bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract PS16-28: Runx3 regulates emt during development lapatinib resistance
Authors: Kim So Hyeon , Min Ahrum , Kim Seongyeong , Park Yoonjung , Kim Yu Jin , Im Seock-Ah 
Published: February 2021

Abstract
RUNX3 regulates EMT during development lapatinib resistanceBackground: Lapatinib is a small molecular inhibitor of HER2 and EGFR tyrosine kinase, which is used for HER2 positive metastatic breast cancer patients. However, significant proportion of patients relapse due to acquired resistance. The epithelial to mesenchymal transition (EMT), which induces cell migration, invasion and cancer stem cell progression, was one of the mechanism that confers to drug resistance. We determined the correlation of lapatinib resistance and EMT, and identified a regulatory factor of EMT which associated with the development process of acquired lapatinib resistance.Methods: Acquired lapatinib resistant SK-BR-3 (SK-BR-3 LR) cells were established by continuously exposing to lapatinib for 7 months. The sensitivity of lapatinib was confirmed by MTT assay. Cell cycle progression was verified using flow cytometry analysis. Expression of signal transduction molecules were determined using quantitative PCR, western blotting and transcriptome data analysis. Cell migration and invasion ability were verified using wound healing assay and Boyden chamber assay. siRNA knock-down system were used for further analysis. Results: Lapatinib resistant (SK-BR-3 LR) cells showed aggressive morphology compared with parental cells. The growth rate and cell cycle progression were increased in SK-BR-3 LR cells. Expression of Snail, Vimentin, SOX2, Nanog, TGF-b1 and Smad proteins increased in SK-BR-3 LR cells. In SK-BR-3 LR cells, cell migration and invasion were significantly increased. Correlated with a promoter methylation of RUNX3, expression of RUNX3 was down-regulated in SK-BR-3 LR cells. In Runx3 knock-down cells TGF-b1, SOX2, smad molecules were up-regulated. Conclusion: SK-BR-3 LR cells showed aggressive phenotype. Expression of EMT markers, cancer stem cell markers, TGF-β pathway associated molecules and Smad proteins were increased in SK-BR-3 LR cells. Also, the increase of cell migration and invasion was observed in LR cells. RUNX3 affected to cell migration and invasion through regulation of EMT associated molecules. Therefore, RUNX3 might be a specified molecule, which partially contributes resistance to lapatinib through regulates EMT.
Citation Format: So Hyeon Kim, Ahrum Min, Seongyeong Kim, Yoonjung Park, Yu Jin Kim, Seock-Ah Im. Runx3 regulates emt during development lapatinib resistance [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 PS16-28.
Abstract PS16-34: Phenotype and prognosis of patients with breast cancer and pathogenic TP53 variants
Authors: Petry Vanessa 
Published: February 2021

Abstract
Background: The lifetime risk of cancer in individuals with Li Fraumeni syndrome (LFS) is more than 70% for men and more than 90% for women. Breast cancer (BC) is the most common type of cancer in premenopause women with pathogenic allelic TP53 variants (PVs). However, little is known about the BC response to systemic therapy and the prognosis in these patients. We aim to analyze the phenotype and the outcomes of patients with LFS and BC. Methods: We evaluated a cohort of patients with PVs or likely PVs of TP53 with BC diagnosis treated from December 1999 to June 2020 from a single tertiary cancer center. Our primary objective is to evaluate the outcomes of these patients. Secondary objective is to describe the BC phenotype, characterizing the clinical and the pathological features.Results: Among 56 patients with PVs or likely PVs of TP53, 25 were diagnosed with BC. Median age at BC diagnosis was 39.2 years (range 23.4-57.4 years). The majority (N= 18, 72%) harbored a germline PV TP53 p.R337H in heterozygosity status. The most common histology type was an invasive carcinoma of no special subtype, 73% were hormone receptor-positive, and 32% were HER2-positive. Three (12%) patients were metastatic at diagnosis. Seven (28%) of the patients with localized disease at diagnosis received neoadjuvant chemotherapy, and other 7 (28%) received adjuvant chemotherapy. Among patients treated with neoadjuvant chemotherapy, 5 (71%) had a tumor response, while 2 (29%) presented with disease progression. No pathologic complete response was achieved. After a median follow-up of 52.6 months, no deaths secondary to breast cancer occurred. Only 1 patient died due to another neoplasm (jaw osteosarcoma), and 3 (12%) patients developed radiotherapy-induced malignancies in the irradiated field. Conclusions: BC in patients with LFS is mainly the invasive carcinoma of no special subtype, enriched in hormone receptor and HER2 positivity. Although response to neoadjuvant chemotherapy is high, no pathologic complete response occurred in this cohort. Favorable outcomes were observed, with a high BC specific survival. Secondary malignancies remain a major concern. Larger cohorts should test whether new genes act as modifiers of p53 function and breast cancer susceptibility.
