bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A35: Characterizing the role of the nuclear coactivator AIB1 in triple-negative breast cancer
Authors: Saenz Francisco R. , Wellstein Anton , Riegel Anna T. 
Published: August 2018

Abstract
Individuals diagnosed with triple-negative breast cancer (TNBC), a highly invasive and frequently metastatic breast cancer subtype, do not benefit from targeted therapies. TNBC is a heterogenous disease and can be further subdivided by intrinsic molecular subtyping into basal-like 1 or 2 (BL-1, BL-2), immunomodulatory (IM), mesenchymal (M), mesenchymal stem-like (MSL), and luminal androgen receptor (LAR). Amplified in Breast Cancer 1 (AIB1) is an oncogene that is frequently overexpressed in higher-grade and invasive breast cancers. AIB1 regulates the transcription of several genes through hormone or growth factor signaling. Many of these signaling pathways are involved in cellular growth, differentiation, migration, and metabolism—all of which become deregulated during oncogenesis. In this study, we silence AIB1 by shRNA and study the phenotypic effects in a panel of TNBC cell lines from different TNBC subtypes in vitro. We have established TNBC HCC1806 cell lines expressing low levels of AIB1 and have characterized their phenotype compared to scramble control cells. We observe significant reduction in AIB1 message and protein as detected by RT-qPCR and Western blot. shAIB1 TNBC cells have a significant reduced survival following the initial knockdown. However, serial passaging of surviving cells show differences in proliferation, especially in low serum conditions. These AIB1LOW cells have a significant increase in motility shown in chemotaxis experiments. However, we observe delayed adhesion of AIB1LOW cells when seeded onto plastic culture vessels. Furthermore, when grown onto Matrigel, AIB1LOW cells have a significant reduced tube formation capacity related to their delayed adhesion or reduced motility on substratum. Additionally, AIB1LOW cells have a differential expression of cell surface markers associated with cancer stem cells (i.e., CD24, CD44, CD133). Consistent with these findings, AIB1LOW cells generate tumorspheres more efficiently under serum free in suspension and when embedded in Matrigel. Moreover, AIB1LOW cells develop aggressive phenotypically different tumors in the cleared mammary fat pad of nude mice compared to controls. The AIB1LOW cells are significantly less sensitive to chemotherapy agents and may represent a resistant population that emerges from cancer stem cells following therapy. Interestingly, AIB1LOW cells have a different regulation of genes associated with hypoxia, glycolysis, and apoptosis and these changes may give guidance as to therapy following emergence of resistance in TNBC patients.
Citation Format: Francisco R. Saenz, Anton Wellstein, Anna T. Riegel. Characterizing the role of the nuclear coactivator AIB1 in triple-negative breast cancer [abstract]. In: Proceedings of the AACR Special Conference: Advances in Breast Cancer Research; 2017 Oct 7-10; Hollywood, CA. Philadelphia (PA): AACR; Mol Cancer Res 2018;16(8_Suppl):Abstract nr A35.
Abstract A37: Combined targeting of estrogen receptor alpha and nuclear transport pathways remodels metabolic pathways to induce apoptosis and overcome tamoxifen resistance
Authors: Cotul Eylem Kulkoyluoglu , Wrobel Kinga , Yosef Landesman , Madak-Erdogan Zeynep 
Published: August 2018

Abstract
Majority of breast cancer specific deaths occur in women with recurrent, ERα (+), metastatic tumors that are endocrine therapy resistant. There is a critical need for novel therapeutic approaches to resensitize recurrent ERα (+) tumors to endocrine therapies. The objective of this study was to elucidate mechanisms of improved effectiveness of combined targeting of ERα and XPO1, a nuclear transport protein in overcoming endocrine resistance. Using Cignalfinder pathway profiling, Seahorse metabolic profiling, and GC/MS whole metabolite profiling, we found that combination of 4-OH-Tam and selinexor (SXR), an XPO1 antagonist being evaluated in multiple later-stage clinical trials in patients with relapsed and /or refractory hematologic and solid tumor malignancies, inhibited Akt phosphorylation by changing the localization of the kinase. Since we observed dramatic changes in Akt activity, we hypothesized that glucose utilization pathways and consequently metabolic profile of breast cancer cells would change in the presence of 4-OH-Tam and SXR. These cells were more dependent on mitochondria for energy production. Their glucose and fatty acid dependency decreased in the presence of SXR and cells were more dependent on glutamine as the mitochondrial fuel source. In order to examine metabolites that might result in the observed phenotype, we performed whole metabolite profiling and identified proline metabolic pathways to be upregulated when cells were treated with SXR+4-OH-Tam. We demonstrated that combined targeting of XPO1 and ERα rewires metabolic pathways, increases demand on mitochondria, and causes increased production of ROS that would eventually lead to apoptosis. Remodeling metabolic pathways to regenerate new vulnerabilities in endocrine-resistant tumors is novel, and given the need for better strategies for improving therapy response of relapsed ERα(+) tumors, our findings show great promise for uncovering the role ERα-XPO1 crosstalk plays in reducing cancer recurrences.
