bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract PS16-27: Small extracellular vesicle-mediated intercellular TGF-β1 transferring promotes adriamycin-resistant transmission in breast cancer cells
Authors: Xu Zhi , Tang JInhai 
Published: February 2021

Abstract
Chemotherapeutic resistance is a major obstacle to control of advanced breast cancer (BCa). We have previously shown that small extracellular vesicles (sEVs) can transmit adriamycin resistance between BCa cells. Here, we demonstrate that sEV-TGF-involves in intercellular drug-resistant transmission from adriamycin-resistant cells to adriamycin-sensitive cells. sEVs were isolated and characterized form the both sensitive and resistant cells. sEVs derived from the resistant cells were incubated with the sensitive cells and resulted in transmitting the resistant phenotype to the recipient cells. Cytokine antibody microarray revealed that most metastasis associated cytokines present at the high levels in sEVs from the resistant cells compared to their levels in sEVs from the sensitive cells, particularly TGF-β1. The sEV-TGF-β1 led to phosphorylation of Smad2/3 and remarkably changed the phenotypes of the recipient cells by suppressing apoptosis and enhancing cell movability. Finally, the sEV-TGF-mediated drug-resistance transmission was validated using a zebrafish xenograft tumor model. The results from this study elaborated that sEV-TGF-β1 intercellular transfer contributes to adriamycin resistance in BCa.
Citation Format: Zhi Xu, JInhai Tang. Small extracellular vesicle-mediated intercellular TGF-β1 transferring promotes adriamycin-resistant transmission in 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 PS16-27.
Abstract PS16-32: Obg-like ATPase 1 enhances chemoresistance of breast cancer via activation of TGF-β/Smad axis cascades
Authors: Xiao Gary , Liu Jianzhou , Miao Xiaoyu 
Published: February 2021

Abstract
Background: Understanding the molecular mechanism of drug resistance helps identify aneffective target for therapy of breast cancer. We investigated in this study the regulatory role ofObg-like ATPase 1 playing in multiple drug resistance of breast cancer.Methods: Paclitaxel resistant cell line (MCF-7-PTR) was developed by a continuous increasingpaclitaxel concentration. MTT assay was used to validate either acquired resistant or OLA1modified cell lines. qRT-PCR, immunoblot, apoptosis and cell cycle assays were performed toassess expression of genes and proteins in cell lines. A series of in vitro assays was performed inthe cells with RNAi-mediated knockdown to elucidate the regulatory role of OLA1 in breast cancer.Findings: We demonstrated that OLA1 was highly correlated with either acquired or intrinsicresistance of breast cancer. Further study showed that escalated expression of OLA1 promotedEMT process in tumor cells through TGF-β/Smad signaling cascades, resulting in the enhancedexpression of anti-apoptosis-related proteins (cleaved caspase3, Bax, Bcl-2) and the strengthendepolymerization of microtubules in tumor cells. Our findings revealed that OLA1 enhanced theanti-apoptotic ability and elucidated a regulatory role of OLA1 in promoting drug resistance ofbreast cancer.Interpretation: OLA1 is highly correlated with drug resistance of breast cancer. Chemo-sensitivity of the disease can be thus enhanced significantly by knocked down OLA1,which ledto inactivation of the TGF-β/Smad signaling cascades, polymerized microtubules, and promotedcell apoptosis. Our data suggest that OLA1 may be developed as a potential target to improvechemotherapy of patients with breast cancer.Keywords: breast cancer; Obg-like ATPase 1; multidrug resistance; γ-tubulin; paclitaxel
Citation Format: Gary Xiao, Jianzhou Liu, Xiaoyu Miao. Obg-like ATPase 1 enhances chemoresistance of breast cancer via activation of TGF-β/Smad axis cascades [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 PS16-32.
