bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract PS16-18: Inhibition of mTOR signaling by rapamycin abrogates mammary stem/progenitor cell activity in aged mice
Authors: Broome Larry E. , Bouamar Hakim , Nelson James F. , Sun Lu-Zhe 
Published: February 2021

Abstract
Previous studies have shown an altered physiology in the mammary gland of aged mice, with mammary ducts displaying increased tertiary branching along with an enriched myoepithelial population compared to younger mice. It is the population of myoepithelial cells residing in the basal layer of mammary ducts that is thought to be responsible for the development of the mammary gland. These qualities have been attributed to the mammary stem cells (MaSCs) that reside in this population and are capable of regenerating the mammary gland when implanted in an empty mammary fat pad, indicating their bipotent nature. It is not known however, if these stem cells are responsible for the aging mammary gland phenotype and the increased risk of cancer seen in aging mammals. Our preliminary studies showed that rapamycin could be utilized as a MaSC inhibitor and clinical trials are currently under way investigating the role of rapamycin in inhibiting MaSC function and abrogating biomarkers associated with invasive BC progression. Mammalian target of rapamycin (mTOR) is a protein kinase that regulates growth, proliferation, and survival in cells and is often upregulated in cancer. Rapamycin is an extremely selective inhibitor of mTORC1 function and its downstream signaling. In this study, aged mice fed ad lib with microencapsulated rapamycin showed decreased mTOR activity in the mammary ducts as shown by immunohistochemistry in aged mice. Treated mouse breast tissue also displayed a decreased population of Lin- CD24low CD49fhi myoepithelial/basal cells along with decreased tertiary branching in the ductal morphology, effectively reversing the aged mammary gland phenotypes. MaSC inhibition by rapamycin was also shown using sphere formation efficiency (SFE) assays after sorting the luminal (Lin- CD24hi CD49flow) and basal (Lin- CD24low CD49fhi) epithelial cells using Florescence Activated Cells Sorting (FACS) in a free suspension culture. Together, these findings show a possible use in regulating MaSCs by rapamycin and its potential in preventing age-related diseases such as breast cancer.
Citation Format: Larry E. Broome, Hakim Bouamar, James F. Nelson, Lu-Zhe Sun. Inhibition of mTOR signaling by rapamycin abrogates mammary stem/progenitor cell activity in aged mice [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS16-18.
Abstract PS17-24: Inhibition of short-form ron eliminates breast cancer metastases through an immune-mediated mechanism
Authors: Lai Shu-Chin Alicia , Gundlapalli Harika , Ekiz Huseyin A , Welm Alana L 
Published: February 2021

Abstract
Metastatic breast cancer is the overwhelming cause of breast cancer mortality and is still incurable. The rapid development of immunotherapy is an exciting new area of research in metastatic breast cancer. However, the extreme immunosuppressive tumor environment poses a major challenge. A better understanding of how the immune system can be harnessed against metastatic cancer is required to improve patient outcomes. We previously showed that expression of the receptor tyrosine kinase Ron in the host, rather than Ron's tumor expression, contributed to tumor-associated immunosuppression and duo inhibition of Ron and CTLA-4 significantly reduced metastatic outgrowth. However, the actual mechanism remains unclear.
The present study provides evidence that the N-terminal truncated isoform, short-form Ron (SF-Ron), is the major contributor in suppressing the anti-tumor immune responses and promoting metastatic outgrowth. Genetic deletion of host SF-Ron nearly eliminated breast cancer metastasis in mice, lead to systemic immune-activation, increased recruitment of lymphocytes to the site of metastasis, and augmented tumor-specific T-cell responses. Lack of SF-Ron also leads to the accumulation of CD4+ T-cells in the metastatic lungs and endowed with anti-tumor potential. Importantly, mice treated with small molecule Ron kinase inhibitor that targets both Ron and SF-Ron, produced significantly higher, active, tumor-specific CD8+ T-cells. Our study indicates that blocking Ron, especially the SF-Ron, remodels the metastatic lung microenvironment to enhance anti-tumor immunity. This study sheds light on the potential non-redundant roles of full-length and SF-Ron isoforms in mediating breast cancer metastasis and anti-tumor immune responses; and highlights the relevance of combining Ron inhibitors with immunotherapeutic agents to potentially improve treatment efficacy for metastatic breast cancer patients.