Citation Format: Eylem Kulkoyluoglu Cotul, Kinga Wrobel, Landesman Yosef, Zeynep Madak-Erdogan. Combined targeting of estrogen receptor alpha and nuclear transport pathways remodels metabolic pathways to induce apoptosis and overcome tamoxifen resistance [abstract]. In: Proceedings of the AACR Special Conference: Advances in Breast Cancer Research; 2017 Oct 7-10; Hollywood, CA. Philadelphia (PA): AACR; Mol Cancer Res 2018;16(8_Suppl):Abstract nr A37.
Abstract A43: Increased cyclin A expression is associated with antiprogestin resistance and progesterone receptor isoforms ratio in experimental models of breast cancer
Authors: Ayre Marina , Bilinski Melina E. , Jacobsen Britta M. , Lanari Claudia , Fabris Victoria T. 
Published: August 2018

Abstract
Deregulation of cyclin A expression has been associated with prognosis and tamoxifen responsiveness in breast cancer. We have previously reported an overexpression of cyclin A in two antiprogestin-resistant tumors derived from a hormone-dependent mammary carcinoma induced by medroxyprogesterone acetate (MPA). MPA-induced tumors show high levels of estrogen (ER) and progesterone receptors (PR) and transit through different stages of hormone dependency. Taking into account that antiprogestin-sensitive tumors show higher levels of PR isoform A (PRA) than isoform B (PRB), and that the opposite ratio is observed in the antiprogestin-resistant tumors, we decided to examine the expression of cyclin A in other experimental models containing different PRA/PRB ratios. An increase in cyclin A expression was observed by Western blot (WB) in the acquired antiprogestin-resistant variant C7-2-HIR and in the constitutive resistant C7-HI tumor (1.7 fold and 1.5 fold, respectively) compared to the antiprogestin-responsive tumor C7-2-HI (p&lt;0.05). The immunohistochemical analysis of paraffin sections of the tumors confirmed these findings, showing a higher percentage of cyclin A positive nuclei in the antiprogestin-resistant tumor C7-HI, versus the responsive tumor C7-2-HI (p&lt;0.01), suggesting an association of cyclin A expression with endocrine resistance in the murine breast cancer model. Next we evaluated the expression of cyclin A in T47D human breast cancer cells that express both PR isoforms and in T47D-YA or T47D-YB cells that express either PRA or PRB, respectively. The WB analysis of the nuclear fraction of cell lysates showed an increase in cyclin A expression in the T47D-YB cells (1.5 fold), compared to T47D and T47D-YA cells (all the cells were serum starved; p&lt;0.01). Immunofluorescence for cyclin A using cultured breast cancer cells revealed a higher percentage of cyclin A positive nuclei in T47D-YB cells compared to T47D cells (p&lt;0.001) or T47D-YA (p&lt;0.01), respectively. Similarly, T47D-YB xenografts showed an increase of cyclin A expression by WB (1.47 fold) compared to T47D and T47D-YA tumors (p&lt;0.05). These results suggest an association between cyclin A expression, the PR isoform ratio, and antiprogestin resistance. Cyclin A may participate in the ligand independent activation of PR in the antiprogestin-resistant variants of these experimental models of breast cancer.
Citation Format: Marina Ayre, Melina E. Bilinski, Britta M. Jacobsen, Claudia Lanari, Victoria T. Fabris. Increased cyclin A expression is associated with antiprogestin resistance and progesterone receptor isoforms ratio in experimental models of breast cancer [abstract]. In: Proceedings of the AACR Special Conference: Advances in Breast Cancer Research; 2017 Oct 7-10; Hollywood, CA. Philadelphia (PA): AACR; Mol Cancer Res 2018;16(8_Suppl):Abstract nr A43.