Abstract PS16-33: Niclosamide reverses cisplatin resistance by inhibiting Bcl-2 and Stat3 in HER2-positive breast cancer
Authors: Liu Junjun 
Published: February 2021

Abstract
Background: Breast cancer is the second leading cause of cancer-related deaths. Chemotherapy resistant breast cancer is poorly differentiated and displays aggressive clinical behavior. These tumors become resistant to cytotoxic agents and tumor relapse has been attributed to the presence of epithelial-mesenchymal transition (EMT) and cancer stem cells (CSCs). Niclosamide has been shown to have broad clinical applications for the treatment of malignant tumors other than those caused by parasites. However, the specific functions and molecular mechanisms of niclosamide in chemo-resistant HER2 positive breast cancer are still unknown. Methods: HER2 positive breast cancer cell line, BT474, was continuously exposed to increasing concentrations of cisplatin (5-20 μM) to establish stable cell line resistant to cisplatin, BT-CR. Cell viability was determined by alamar blue. Apoptosis was determined by flow cytometry. Mammosphere formation assay was conducted to observe the self-renewal potential. Invasion ability was analyzed by transwell assay. Protein expression was determined by western-blot. Results: BT-CR had EMT and stem-like phenotype with higher invasion ability compared to naive sensitive cells. Alamar Blue assay showed combination of niclosamide with cisplatin could reverse cisplatin resistance. The combination index value of niclosamide combined with cisplatin was less than 1. Niclosamide in combination with cisplatin significantly enhanced apoptosis of BT-CR cells to over 50%. Western-blot showed niclosamide and cisplatin could reverse the EMT phenotype of BT-CR with E-cadherin up-regulated and N-cadherin and vimentin down-regulated. A significant reduction of Bcl-2 and Stat3 phosphorylation (Tyr705) levels was also confirmed. After treatment of niclosamide combined with cisplatin, the inhibition of mammosphere forming efficiency and capability of invasion was also observed in BT-CR. Conclusion: Our results revealed that niclosamide combined with cisplatin inhibited cell growth, invasion, EMT and stem-like phenotype in cisplatin resistant BT474 cells. The inhibitory effect of niclosamide was exerted by increasing apoptosis and down-regulated Bcl-2 expression, whilst inhibiting phosphorylation levels of STAT3. The results suggested that niclosamide combined with cisplatin appears to be a novel therapeutic way in chemo-resistant breast cancer.
Citation Format: Junjun Liu. Niclosamide reverses cisplatin resistance by inhibiting Bcl-2 and Stat3 in HER2-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 PS16-33.
Abstract PS17-16: Sar439859, a novel selective estrogen receptor degrader (serd), demonstrates effective and broad antitumor activity in wild-type and mutant er-positive breast cancer models
Authors: Shomali Maysoun , Sun Fangxian , Levit Mikhail , Pollard Jack , Lee Joon Sang , Schio Laurent , El-Ahmad Youssef , Soria Chris , Cohen Patrick , Debussche Laurent , Bouaboula Monsif 
Published: February 2021

Abstract
Primary treatment for estrogen receptor-positive (ER+) breast cancer is endocrine therapy. However, substantial evidence indicates a continued role for ER signaling in tumor progression. Selective estrogen receptor degraders (SERDs), such as fulvestrant, induce effective ER signaling inhibition, although clinical studies with fulvestrant report insufficient blockade of ER signaling, possibly due to suboptimal pharmaceutical properties. Furthermore, activating mutations in the ER have emerged as a resistance mechanism to current endocrine therapies. New oral SERDs with improved drug properties are under clinical investigation, but the biological profile that could translate to improved therapeutic benefit remains unclear. Here we describe the discovery of SAR439859, a novel, orally bioavailable SERD with potent antagonist and degradation activities against both wild-type and mutant Y537S ER. Driven by its fluoropropyl pyrrolidinyl side chain, SAR439859 has demonstrated broader and superior ER antagonist and degrader activities across a large panel of ER+ cells, compared with other SERDs characterized by a cinnamic acid side chain, including improved inhibition of ER signaling and tumor cell growth. Similarly, in vivo treatment with SAR439859 demonstrated significant tumor regression in ER+ breast cancer models including MCF7-ESR1 wild type and mutant-Y537S mouse tumors, and HCI013, a patient-derived tamoxifen-resistant xenograft tumor. These findings indicate that SAR439859 may provide therapeutic benefit to patients with ER+ breast cancer, including those have resistance to endocrine therapy with both wild-type and mutant ER. This presentation will highlight the global profile and key features of new SERD and its translation to patient.
