to better survival in HR positive MBC. Anti-estrogen potentiated the effect of 5-FU in MCF-7. MiR-579-3p was upregulated in durable responders and tamoxifen treated MCF-7 cell line. Further study is planned to analyze the role of miR-579-3p and its potential target, MDM2 in breast cancer.
Citation Format: Jieun Lee, Seung Yeon Joe, Ji-Sun Lee, Dong-Min Kim, Ahwon Lee. Enhanced miR-579-3p by anti-estrogen treatment may affect capecitabine response in hormone receptor positive metastatic breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P3-10-02.
Abstract P3-12-18: Mortality after late breast cancer recurrence in Denmark
Authors: Pedersen Rikke Noergaard , Mellemkjær Lene , Ejlertsen Bent , Nørgaard Mette , Cronin-Fenton Deirdre 
Published: March 2022

Abstract
Purpose: Late recurrence (i.e., ≥10 years after primary diagnosis) may have a more favorable prognosis than earlier recurrence. We investigated the risk of breast cancer (BC) death after late recurrence and identified prognostic factors. Furthermore, we compared survival between late and early recurrence. Methods: Using the Danish Breast Cancer Group and other nationwide databases, we identified women with early or late BC recurrence during 2004-2018, who were alive 6 months after recurrence. We followed them until BC death, death from other causes, emigration, ten years or 31/12/2018. We calculated mortality rates (MRs) per 1000 person-years (PY) and cumulative BC mortality, for early versus late recurrence and by characteristics of the primary tumor and of the late recurrence. Using Cox regression, we calculated adjusted hazard ratios (HRs) for BC death, accounting for death from other causes as competing risk. Results: Among 2,004 patients with late recurrence, 721 died of BC with a median survival time of 3 years (MR= 84.8 per 1000 PY; 10-year cumulative mortality=50%). Among 1,573 patients with early recurrence, 1,092 BC deaths occurred with a median survival time of 2.6 years (MR= 173.9 per 1000 PY; 10-year cumulative mortality=72%). Advanced stage at primary diagnosis, distant metastases, and adjuvant recurrence treatments were associated with increased mortality, while breast-conserving surgery at primary diagnosis, loco-regional recurrence, and recurrence surgery were associated with lower mortality. Conclusion: Patients with late recurrence had a more favorable prognosis than patients with early recurrence. The localization of recurrent disease was the main prognostic factor for BC death.
Citation Format: Rikke Noergaard Pedersen, Lene Mellemkjær, Bent Ejlertsen, Mette Nørgaard, Deirdre Cronin-Fenton. Mortality after late breast cancer recurrence in Denmark [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P3-12-18.
Abstract P3-13-07: A comprehensive germline genetic landscape in young Jewish & Arab women with breast cancer
Authors: Rennert Gad , Nehoray Bita , Lejbkowicz Flavio , Dishon Sara , Kalet Shiri , Herzog Joseph , Slavin Thomas , Castillo Danielle , Tsang Kevin , Sand Sharon , Rennert Hedy S , Weitzel Jeffrey 
Published: March 2022

Abstract
Background: After decades of research on Ashkenazi Jewish (AJ) founder mutations in BRCA1 and BRCA2 (BRCA), there is still little known about genetics in non-AJ and Arab breast cancer populations in Israel and non-BRCA pathogenic variants (PV) in the total population. We used multigene panel testing (MGPT) to characterize the spectrum and prevalence of PV in cancer susceptibility genes in various Jewish and Arab demographic subgroups. Methods: A population-based cohort of women diagnosed with breast cancer before the age of 46 in a defined geographical area in Northern Israel was recruited as part of the BCINIS study and underwent MGPT. Probability matrices of proportion of PV by gene, and by ethnic sub-group (AJs, Sephardi Jews of North African origin, Sephardi Jews of other Eastern origins, Arabs), age-sub-group (35 and under, 36-45) and first-degree family history of breast, ovary or pancreatic cancer were calculated. Results: Overall, 1650 women were tested, including 1012 Jewish, 530 Arab and 108 non-Jewish/non-Arab women. We detected 375 PV among 363 women (22.7%): 212 in AJ (33.4% of AJs), 61 in Sephardi Jews (14.2% of Sephardi), and 69 in Arabs (13.0% of Arab). Only 162 of the PV (43.2%) were the BRCA AJ founders, another 39 BRCA PV (10.4%) were reported previously, while 15 BRCA PV (4.0%) are likely private. The remaining non-BRCA PV (42.4%) were distributed across 18 genes, with findings predominantly in CHEK2, MUTYH, ATM, BLM, ERCC3, PALB2, and FANCA. The prevalence of PV varied significantly across the ancestral subsets, from 95.5% probability in AJ women diagnosed before age 36 and with first degree family history to only 9.3% in Arab women diagnosed at age 36-45 and without family history. Conclusions: In this comprehensive, population-based, cohort of women with young onset breast cancer, the presence of PV in more than 15 genes is compelling and informs a necessarily broader approach to genetic testing and counseling.
Citation Format: Gad Rennert, Bita Nehoray, Flavio Lejbkowicz, Sara Dishon, Shiri Kalet, Joseph Herzog, Thomas Slavin, Danielle Castillo, Kevin Tsang, Sharon Sand, Hedy S Rennert, Jeffrey Weitzel. A comprehensive germline genetic landscape in young Jewish & Arab women with breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P3-13-07.
Abstract P4-01-04: FGFR inhibitor mediated dismissal of SWI/SNF complexes from YAP-dependent enhancers induces therapeutic resistance in triple negative breast cancer
Authors: Li Yihao , Qiu Xintao , Wang Xiaoqing , Liu Hui , Geck Renee Geck , Tewari Alok , Chow Kin-Hoe , Xiao Tengfei , Cejas Paloma , Nguyen Quang-Dé , Long Henry , Liu Shirley X , Toker Alex , Brown Myles 
Published: March 2022