Citation Format: Shu-Chin Alicia Lai, Harika Gundlapalli, Huseyin A Ekiz, Alana L Welm. Inhibition of short-form ron eliminates breast cancer metastases through an immune-mediated mechanism [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS17-24.
Abstract PS17-29: Surgically induced weight loss corrects obesity associated tumor progression and improves responsiveness to immunotherapy
Authors: Sipe Laura , Chaib Mehdi , Korba Emily B , Lovely Mary C , Clements Jared C , John Neena A , Pingili Ajeeth K , Pierre Joseph F , Makowski Liza 
Published: February 2021

Abstract
Background: Obesity leads to a higher risk of cancer invasion, metastases, recurrence, mortality, and impaired therapeutic response through various mechanisms. One of these mechanisms is microenvironment dysfunction, where changes in immune cells, microbes, metabolites, and growth factors contribute to tumor aggressiveness. We study obesity-induced changes to the tumor microenvironment in Triple Negative Breast Cancer (TNBC), an aggressive subtype associated with obesity. The goal to compare tumor progression in lean vs. obese vs. weight loss manipulations to identify causal and targetable pathways associated with reprogramming the tumor microenvironment. Clinically, bariatric surgery induced weight loss reduced the risk of BC, with the greatest benefit detected in pre-menopausal patients with ER- tumors, like TNBC. We hypothesize surgically-induced weight loss will diminish obesity-associated tumor progression. Methods: To study weight gain and loss that best mimics human adiposity, we utilized obesogenic C57BL/6 females with a syngeneic orthotopic transplant of TNBC cells. Female mice placed on a high fat diet (HFD) at weaning became obese compared to mice on a low fat diet (LFD). After 16 weeks on an HFD diet, mice underwent the bariatric surgery Vertical Sleeve Gastrectomy (VSG). The VSG resulted in reduced body weight, adiposity, and correction of metabolic profiles compared to obese mice. Two weeks post-surgery, TNBC cells were OT into the mammary fat. Results: As expected, tumor growth was increased in obese mice compared to lean. Importantly, surgical weight loss rescued obese tumor progression. We identified key changes in tumor infiltrating of immune cells that could be responsible for the beneficial effects of bariatric surgery on tumor progression. We then exploited these changes with immunotherapy, which was uniquely effective in mice that underwent bariatric surgery. Conclusions: In conclusion obesity promotes a pro-tumor microenvironment, that can be corrected through surgically induced weight loss.
Citation Format: Laura Sipe, Mehdi Chaib, Emily B Korba, Mary C Lovely, Jared C Clements, Neena A John, Ajeeth K Pingili, Joseph F Pierre, Liza Makowski. Surgically induced weight loss corrects obesity associated tumor progression and improves responsiveness to immunotherapy [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS17-29.