Citation Format: Maysoun Shomali, Fangxian Sun, Mikhail Levit, Jack Pollard, Joon Sang Lee, Laurent Schio, Youssef El-Ahmad, Chris Soria, Patrick Cohen, Laurent Debussche, Monsif Bouaboula. Sar439859, a novel selective estrogen receptor degrader (serd), demonstrates effective and broad antitumor activity in wild-type and mutant er-positive breast cancer models [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 PS17-16.
Abstract PS17-39: Inhibition of acetate metabolism enhances host anti-tumor immunity
Authors: Miller Katelyn , Schug Zachary T. 
Published: February 2021

Abstract
Acquired resistance to anti-cancer therapy is an enormous challenge. One of the main factors contributing to therapy resistance is tumor hypoxia. The stress imposed by tumor hypoxia forces cancer cells to adapt in order to survive. These metabolically adapted cancer cells are often more invasive, more malignant, and more drug resistant. As a result, the cancer cells that emerge from hypoxic tumor regions are more likely to cause patient relapse. There is therefore a critical need to understand the mechanisms that promote the survival of cancer cells in stressful tumor microenvironments. We previously showed that the enzyme acetyl-CoA synthetase 2 (ACSS2) supports cancer cell metabolism in hypoxic and nutrient-depleted environments. ACSS2 endows cancer cells with the ability to use acetate as an alternative nutrient source to drive acetyl-CoA biosynthesis during stress and genetic silencing of ACSS2 inhibits human breast tumor growth in xenograft models. Given the important role of acetate metabolism in breast cancer we expanded upon our studies by using immunocompetent hosts and syngeneic mouse tumor models. Our results revealed a previously unknown role of ACSS2 in modulating host anti-tumor immunity. We found that ACSS2 deficient tumors are unable to grow when host immunity is intact. Depletion of host immunity (T cells) using genetic or pharmacological models rescues the growth of ACSS2 deficient tumors. Pharmacological inhibition of ACSS2 in tumors in vivo displayed gene signatures associated immune infiltration and activation within the tumor microenvironment. Moreover, ACSS2 deficient breast cancer cell lines show a marked susceptibility to T cell killing in vitro. Our current research demonstrates a novel role for acetate metabolism in supporting tumor extrinsic modulation of host anti-tumor immunity. Since activation of acetate metabolism via ACSS2 is a near universal hallmark of metabolically stressed cancer cells, targeting acetate metabolism represents an unrealized opportunity with significant upside for improving current therapeutic modalities in breast cancer.
Citation Format: Katelyn Miller, Zachary T. Schug. Inhibition of acetate metabolism enhances host anti-tumor immunity [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 PS17-39.