Abstract A50: Modeling and targeting of oncogenic proteotoxic stress in drug-resistant breast cancer
Authors: Singh Navneet , Modur Vishnu , Muhammad Belal , Komurov Kakajan 
Published: August 2018

Abstract
ERBB2/HER2-positive breast cancers are associated with poor prognosis, and resistance to HER2-targeted therapy (trastuzumab and lapatinib) presents a significant clinical hurdle. There are no treatment options for metastatic HER2+ BCs that have progressed on HER2-targeted therapy. At present, most of the research on therapeutic strategies in therapy-refractory Her2+ BCs focuses on resensitizing tumor cells to HER2-targeting agents. We have shown that targeting of nononcogenic vulnerabilities, specifically adaptive proteotoxic stress response, is a promising therapeutic approach in this subset of BCs (Singh N. et al, HER2-mTOR signaling-driven breast cancer cells require ER-associated degradation to survive. Science Signaling 2015). We showed that Her2+ BCs have specific dependence on the endoplasmic reticulum (ER)-associated degradation (ERAD) pathway to suppress the hyperactive Her2/mTOR pathway-driven proteotoxic stress. Here, we explore the kinetics of protein homeostatic changes during the course of Her2-targeted drug therapy, and identify optimal therapeutic windows for the targeting of ERAD in the therapy-refractory Her2+ BCs.
Using an integrated systems approach, we have modeled the dynamics of signaling and protein homeostasis changes in Her2+ cells during remission, resistance, and relapse phases of Her2-targeted therapy. We found that the resistance and relapse phases of anti-Her2 drug (lapatinib and trastuzumab) treatment are associated with Her2-independent acquisition of mTOR signaling, as previously reported. However, these signaling pathway changes also resulted in heightened proteotoxic burden on the ER due to increased protein synthesis rates, which was further exacerbated upon the release of cells from anti-Her2 treatment. Accordingly, cells in the relapse phase, and even more so upon further drug withdrawal, showed significantly heightened sensitivity to the inhibition of ERAD. This study reveals the kinetics of protein homeostasis associated with the signaling pathway changes during acquired resistance to anti-Her2 therapy, and suggests optimal therapeutic windows for the targeting of ERAD in therapy-refractory Her2+ BCs.
Citation Format: Navneet Singh, Vishnu Modur, Belal Muhammad, Kakajan Komurov. Modeling and targeting of oncogenic proteotoxic stress in drug-resistant breast cancer [abstract]. In: Proceedings of the AACR Special Conference: Advances in Breast Cancer Research; 2017 Oct 7-10; Hollywood, CA. Philadelphia (PA): AACR; Mol Cancer Res 2018;16(8_Suppl):Abstract nr A50.
Abstract A61: BRCA1-associated R-loop accumulation at noncoding putative ERα enhancer area blocks luminal epithelial differentiation
Authors: Chiang Huai-Chin , Zhang Xiaowen , Hu Yanfen , Li Rong 
Published: August 2018

Abstract
Most BRCA1-associated breast tumors are basal-like, yet originate from luminal progenitor cells. BRCA1 is best known for its functions in double-strand break (DSB) repair and resolution of DNA replication stress. However, it is unclear whether loss of these ubiquitously important functions of BRCA1 fully explains the cell lineage-specific increase in breast tumor development. By sorting and profiling lineage-specific cells from precancerous human breast tissue, we found that BRCA1 mutation carriers tend to have a luminal cell-specific accumulation of R-loop, a transcriptional byproduct of DNA-RNA hybrid structure important for transcriptional regulation and genomic instability. R-loops accumulate preferentially at enhancers and transcription start sites (TSS) of luminal fate-related genes. Using CRISPR-Cas9 system, we have deleted an ERα enhancer area with BRCA1-associated R-loops accumulation in MCF7 cells. The deletion of this noncoding putative ERα enhancer area reduced the gene expression level of the neighboring genes of the deleted region, including ERα, RMND1, and CCDC170. In addition, compare to the reduced expression level of ERα, RMND1, and CCDC170 in BRCA1 knockdown of the parental MCF7, knocking down BRCA1 in these deletion clones showed less reduction of these genes. On the other hand, overexpression of RNASEH1, an enzyme that specifically removes R-loop, had little effect in these genes after BRCA1 knockdown. These results indicate BRCA1-associated R-loop accumulation at least partially affects luminal gene transcription. To investigate whether BRCA1-assocaited R-loop accumulation directly contributes to luminal differentiation blockage, we overexpressed RNASEH1 in breast epithelial cells freshly isolated from BRCA1 mutation carriers; flow cytometry comparing different breast lineage revealed a luminal population shift toward more mature luminal. All in all, the results imply that BRCA1 promotes luminal epithelial differentiation by alleviating R-loop accumulation at enhancer of ERα. Aberration in luminal transcription could contribute to lineage-specific BRCA1-associated tumorigenesis.