Abstract PS17-38: Comprehensive association analysis of 21-gene recurrence score and overweight in breast cancer patients
Authors: Tong Yiwei , Gao Weiqi , Wu Jiayi , Zhu Siji , Huang Ou , He Jianrong , Zhu Li , Chen Weiguo , Li Yafen , Shen Kunwei , Chen Xiaosong 
Published: February 2021

Abstract
Background: The association between 21-gene recurrence score (RS) and host factors such as overweight remains unclear for breast cancer patients. The objectives of the current study are to comprehensively analyze the distribution, single gene expression, and prognostic predictive value of RS between overweight or non-overweight patients.Patients and methods: Luminal-like patients receiving surgery between January 2009 and December 2018 in the Comprehensive Breast Health Center, Shanghai Ruijin Hospital, with 21-gene RS results were retrospectively retrieved. Association and subgroup analysis between BMI and 21-gene RS were conducted. Single-gene expression in 21-gene RS panel was compared between overweight and non-overweight groups. Recurrence-free survival (RFS) and overall survival (OS) were calculated according to RS category and BMI status.Results: Among 1876 patients included, 442 (23.56%), 995 (53.04%) and 439 (23.40%) were classified into low, intermediate and high risk groups. RS category was significantly differently distributed between overweight and non-overweight patients (P=0.035). Overweight patients had a trend of lower RS score than patients with normal weight (25.13 vs 26.17, P=0.080). The effect of BMI on RS significantly varied according to age (P=0.012) and menstruation status (P&lt;0.001). Compared to non-overweight patients, overweight ones presented with higher ER (P&lt;0.001), PR (P&lt;0.001), CEGP1 (P=0.017), Ki67 (P=0.020) and STMY3 (P=0.026) mRNA expression levels. Regarding menstrual status, postmenopausal women with BMI≥24 kg/m2 were associated with higher ER group score (P&lt;0.001), with higher ER (P=0.041), PR (P&lt;0.001), CEGP1 (P=0.005), as well as GRB7 (P=0.015) expression, which was not significant in premenopausal women. After a median follow-up of 39.40 months (range 1.67-119.53), overweight patients had similar RFS (P=0.670) and OS (P=0.077) to non-overweight ones. Moreover, RS category could significantly predict RFS in the whole population (P&lt;0.001), in either those overweight (P=0.003) or non-overweight (P=0.019).Conclusion: 21-gene RS was differently distributed between overweight and non-overweight patients, which interacted with age and menopausal status. ER, PR, CEGP1, Ki67 and STMY3 genes were more expressed in overweight patients. RS category could predict RFS regardless of BMI status, which warranted further validation.
Citation Format: Yiwei Tong, Weiqi Gao, Jiayi Wu, Siji Zhu, Ou Huang, Jianrong He, Li Zhu, Weiguo Chen, Yafen Li, Kunwei Shen, Xiaosong Chen. Comprehensive association analysis of 21-gene recurrence score and overweight in breast cancer patients [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS17-38.
Abstract PS17-55: Reactive oxygen species scavengers in triple negative breast cancer
Authors: Duhoux Francois P , Capelôa Tânia , Sonveaux Pierre , Derouane Francoise 
Published: February 2021

Abstract
Reactive oxygen species (ROS) are well known to play important roles in cancer. In particular, ROS of mitochondrial origin (mtROS) promote DNA mutations and cell death when produced at high levels, but rather stimulate autophagy and metastatic spread when produced at subcytotoxic levels [1]. Multiple metabolic pathways and oncogenic regulators linked to ROS have been studied in cancer cells, including MAPK/ERK, PI3K/AKT, PTEN, PKD, BREF2, HIF-1, NF-κB and p53 [2]. Abnormalities in these pathways can contribute to tumor development.By producing mtROS, mitochondria control and could even trigger metastatic spread, meaning that the use of specific mitochondria-targeted superoxide inhibitors/scavengers, such as mitoquinol mesylate (MitoQ), could reduce and/or prevent metastatic dissemination. This has been studied and reported with the use of MitoTempo, which prevents metastasis of naturally metastatic MDA-MB-231 human breast cancer cells implanted in mice [1]. Here, we show that MitoQ impairs MDA-MB-231 and SkBr3 human breast cancer cell migration and invasion in vitro, and MDA-MB-231 metastasis to the lungs in mice in vivo. In metastatic take assays, tail vein-injected MDA-MB-231 cells pretreated with MitoQ formed significantly less metastases after 4 weeks compared to vehicle. In spontaneous metastatic assays, mice bearing orthotopic MDA-MB-231 tumors were treated with ± 20 mg/kg MitoQ (per os) for 6 weeks. Primary tumors were surgically removed to allow metastatic outgrowth. In this model, MitoQ decreased primary tumor recurrence as well as the number of lung micro-metastases. Additionally, RNAseq studies in two human breast cancer cell lines identified that MitoQ significantly modulated a common set of metabolic genes in vitro and in vivo. They can be used as biomarkers of response. These results, together with a successful Phase I clinical trial and the fact that MitoQ does not interfere with the cytotoxic effects of chemotherapy, confirm that MitoQ is a potential candidate to be clinically tested in triple negative breast cancer patients.