Abstract PS18-09: Novel chimeric small molecule AC682 potently degrades estrogen receptor with oral anti-tumor efficacy superior to fulvestrant
Authors: He Wei , Zhang Hui , Perkins Lorena , Bouza Lissette , Liu Ke , Qian Yimin , Fan Jie 
Published: February 2021

Abstract
Modulation of estrogen activity and/or synthesis has been the mainstay therapeutic strategy for estrogen receptor (ER)-positive breast cancer. Fulvestrant, which provides superior clinical benefit over aromatase inhibitors and selective ER modulators, achieves its potent ER signaling inhibition through unique ER degradation activity beyond direct antagonism. Despite this superiority, the efficacy of fulvestrant appears limited by poor drug exposure through intramuscular injection. Up to 50% of ER baseline levels remained after 6 months of fulvestrant treatment. Therefore, an oral ER degrader with optimal pharmacokinetic profile may lead to better convenience and efficacy than fulvestrant. Here we report preclinical characterization of our novel oral ER degrader development candidate, AC682, a chimeric small molecule containing both ligands of ER and E3 ligase discovered with our ACCU-Degron technology. Through engaging E3 ligase and ER simultaneously, AC682 induced potent ER degradation with a sub-nanomolar half-maximal degradation concentration (DC50) in multiple ER-positive breast cancer cell lines tested, including a tamoxifen-resistant long-term estrogen deprived (LTED) cell line and cell lines expressing clinically-relevant ESR1 variants (Y537S and D538G). Proteasome-dependent ER degradation by AC682 peaked after a few hours of treatment, resulting in diminished expression of ER-regulated genes and subsequent cell growth inhibition. In the in vivo setting, oral dosing of AC682 achieved substantial drug exposure and oral bioavailability, with well tolerance in multiple animal species. In estradiol-dependent MCF7 xenograft tumors, oral daily dosing of AC682 led to dose-dependent tumor growth inhibition/regression and concomitant tumor ER protein reduction more than 90% at study termination. In particular, 3 mg/kg oral daily dosing achieved tumor stasis. When administrated in combination with CDK4/6 inhibitor Palbociclib, AC682 showed clear synergy in both the estradiol-dependent MCF7 model and a tamoxifen-resistant MCF7 model. In a patient-derived xenograft model, which bears ESR1 Y537S mutation and is hormone-independent, AC682 significantly inhibited tumor growth whereas fulvestrant only showed weak efficacy. In conclusion, oral chimeric ER degrader AC682 demonstrated robust ER degradation and anti-tumor efficacy in preclinical models, supporting its continued investigation in the clinic.
Citation Format: Wei He, Hui Zhang, Lorena Perkins, Lissette Bouza, Ke Liu, Yimin Qian, Jie Fan. Novel chimeric small molecule AC682 potently degrades estrogen receptor with oral anti-tumor efficacy superior to fulvestrant [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 PS18-09.
Abstract PS18-24: Impact of protein corona formation on Fn14-targeted DART nanoparticle selectivity, uptake, and cytotoxicity on TNBC cells
Authors: Carney Christine P , Kapur Anshika , Pandey Nikhil , Dancy Jimena G , Wadajkar Aniket S , Woodworth Graeme F , Winkles Jeffrey A , Kim Anthony J 
Published: February 2021

Abstract
Despite dramatic improvements in the treatment of primary breast cancers, there currently are no effective targeted therapeutics for women diagnosed with metastatic triple negative breast cancer (mTNBC), resulting in an overall survival of just ~13 months in these patients. Drug-loaded nanoparticles (NPs) offer the potential to improve the therapeutic efficacy and pharmacokinetic profile of drugs through use of passive and active targeting to metastatic tumors. However, effective and active targeting of nanodrug formulations to tumor cells is complicated by the adsorption of proteins to NP surfaces upon exposure to the systemic circulation. Termed ‘protein coronas’, this protein coat can drastically reduce the blood circulation time and targeting capability of NPs in vivo. We have developed paclitaxel (PTX)-loaded NPs that are engineered for decreased non-specific adhesivity and receptor-targeting (‘DART’) characteristics, which balance minimal recognition by circulating immune cells and low non-specific binding to tumor extracellular matrix proteins with maximal targeting to tumor tissues. These DARTs selectively bind the fibroblast growth factor-inducible 14 (Fn14) cell surface receptor, which is overexpressed in over a dozen solid cancers and their metastases, including mTNBC tumors. We recently demonstrated the enhanced therapeutic efficacy of Fn14-targeted DARTs in comparison to a non-targeted nanoformulation and Abraxane, an FDA-approved nanoformulation for mTNBC, in xenograft models of primary and intracranial TNBC. In addition, we found that these DARTs retain targeting capability and traffic to Fn14+ tumors in the presence of an endogenous protein corona in vitro and in vivo. This encouraged further investigation into the specific mechanisms of DART NP uptake in tumor cells in both the presence and absence of protein coronas using surface plasmon resonance, flow cytometry, total internal reflection fluorescence and confocal microscopy, and cytotoxicity assays. Understanding the role of protein coronas on this drug delivery platform is crucial for its clinical development and these results provide valuable new information pertaining to the optimization of NP surface properties for minimizing the impact of protein coronas and improving mTNBC tumor targeting in vivo.