Citation Format: Huai-Chin Chiang, Xiaowen Zhang, Yanfen Hu, Rong Li. BRCA1-associated R-loop accumulation at noncoding putative ERα enhancer area blocks luminal epithelial differentiation [abstract]. In: Proceedings of the AACR Special Conference: Advances in Breast Cancer Research; 2017 Oct 7-10; Hollywood, CA. Philadelphia (PA): AACR; Mol Cancer Res 2018;16(8_Suppl):Abstract nr A61.
Abstract B26: Thermally abused frying oil enhances metastatic progression in vivo and in vitro: A link to elevated fumarate levels
Authors: Hughes Jennifer R. , Joyce Kaitlyn M. , Cam Anthony , Helferich William G. , Madak-Erdogan Zeynep 
Published: August 2018

Abstract
For the past four decades, dietary fat intake has composed a significant portion of the typical Western diet, at 33-35% of total kilocalories. Approximately 8% of this dietary fat is from consumption of deep fat fried foods. Oil has been demonstrated to be absorbed by food during frying and contributes between 8 to 40% of the food’s final weight. As oils are used and reused for frying, complex chemical reactions take place creating deleterious polar compounds (e.g., acrylamide, sterol derivatives, or other reactive oxidative species.) Although these compounds are associated with health risks, i.e., heart disease, diabetes mellitus, and cancer, there is no regulation in the United States for upper limits of polar material in frying oil. This raises an important question as to whether thermally abused fryer oil (TAFO) can alter metastatic breast cancer progression. We initially conducted an in vivo study in which a modest amount of dietary fat, 25% of kilocalories, came from fresh fryer oil or TAFO. Ovariectomized BALB/C mice fed the diet containing TAFO for 16 weeks and inoculated with luciferase-expressing 4T1 murine mammary cancer cells had significantly more metastasis to lungs than control-fed animals (p &lt; 0.05, n=21). Serum metabolic analysis in these animals revealed significantly elevated levels of fumarate, a known onco-metabolite, in TAFO-fed compared with control-fed animals (p &lt; 0.05, n=9). To confirm that fumarate was mechanistically involved in metastatic progression, we conducted in vitro studies. 4T1 cells exposed to 500 nM to 10 µM monomethyl fumarate (MMF), a cell-permeable form of fumarate, trended toward an increase in the healing rate over 24 hours in a wound healing (scratch) assay compared to control (n =2). This preliminary evidence supports the hypothesis that fumarate accumulation creates a protumorigenic and metastatic environment and needs confirmation in subsequent investigation. This information can help elucidate mechanistic details of the effects of TAFO on breast cancer metastasis. Further work will assess rates of 4T1 cellular proliferation and invasion induced by MMF. In summary, dietary intake of TAFO increased metastasis of tumor cells to lungs, and dysregulation of the metabolite fumarate may be mechanistically involved.
Citation Format: Jennifer R. Hughes, Kaitlyn M. Joyce, Anthony Cam, William G. Helferich, Zeynep Madak-Erdogan. Thermally abused frying oil enhances metastatic progression in vivo and in vitro: A link to elevated fumarate levels [abstract]. In: Proceedings of the AACR Special Conference: Advances in Breast Cancer Research; 2017 Oct 7-10; Hollywood, CA. Philadelphia (PA): AACR; Mol Cancer Res 2018;16(8_Suppl):Abstract nr B26.
Abstract B35: Palbociclib treatment activates FAK and use of palbociclib in combination with the FAK inhibitor PF-562,271 enhances antitumor activity in ER-positive breast cancer cells
Authors: Howe Grant , Allen Victoria , Addison Christina L. 