References:
1.Porporato PE et al. A mitochondrial switch promotes tumor metastasis. Cell Rep. 2014;8(3):754-66.2.Payen VL, et al. Pro- and antitumor effects of mitochondrial reactive oxygen species. Cancer Metastasis Rev. 2019;38(1-2):189-203.
Citation Format: Francois P Duhoux, Tânia Capelôa, Pierre Sonveaux, Francoise Derouane. Reactive oxygen species scavengers in triple negative breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS17-55.
Abstract PS18-22: Association of molecular biomarkers heterogeneity and treatment pattern, disease outcomes in multifocal or multicentric breast cancer patients
Authors: Li Shuai , Wu Jiayi , Huang Ou , He Jianrong , Zhu Li , Chen Weiguo , Li Yafen , Chen Xiaosong , Shen Kunwei 
Published: February 2021

Abstract
Background: To evaluate the rates of estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), and Ki-67 heterogeneity in multifocal or multicentric breast cancer (MMBC) and its association with treatment pattern and disease outcomes.Methods: MMBC patients with ER, PR, HER2, and Ki67 results for each tumor focus were retrospectively analyzed. Patients with concordant ER, PR, HER2, and Ki67 status among all invasive tumor foci were categorized into the Homo group, while the rest were defined as the Hetero group. Chi-square or Fisher test were performed to compare the treatment options between the Hetero and Homo groups. Disease-free survival (DFS) and overall survival (OS) rates were estimated from Kaplan-Meier curves and compared between two groups.Results: A total of 330 patients were included. Concordance rates of ER, PR, HER2, Ki67, and molecular subtype were 97.0%, 93.9%, 96.5%, 91.2%, and 88.2%, respectively (all P values &lt; 0.001). There were 53 (16.1%) and 287 (83.9%) patients classified into the Hetero and Homo groups. Adjuvant endocrine therapy was more frequently assigned for patients in the Hetero group than in the Homo group (84.9% vs. 71.7%, P = 0.046). There was no difference in terms of adjuvant anti-HER2 therapy (28.3% vs. 19.6%, P = 0.196) and chemotherapy (69.9% vs. 69.8%, P = 0.987) usage between two groups. At a median follow-up of 36 months, DFS rates were 81.2% for the Hetero group and 96.5% for the Homo group (HR = 2.81, 95% CI: 1.00-7.88, P = 0.041). The estimated 3-year OS rates for these two groups were 95.8% and 99.5%, respectively (HR = 4.31, 95% CI: 0.83-22.46, P = 0.059).Conclusion: Heterogeneity of ER, PR, HER2, or Ki67 was present in 16.1% patients with MMBC. Biomarkers heterogeneity influenced adjuvant endocrine therapy usage and was associated with worse disease outcomes, indicating further clinical evaluation.
Citation Format: Shuai Li, Jiayi Wu, Ou Huang, Jianrong He, Li Zhu, Weiguo Chen, Yafen Li, Xiaosong Chen, Kunwei Shen. Association of molecular biomarkers heterogeneity and treatment pattern, disease outcomes in multifocal or multicentric breast cancer patients [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS18-22.