Citation Format: Vanessa Petry. Phenotype and prognosis of patients with breast cancer and pathogenic TP53 variants [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 PS16-34.
Abstract PS17-25: Repurposing anti-depressant imipramine for treating breast cancers
Authors: Timilsina Santosh , Rajamanickam Subapriya , Rao Arhan , Subbarayalu Panneerdoss , Jatoi Ismail , Chen Yidong , Vadlamudi Ratna , Kaklamani Virginia G , Rao Manjeet 
Published: February 2021

Abstract
About 1 in 8 women will develop invasive breast cancer during their life time and more than 41,000 women die every year in the United States alone. Most of these deaths are attributed to relapse, distant metastasis and therapy resistance. For example, despite initial response to therapy, a significant proportion of ER+ BCs become therapy resistant and progress to incurable metastases. Similarly, TNBCs, which is highly aggressive and are more likely to occur in Hispanic and black women, have higher propensity to relapse and contribute to disproportionate number of deaths. Unfortunately, the patients who do survive, have reduced quality of life due to the chemotherapy-associated toxicity. One mechanism that helps BCs to survive and become therapy-resistant is their unique ability to keep repairing their DNA. The aim of this study was to identify and test whether any FDA-approved non-cancer drug/s can block DNA repair ability and consequently growth of BC cells. Treatment of BC cells with a set of FDA approved drugs showed that antidepressants imipramine can inhibit the BC cell growth. Imipramine treatment significantly reduced the short and long-term viability of TNBC and ER+ breast cancer cells. Further, imipramine treatment inhibited the migration and invasion of breast cancer cells. Systemic delivery of imipramine suppressed the breast cancer cells growth in orthotopic mouse xenograft model. Our results revealed that imipramine treatment induced G1/S cell cycle arrest and apoptosis in breast cancer cells. Importantly, imipramine blocked the DNA repair capacity of BC cells by inhibiting the expression of DNA repair proteins including FOXM1 and RAAD51. Notably, imipramine treatment improved the efficacy of the PARP inhibitor “olapraib” in TNBC and sensitized the tamoxifen response in tamoxifen resistant ER+ breast cancer cells. Our results suggest that imipramine can be used as a single or therapeutic adjuvant for treating therapy sensitive and therapy resistant breast cancers. Based on these results, we are currently conducting a clinical trial to test the therapeutic efficacy of imipramine for treating breast cancer patients (https://www.cancer.gov/about-cancer/treatment/clinical-trials/search/v?id=NCI-2017 01937&r=1).
Citation Format: Santosh Timilsina, Subapriya Rajamanickam, Arhan Rao, Panneerdoss Subbarayalu, Ismail Jatoi, Yidong Chen, Ratna Vadlamudi, Virginia G Kaklamani, Manjeet Rao. Repurposing anti-depressant imipramine for treating breast cancers [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 PS17-25.
Abstract PS17-33: Sumo-modified androgen receptors support the metastatic phenotype of endocrine-resistant hormone receptor-positive breast cancer
Authors: Bawa-Khalfe Tasneem , Bahnassy Shaymaa , Thangavel Hariprasad , Quttina Maram , Khan Ashfia Fatima , Dhanyalayam Dhanya , Ritho Joan , Karami Samaneh , Ren Jing 
Published: February 2021

Abstract
Background: Conventional endocrine therapy is the first-line treatment for hormone receptor positive (HR+) breast cancer (BCa) subtype. Frequently, intrinsic and acquired ET resistance (ET-R) persists to support a disease with poor prognosis and limited therapy than the ET-sensitive carcinoma. High levels of androgen receptors (AR) in HR+ BCa correlate with insensitivity to ET tamoxifen and greater susceptibility to cancer metastasis. However, targeting AR with antagonist enzalutamide (Enz) in ET-R HR+ BCa present conflicting results. In the current report, we present novel findings of a constitutively active modified AR population that accumulates in the ET-R HR+ BCa cells to drive cell migration and metastatic phenotype.