Published: August 2018

Abstract
Cell survival and proliferation is tightly regulated by a number of interacting coordinated signaling proteins including the cyclin-dependent kinases (CDK). Palbociclib, a CDK4/6 inhibitor, has recently been shown to be very effective in the treatment of estrogen receptor (ER) positive breast cancer; however, many patients develop an acquired resistance through as yet incompletely characterized mechanisms. One recently proposed mechanism is compensation by CDK2 (Herrera-Abreu et al., Can Res 2016;76:2301). Focal adhesion kinase (FAK) is a tyrosine kinase that plays a central role in signaling pathway crosstalk and cell survival and invasion. FAK has been previously shown to activate CDK2 in hepatocytes (Flinder et al., J Cell Phys 2013;228:1304), and given its important role in mediating cell survival, we were interested in determining whether FAK-mediated upregulation of CDK2 occurs in palbociclib-treated breast cancer cells, thereby limiting its efficacy. ER-positive MCF7, MDA-MB-134VI, and T47D breast cancer cell lines were thus treated with increasing doses of palbociclib. We observed dose-dependent increases in phospho-FAK Y397, a marker of the active kinase, following palbociclib treatment. We thus used PF-562,271, a selective FAK tyrosine kinase inhibitor, in combination with palbociclib and, not surprisingly, observed an enhanced ability to inhibit cell viability as compared to use of either drug alone. This was concomitant with observed increases in the CDK4/6 inhibitor p27, and with decreases in phospho-RB, which are indicative of reduced CDK2 activity, following treatment with PF-562,271. Our results highlight an unexpected side effect of palbociclib treatment, namely FAK activation, which could potentially contribute to resistance due to activation of CDK2 and inhibition of p27. The mechanism by which palbociclib activates FAK is currently under investigation.
Citation Format: Grant Howe, Victoria Allen, Christina L. Addison. Palbociclib treatment activates FAK and use of palbociclib in combination with the FAK inhibitor PF-562,271 enhances antitumor activity in ER-positive breast cancer cells [abstract]. In: Proceedings of the AACR Special Conference: Advances in Breast Cancer Research; 2017 Oct 7-10; Hollywood, CA. Philadelphia (PA): AACR; Mol Cancer Res 2018;16(8_Suppl):Abstract nr B35.
Abstract B45: Studying the interactome of breast cancer: The cancer cell map initiative
Authors: Kim Minkyu , Kim Kyumin , Soucheray Margaret , Swaney Danielle , Krogan Nevan 
Published: August 2018

Abstract
Recent progress in genome sequencing has revealed numerous mutations in cancer genomes, but how many of these alterations result in changes in normal cellular processes is poorly understood. In addition, the biologic functions of the majority of genes (e.g., BRCA1/2) with cancer-associated mutations have not been fully characterized, despite their expression and/or activity being highly correlated with cancer. Through years of study, it is becoming clear that cancer is a disease that arises not only because of defects in individual genes and proteins, but also because of the action of hallmark cellular processes and biologic pathways. Therefore, what is urgently needed is to put the cancer genomic information into biologic context by mapping mutated genes onto the complexes and pathways in which they function. The goal of this study is to uncover the comprehensive protein-protein interaction networks and pathways in various breast cancer subtypes to better understand how mutated cancer genes and genomes hijack and rewire pathways and complexes during the course of breast tumorigenesis. Here we catalog protein-protein interactions for more than 40 genes recurrently mutated in breast cancer, using affinity purification and mass spectrometry (AP-MS). Our interaction network reveals subtype and mutation-specific protein-protein interactions, most of which are not previously reported. We anticipate the breast cancer interactome study will uncover many previously unidentified aberrant pathways and protein complexes uniquely operating in breast cancer cells, and thus pinpoint proteins central in these pathways and complexes that may potentially serve as distinct biomarkers or therapeutic targets for tumors having the same or similar subtypes and/or genomic mutations.
Citation Format: Minkyu Kim, Kyumin Kim, Margaret Soucheray, Danielle Swaney, Nevan Krogan. Studying the interactome of breast cancer: The cancer cell map initiative [abstract]. In: Proceedings of the AACR Special Conference: Advances in Breast Cancer Research; 2017 Oct 7-10; Hollywood, CA. Philadelphia (PA): AACR; Mol Cancer Res 2018;16(8_Suppl):Abstract nr B45.