Citation Format: Christine P Carney, Anshika Kapur, Nikhil Pandey, Jimena G Dancy, Aniket S Wadajkar, Graeme F Woodworth, Jeffrey A Winkles, Anthony J Kim. Impact of protein corona formation on Fn14-targeted DART nanoparticle selectivity, uptake, and cytotoxicity on TNBC 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 PS18-24.
Abstract PS18-39: Estrogen receptor beta agonists for triple negative breast cancer
Authors: Datta Jharna , Willingham Natalie , Manouchehri Jasmine , David Joel , Sheth Mirisha , Ramaswamy Bhuvaneswari , Ganju Ramesh , Cherian Mathew A 
Published: February 2021

Abstract
Background:Triple negative breast cancer (TNBC) represents about 10-15% of all breast cancers. Given the lack of targeted therapies, chemotherapy and immunotherapy are the only treatment options. The five-year survival rate of TNBC patients is approximately 15% less than other forms of breast cancer. Therefore, there is an urgent need to develop novel effective therapeutics for TNBC.Material and Methods:RNA isolated from human immortalized mammary epithelial MCF10A, and various TNBC cell lines was DNase treated and quantitative RT-PCR (qRT-PCR) performed using gene-specific primers spanning exon-exon junctions that include introns in the corresponding genomic sequence to avoid genomic DNA amplification. Gene expression was calculated by ΔΔCt method using GAPDH as an internal control. Immuno-blot analyses were performed on lysates prepared from cells in log phase of growth. Proteins were detected by Enhanced Chemi-Luminescence (ECL) method. Viability of cells treated with ERβ specific agonists was determined by using CellTiter-Glo® 2.0 assay. MB231 cells were treated with ERβ agonists following transfection with pcDNA3 (vector) or Flag-tagged ESR2 plasmids. Western blot analyses using specific antibodies and qRT-PCR were performed with the protein extracts and RNA isolated from the cells, respectively. Results:Our experiments demonstrate that ESR2 (ERβ) is differentially expressed and its level of expression is about 3 to 22-fold higher in TNBC cell lines tested than MCF10A. We have shown that viability of estrogen receptor (ER) positive breast cancer cell lines can be significantly inhibited by selective activation of ERβ. A highly selective ERβ agonist has been invented in the Drug Development Institute at the Ohio State University. Treatment of TNBC lines with these ERβ agonists exhibited a dramatic reduction of cell viability. While comparable IC50 values were observed with our in house and commercially available compounds, TNBC had 2-3-fold lesser IC50 values than ER-positive cell lines. Increased expression of FOXO3 and c-Myc1 and decreased expression of c-Myc2 isoform was noted in ERβ overexpressing MB231 cells upon treatment with ERβ agonists.Conclusion:Our results demonstrate that treatment with highly selective ERβ agonists could be an effective therapeutic strategy for TNBC patients. To improve and develop novel therapeutics for TNBC understanding the mechanism of action of these compounds will be crucial.
Citation Format: Jharna Datta, Natalie Willingham, Jasmine Manouchehri, Joel David, Mirisha Sheth, Bhuvaneswari Ramaswamy, Ramesh Ganju, Mathew A Cherian. Estrogen receptor beta agonists for 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 PS18-39.