Abstract
How cancer cells adapt to evade the therapeutic effects of drugs targeting oncogenic drivers is poorly understood. Here we report an epigenetic mechanism leading to the adaptive resistance of triple-negative breast cancer (TNBC) to fibroblast growth factor receptor (FGFR) inhibitors. Prolonged FGFR inhibition suppresses the function of BRG1-dependent chromatin remodeling leading to an epigenetic state that derepresses YAP-associated enhancers. These chromatin changes induce the expression of several amino acid transporters resulting in increased intracellular levels of specific amino acids that reactivate mTORC1. Consistent with this mechanism, addition of mTORC1 or YAP inhibitors to FGFR blockade synergistically attenuated the growth of TNBC patient-derived xenografts (PDX) models. Collectively, these findings reveal a novel feedback loop involving an epigenetic state transition and metabolic reprogramming that leads to adaptive therapeutic resistance and provide new therapeutic strategies to overcome this mechanism of resistance.
Citation Format: Yihao Li, Xintao Qiu, Xiaoqing Wang, Hui Liu, Renee Geck Geck, Alok Tewari, Kin-Hoe Chow, Tengfei Xiao, Paloma Cejas, Quang-Dé Nguyen, Henry Long, Shirley X Liu, Alex Toker, Myles Brown. FGFR inhibitor mediated dismissal of SWI/SNF complexes from YAP-dependent enhancers induces therapeutic resistance in triple negative breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P4-01-04.
Abstract P4-01-13: Low tumor TLR9 expression results in resistance to growth inhibitory and autophagy responses to common breast cancer treatments
Authors: Selander Katri , Klaper Juha , Petruk Nataliia , Ramm Mauricio , Jukkola Arja , Eskelinen Eeva-Liisa 
Published: March 2022

Abstract
Background: Toll like receptor-9 (TLR9) is an intracellular, innate immune system DNA-receptor, which is widely expressed in cancers. We previously demonstrated that low tumor TLR9 protein expression is associated with poor prognosis among triple negative breast cancer (TNBC) patients. A similar result is now detected also in larger, mRNA expression based datasets (Kmplot.com), which extend our initial observation to basal and luminal B clinical subtypes. The reason for TLR9 association with poor prognosis is not known.Aim: Since poor outcomes in early breast cancer are due to adjuvant treatment failures, we studied the role of TLR9 in breast cancer chemotherapy responses, growth inhibition and autophagy. Materials and Methods: Chemotherapy effects on the growth of control shRNA and TLR9 shRNA TNBC MDA-MB-231 and estrogen receptor expressing (ER+) T47-D cells were studied with cell confluency assays in vitro and in orthotopic mouse models in vivo. Autophagy was assessed with LC3I and II Western blots. Association of tumor TLR9 status with autophagy will be further studied in a cohort of neo-adjuvant treated patients, by comparing pre-treatment TLR9 expression with post-treatment LC3 vesicular expression, with immunohistochemistry. Autophagy gene expression will also be studied with RNAseq. Results: TLR9 shRNA cells were significantly less sensitive to the growth inhibitory effects of standard breast cancer chemotherapies than the corresponding control shRNA cells in vitro. The TLR9 shRNA T47-D cells were also significantly less sensitive to tamoxifen, than corresponding control shRNA cells. Docetaxel inhibited the growth of tumors formed by control shRNA cells, but not by TLR9 shRNA MDA-MB-231 cells in an orthotopic mouse model in vivo. Further chemotherapies and autophagy responses are being tested in this model as well. Standard chemotherapies induced accumulation of LC3IIB in control shRNA cells, but not in TLR9 cells, as demonstrated with Western blots. Conclusions: Decreased expression of tumor TLR9 is associated with 1) poor prognosis among basal and luminal B subtype patient samples, and in 2) decreased growth inhibitory and 3) decreased autophagy responses to common breast cancer chemotherapies and tamoxifen. Our results suggest that treatment responses, and thereby survival of patients with low-TLR9 tumors, may be improved by enhancing TLR9-associated autophagy.
Citation Format: Katri Selander, Juha Klaper, Nataliia Petruk, Mauricio Ramm, Arja Jukkola, Eeva-Liisa Eskelinen. Low tumor TLR9 expression results in resistance to growth inhibitory and autophagy responses to common breast cancer treatments [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P4-01-13.
Abstract P4-01-14: The RXR agonist, IRX4204, increases the anti-tumor activity of HER2-targeted therapies in HER2-amplified breast cancer
Authors: Moyer Cassandra L , Mazumdar Abhijit , Hill Jamal , Sanders Martin E , Brown Powel 
Published: March 2022