Abstract PS18-32: Hyperleptinemia in obese state renders luminal breast cancers refractory to tamoxifen coordinating a crosstalk between Med1, miR205 and Erb B kinases
Authors: Nagalingam Arumugam , Muniraj Nethaji , Siddharth Sumit , Avtanski Dimiter , Parida Sheetal , Kuppusamy Pajamurthy , Saxena Neeraj K , Muniraj Nethaji 
Published: February 2021

Abstract
Background and Aim: Obese state is associated with increased breast cancer growth, metastasis, and poor overall survival. In this study, we seek to decipher the underlying molecular mechanisms by which obesity/hyperleptinemia reduces the efficacy of tamoxifen. Methods: The impact of obesity on tamoxifen was evaluated utilizing clonogenicity, high-fat-diet- induced obese mice and leptin-treated xenograft-models. Mechanistic studies involved immunoblotting, real-time PCR, immunocytochemistry, chromatin immunoprecipitation assay, phosphokinase array and in silico analysis. Results: Obese mice with hyperleptinemia exhibit increased tumor progression and respond poorly to tamoxifen compared to non-obese mice. Exogenous leptin abrogates tamoxifen-mediated growth inhibition and potentiates breast tumor growth even in the presence of tamoxifen. Mechanistically, leptin induces nuclear translocation of phosphorylated-ER and increases the expression of ER-responsive genes while reducing tamoxifen-mediated gene repression by abrogating tamoxifen-induced recruitment of corepressors NCoR, SMRT and Mi2. Further, we found that coactivator Med1 potentially associates with 48 (out of 75) obesity-signature genes. Interestingly, leptin upregulates Med1 expression by decreasing miR-205 and increases its functional activation via phosphorylation that is mediated by activation of Her2 and EGFR. It is important to note that Med1 silencing abrogates the negative effects of leptin on tamoxifen efficacy. Additionally, honokiol or adiponectin treatment effectively inhibits leptin-induced Med1 expression and improve tamoxifen efficacy in hyperleptinemic state.Conclusion: In conclusion, these studies show the molecular mechanisms by which obese/hyperleptinemic state may contribute to poor response to tamoxifen implicating leptin-miR205-Med1 and leptin-Her2-EGFR-Med1 axes and present bioactive compound honokiol and adipocytokine adiponectin as agents that can block leptin’s negative effect on tamoxifen.
Citation Format: Arumugam Nagalingam, Nethaji Muniraj, Sumit Siddharth, Dimiter Avtanski, Sheetal Parida, Pajamurthy Kuppusamy, Neeraj K Saxena, Nethaji Muniraj. Hyperleptinemia in obese state renders luminal breast cancers refractory to tamoxifen coordinating a crosstalk between Med1, miR205 and Erb B kinases [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS18-32.
Abstract PS18-49: A transcriptome approach to reveal CTDP1 knockdown induced G1 cell cycle arrest in triple negative breast cancer cells
Authors: Law Henry Chun Hin , Woods Nicholas 
Published: February 2021

Abstract
CTDP1 (C-terminal domain phosphatase 1) is the only phosphatase domain with a BRCT-domain and known to be associated with transcription and mitosis in eukaryotic systems. Our previous research showed that CTDP1 participates in the DNA damage response by mediating interstrand DNA repair through the Fanconi anemia pathway. This study also revealed that CTDP1 is an essential gene in breast cancer cell lines but not in normal breast derived epithelial MCF10A cells. This project aims to identify the changes in transcripts, kinases and interactors leading to the cell death induced by CTDP1 knockdown in the triple-negative breast cancer cell lines. Since RNA Pol II is one of the major targets of CTDP1 phosphatase activity, we initially hypothesized that the cellular changes were mediated by transcriptional regulation. The global transcriptomic profiling of shCTDP1 MDA-MB-231 cells detected more than 29000 gene products, where 1000 and 616 genes were found consistently up- and down-regulated, respectively. The downregulation of cell cycle-associated genes CCNA2, TOP2A and POLA1 in the MDA-MB-231 cells were confirmed with q-RT-PCR. While the upregulated genes did not show enrichment in the Reactome pathway database, the downregulated genes were significantly associated with DNA damage response, mitosis and transcription, which is consistent with the known functions of CTDP1. The transcription factor binding motifs analysis with iRegulon reveals that the E2F1 transcription activity decreased as CTDP1 was knocked down in MDA-MB-231. The subsequent cell cycle analysis supports this prediction and showed G1 arrest as CTDP1 is knocked down in MDA-MB-231 and MDA-MB-453, but not in MCF10A. A kinase array analysis was also conducted to further identify kinases activated or deactivated as CTDP1 is knocked down. A nested network analysis of the predicted transcription factors, kinases and CTDP1 interactors is used to identify potential pathways contributing to cell death of the triple-negative breast cancer cells upon loss of CTDP1 expression.
Citation Format: Henry Chun Hin Law, Nicholas Woods. A transcriptome approach to reveal CTDP1 knockdown induced G1 cell cycle arrest in triple negative breast cancer cells [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS18-49.