Methods: Cell-free protein modification tests, in-house SUMOylation assays, and PLA imaging were used to determine the AR protein profile in multiple ET-sensitive, intrinsic-, and acquired-ET HR+-BCa lines. Reporter assay and targeted transcriptome studies evaluate the genomic activity of native and modified-AR mimetic. Finally, the inhibitory effect of Enz with or without combination therapy was determined using migration and spheroid growth studies.
Results: In acquired and intrinsic ET-R BCa cell lines, a constitutively active, higher molecular weight SUMO-modified AR (SUMO-AR) persists at the chromatin. The SUMO-AR is resilient to ubiquitin-mediated proteasomal degradation. We now report that the canonical AR chaperone protein HSPB1/Hsp27 functions as a novel SUMO-E3 ligase for AR. SUMO-AR interacts with a unique repertoire of biomolecules as compared to unmodified AR in the same cell lines. An increase in the SUMO protein and global SUMO-modified proteome supports this multimeric complex. The ligand-independent SUMO-AR activity promotes a gene-expression profile that favors epithelial-mesenchymal transition. Treatment with Enz alone or in combination with a SUMO inhibitor attenuates migration and metastatic phenotype of ET-R HR+ BCa.
Conclusion: SUMO-AR dictates metastatic susceptibility and Enz responsiveness of ET-R HR+ BCa. Consistently, targeting both unmodified and SUMO-modified AR serves as a better therapeutic strategy for advanced HR+ BCa.
Citation Format: Tasneem Bawa-Khalfe, Shaymaa Bahnassy, Hariprasad Thangavel, Maram Quttina, Ashfia Fatima Khan, Dhanya Dhanyalayam, Joan Ritho, Samaneh Karami, Jing Ren. Sumo-modified androgen receptors support the metastatic phenotype of endocrine-resistant hormone receptor-positive 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 PS17-33.
Abstract PS17-49: Investigating CDK4/6 inhibition in triple negative breast cancer
Authors: Guo Qiuchen , Goreczny Gregory J , Spasic Milos , Maynard Adam , McAllister Sandra S 
Published: February 2021

Abstract
The purpose of our study is to evaluate the immunological effects of CDK4/6 inhibitors in pre-clinical models of triple negative breast cancer (TNBC). CDK4/6 inhibitors, including abemaciclib, are currently approved to treat patients with metastatic hormone receptor-positive (HR+), Her2-negative breast cancer. We previously reported in our Her2+ model that CDK4/6 inhibitors promote anti-tumor immunity through inducing tumor cell antigen presentation via activating tumor endogenous retroviral elements, which induce type III interferon production and MHC-I upregulation (Goel, DeCristo, et al., Nature, 2017). We also uncovered important anti-tumor effects on the immune system: CDK4/6 inhibitors decrease T regulatory cell proliferation without affecting cytotoxic CD8 T cell numbers. TNBC has been considered a poor candidate for CDK4/6 inhibitor therapy, as tumors often lose retinoblastoma (Rb) protein expression/function, which is critical for CDK4/6 inhibitor-induced cell cycle arrest. However, Rb mutation or loss occurs in only ~20% of TNBC cases and we found Rb expressing murine and human TNBC cell lines decreased proliferation in vitro in response to abemaciclib. In our preclinical model of TNBC, abemaciclib induced tumor regression. Consistent with previous findings, TNBC tumor cells upregulated MHC-I upon abemaciclib treatment, suggesting increased antigen presentation. Tumor cell-surface PD-L1 was also increased with abemaciclib both in vitro and in vivo, as assessed by flow cytometry and RT-qPCR. These results are encouraging, given that αPD-L1 therapy (Atezolizumab) in combination with chemotherapy (nab-paclitaxel) has recently been approved as standard care for metastatic TNBC and the IMpassion130 trial reported enhanced progression-free and overall survival in patients with PD-L1+ tumors. We also found that abemaciclib increased CD8+ and CD4+ T cells and decreased PD1+ CD8 and CD4 cells in the spleen. Furthermore, total numbers of naïve CD8+ and CD4+ T cells increased with abemaciclib treatment, suggesting a favorable anti-tumor systemic immunological effect. Our data suggest the potential efficacy of CDK4/6 inhibitors in combination with αPD-L1 in the treatment of Rb+ TNBC. Deeper analysis of the mechanisms involved in regulating PD-L1 and enhancing naïve T cells should enable us to evaluate combination therapies using CDK4/6 inhibitors for this particularly deadly breast cancer subtype.