Abstract
Background: HER2 targeted monoclonal antibodies and tyrosine kinase inhibitors (TKI) are effective treatments for HER2-amplified primary tumors. However, the challenge persists that primary and acquired resistance to anti-HER2 therapy is common, and that anti-HER2 targeted therapies fail to achieve a cure in the metastatic setting. There is a critical need for safe and effective therapies that can overcome anti-HER2 drug resistance and eliminate breast cancer metastases. Here, we present data demonstrating the activity of IRX4204, a highly specific agonist of the nuclear retinoid X receptor (RXR), to inhibit the growth of HER2-amplified breast cancer cell lines alone and in combination with current anti-HER2 therapies. Methods: In vitro cell growth assays were conducted to evaluate the efficacy of IRX4204 alone and in combination with trastuzumab, tucatinib, neratinib or T-DM1, using a panel of breast cancer cell lines expressing various levels of HER2. A calculated coefficient of drug interaction (CDI) and isobologram analysis was used to assess the additive, synergistic or antagonistic effects of IRX4204 with each anti-HER2 targeted therapy. Results: IRX4204 treatment alone inhibited the growth of HER2-overexpressing cell lines, SkBr3, AU565, HCC1419 and ZR75-1 in vitro, but not the growth of HER2-normal cell lines MCF7, MDA-MB-231, or HCC1143. When combined with trastuzumab, tucatinib, neratinib or T-DM1, additive or synergistic effects were observed in all of the drug-sensitive cell lines. Moreover, IRX4204 in combination with neratinib or tucatinib inhibited the growth of a TKI-resistant breast cancer cell line (HCC1954). Conclusion: These data demonstrate a novel use of an RXR agonist, IRX4204, to inhibit the growth of HER2-amplified breast cancer cell lines and to enhance the activity of anti-HER2 therapy in vitro. These results also demonstrate that IRX4204 can overcome anti-HER2 resistance to inhibit the growth of HER2-positive cells. These data demonstrate that IRX4204 can enhance the anti-cancer activity of anti-HER2 therapies even in TKI-resistant cells. In vivo experiments and mechanistic studies are ongoing.
Citation Format: Cassandra L Moyer, Abhijit Mazumdar, Jamal Hill, Martin E Sanders, Powel Brown. The RXR agonist, IRX4204, increases the anti-tumor activity of HER2-targeted therapies in HER2-amplified breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P4-01-14.
Abstract P4-11-10: Association of sports activity during the first five years of survival with quality of life among Chinese breast cancer survivors
Authors: Yeo Winnie , Lei Yuanyuan , Cheung Kali , Lee Roselle , Kwok Carol , Cheng Ashely , Cheng Ashely , Mo Frankie , Ho Suzanne 
Published: March 2022

Abstract
Background: The objective of this study was to investigate the association between participation of sports activity (SA) and quality of life (QoL) among Chinese women with early stage breast cancer (BC) during the first five years post BC diagnosis. Methods: BC survivors underwent assessment of QoL and level of SA at 3 time-points: 18-, 36- and 60-months after diagnosis. SA was measured using a validated modified Chinese Baecke questionnaire in the prior 12 months; QoL was measured using EORTC-QLQC30. Results: In total, 1289, 1125 and 1116 BC survivors were included at 18-, 36- and 60-month follow-up, respectively. At 18-month, the percentages of patients belonged to no [0 metabolic equivalent of task (MET)-hours per week], low-level (&lt;10 MET-hours/week) and high-level (≥10 MET-hours/week) SA groups were 20.7%, 45.5% and 33.8%, respectively; the corresponding figures at 36-month were 29.4%, 38.9% and 31.6%, respectively; and tat of 60-month were 32.8%, 36.7% and 30.5%, respectively. Generalized Estimating Equations analyses showed that higher level of SA was associated with better QoL in several items, including global health status/QoL, physical functioning, role functioning and emotional functioning (P for trend &lt; 0.05 for all), as well as less symptoms in fatigue, pain, loss of appetite and constipation (P for trend &lt; 0.05 for all). Conclusions: Findings from the present study support the notion that SA has beneficial effect on QoL during the first 5 years of BC survivorship. Health promotion programs should encourage participation for SA after breast cancer diagnosis.Acknowledgements: This work was supported by World Cancer Research Fund International (Grant Number WCRF 2010/249 and WCRF 2014/1197) and Madam Diana Hon Fun Kong Donation for Cancer Research.
Citation Format: Winnie Yeo, Yuanyuan Lei, Kali Cheung, Roselle Lee, Carol Kwok, Ashely Cheng, Ashely Cheng, Frankie Mo, Suzanne Ho. Association of sports activity during the first five years of survival with quality of life among Chinese breast cancer survivors [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P4-11-10.