Citation Format: Qiuchen Guo, Gregory J Goreczny, Milos Spasic, Adam Maynard, Sandra S McAllister. Investigating CDK4/6 inhibition 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 PS17-49.
Abstract PS17-57: Breast cancer patients have reduced levels of short chain fatty acid producing beneficial gut bacteria
Authors: Vikas Praveen , Cady Nicole , Knobbe Jessica , Hoang Jemmie , Yadav Meeta , Curry Melissa , Cherwin Cathernine , Sugg Sonia , Phadke Sneha , Filardo Edward , Mangalam Ashuthosh 
Published: February 2021

Abstract
The role of the human gut microbiome has been increasingly appreciated in respect to its influence on human health and disease. It has been proposed that dysbiosis in the gut microbiome and subsequent induction of chronic inflammatory state might have an influence on breast cancer development and prognosis. Therefore this study was undertaken to determine the role of gut microbiome in breast cancer. The Breast Molecular Epidemiology Resource (BMER) resources of the Holden Comprehensive Cancer Center (HCCC) were used to recruit 23 women with breast cancer. Fecal samples were used to characterize the gut microbiome of our patient population using 16S rRNA amplification and Illumina sequencing. Reads were then mapped back to amplicon sequence variant using DADA2 pipeline and compared to a cohort of race, age, and gender matched cohort of regional healthy controls. In our preliminary analysis, we observed that breast cancer patients have distinct microbiota compared to age and gender matched healthy controls. We identified depletion of the anti-inflammatory short chain fatty acid producing bacteria specifically Faecalibacterium, Anaerostipes, Parabacteroides and Phascolarctobacterium in feces from BC patients. Additionally, breast cancer cohort showed enrichment of the pro-inflammatory bacteria such as Eubacterium (dolichum), Bifidobacterium, and Blautia. These bacteria have been previously been identified to change with clinical disease stage and/or BMI, as has genus Bifidobacterium (increased in BC cohort). Within BC group, patients with high grade showed lower levels of Eggerthella lenta and Desulfovibrio whereas patients receiving chemotherapy showed depletion of Sulphur reducing Desulfovibrio and methane producing archaea Methanobrevibacter. Further analysis may lead to insights into the interplay between gut microbiome and breast cancer, as well as the feasibility of therapeutic strategies in the form of novel and existing probiotics.
Citation Format: Praveen Vikas, Nicole Cady, Jessica Knobbe, Jemmie Hoang, Meeta Yadav, Melissa Curry, Cathernine Cherwin, Sonia Sugg, Sneha Phadke, Edward Filardo, Ashuthosh Mangalam. Breast cancer patients have reduced levels of short chain fatty acid producing beneficial gut bacteria [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 PS17-57.
Abstract PS18-17: Mdm2 inhibition synergises with endocrine therapy or cdk4/6 inhibition for the treatment of estrogen receptor-positive breast cancer
Authors: Portman Neil , Milioli Heloisa , Alexandrou Sarah , Coulson Rhiannon , Yong Aliza , Fernandez Kristine , Chia KeeMing , Halilovic Ensar , Segara Davendra , Parker Andrew , Haupt Sue , Haupt Ygal , Tilley Wayne , Swarbrick Alex , Caldon Liz , Lim Elgene 
Published: February 2021

Abstract
Background: Resistance to endocrine therapy is a major clinical challenge in the management of estrogen receptor (ER)-positive breast cancer. In this setting p53 is frequently wildtype and its activity may be suppressed via upregulation of its key regulator MDM2. This underlies our rationale to evaluate MDM2 inhibition as a therapeutic strategy in treatment resistant ER-positive breast cancer.
Methods: We used the MDM2 inhibitor NVP-CGM097 to treat in vitro and in vivo models alone and in combination with fulvestrant or palbociclib. We perform cell viability, cell cycle, apoptosis and senescence assays to evaluate antitumor effects in p53 wildtype and p53 mutant ER positive cell lines (MCF-7, ZR75-1, T-47D) and MCF-7 lines resistant to endocrine therapy and to CDK4/6 inhibition. We further assess the drug effects in patient-derived xenograft (PDX) models of endocrine-sensitive and -resistant ER positive breast cancer.
Results: We demonstrate that MDM2 inhibition results in cell cycle arrest and increased apoptosis in p53-wildtype in vitro and in vivo breast cancer models, leading to potent anti-tumour activity. We find that endocrine therapy or CDK4/6 inhibition synergises with MDM2 inhibition but does not further enhance apoptosis. Instead, combination treatments result in profound regulation of cell cycle-related transcriptional programmes, with synergy achieved through increased antagonism of cell cycle progression. Combination therapy pushes cell lines resistant to fulvestrant or palbociclib to become senescent and significantly reduces tumour growth in a fulvestrant resistant patient derived xenograft model.
Conclusions: We conclude that MDM2 inhibitors in combination with ER degraders or CDK4/6 inhibitors represent a rational strategy for treating advanced, endocrine resistant ER-positive breast cancer, operating through synergistic activation of cell cycle co-regulatory programs.
Citation Format: Neil Portman, Heloisa Milioli, Sarah Alexandrou, Rhiannon Coulson, Aliza Yong, Kristine Fernandez, KeeMing Chia, Ensar Halilovic, Davendra Segara, Andrew Parker, Sue Haupt, Ygal Haupt, Wayne Tilley, Alex Swarbrick, Liz Caldon, Elgene Lim. Mdm2 inhibition synergises with endocrine therapy or cdk4/6 inhibition for the treatment of estrogen receptor-positive 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 PS18-17.
Abstract PS18-35: Disparities in reporting of race and participation by race in genomic studies
Authors: Khanna Niloufar R , Dixit Niharika 
Published: February 2021

Abstract
Background: Black/African American(B/AA) women are more likely to die of breast cancer as compared to White (Wh) women but are underrepresented in genomic research. Current genomic research that aims to classify breast cancer in order to personalize treatment in early breast cancer or to identify targets for therapy in advanced breast cancer fails to adequately represent B/AA women and other minority groups. This negatively impacts our current knowledge of breast cancer in non-Wh women and raises questions about the applicability of such testing in minority groups.
Objective: To evaluate the frequency of race reporting and representation of non-White women in genomic studies.
Methods: This a database study of all PubMed reported genomic testing studies to classify breast cancer for prognostic or predictive purposes. A PubMed search was conducted with articles from inception to the present with the following keyword search terms: “Breast Cancer Gene Expression Assay” AND “Race”, “PAM50” AND “Race”, “MammaPrint” AND “Race”, “Oncotype Dx” AND “Race”, “76 gene prognostic score” AND “Race”, Intrinsic Subtype” AND “Breast Cancer” AND “Race”. This search yielded 129 articles. 31 articles were removed due to lack of relevance.
Results: Of the 98 articles remaining after applying inclusion/exclusion criteria, 39 (40%) failed to report race in their analysis. Of the remaining 59 articles, 57 (96.61%) included Wh participants in their study, 54 (91.53%) included B/AA participants, 13 (22.04%) included Hispanics/Latinos, and 20 (33.90%) included Asians. Two of the major clinical trials of widely used testing such as Oncotype Dx and MammaPrint but did not report race in the pivotal studies. The genomic studies that included B/AA women were more likely to be health services research studies. The genomic studies that focused on triple-negative breast cancer (TNBC) were also more likely to have B/AA participants that ranged from 6%-52% of participants. For Oncotype Dx testing, B/AA women were more likely to have a later stage at diagnosis. While the number of patients with low risk was similar in all race groups, B/AA women were more likely to have high Ki-67 with uncertain significance of these findings.
Conclusions: A significant number of genomic studies did not report race and ethnicity. Racial and ethnic minorities continue to be under-represented in genomic research and this raises questions about the wider applicability of this research in these populations. Large clinical studies should specifically report the race and ethnicity of participants to inform decision making. In addition, funders should require reporting of race in genomic studies.
Citation Format: Niloufar R Khanna, Niharika Dixit. Disparities in reporting of race and participation by race in genomic studies [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 PS18-35.