bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract P3-01-02: Trends in positive predictive values following transition from screen film to digital mammography
Authors: Motiuk DA , Dahl P , Roy E , Docktor B-J , Burrowes P 
Published: March 2017

Abstract
Purpose
Our health region converted from screen-film mammography (SFM) to digital mammography (DM) in 2005. DM has several advantages over SFM, including superior contrast resolution, less noise, and opportunities for image optimization through post-acquisition processing; although, the spatial resolution of DM is inferior to SFM. We sought to determine what effect this transition may have had on positive predictive values (PPVs) for malignant and premalignant lesions.
Methods
From our institution's breast biopsy database, we retrospectively reviewed core biopsy results for mammographic calcifications performed in the years 2001-2004 (SFM years) and 2009-2012 (DM years). We subsequently determined the PPV3 (detection of malignancy after biopsy) for each group of years (SFM and DM). We then performed subgroup analysis to calculate PPVs for each of ductal carcinoma in-situ (DCIS) without invasion, DCIS with invasion, and premalignant lesions. Premalignant lesions included atypical ductal hyperplasia, atypical lobular hyperplasia, and lobular carcinoma in-situ.
Results
A total of 4787 biopsies in 4633 patients were reviewed. The comparative detection of cancer after biopsy performed for mammographic calcification between SFM and DM was not statistically significant (PPV3 = 23.5% and 24.0%, respectively; P=.71). Upon further analysis, however, PPV for premalignant lesions increased (SFM=6.6% and DM=8.9%; P&lt;.01) and PPV for DCIS without invasion increased (SFM=15.5% and DM=18.2%; P=.015), while PPV for DCIS with invasion decreased (SFM=8.0% and DM=5.8%; P&lt;.01).
Conclusion
We observed no significant impact on PPV3 for calcifications following the transition from SFM to DM; however, our subgroup analysis suggests that with digital mammography we are now detecting a statistically significantly lower proportion of DCIS with invasion but greater proportions of DCIS without invasion and premalignant lesions. As the natural history of these lower-grade lesions, particularly in the premalignant category, is still not entirely understood, the significance of potentially detecting more of these earlier cancers/precancers is uncertain.
Citation Format: Motiuk DA, Dahl P, Roy E, Docktor B-J, Burrowes P. Trends in positive predictive values following transition from screen film to digital mammography [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P3-01-02.
Abstract P3-04-05: Identification of SAR439859, an orally bioavailable selective estrogen receptor degrader (SERD) that has strong antitumor activity in wild-type and mutant ER+ breast cancer models
Authors: Shomali M , Cheng J , Koundinya M , Weinstein M , Malkova N , Sun F , Hebert A , Cindachao M , Hoffman D , McManus J , Levit M , Pollard J , Vincent S , Besret L , Adrian F , Winter C , El-Ahmad Y , Halley F , Hsu K , Lager J , Garcia-Echeverria C , Bouaboula M 
Published: March 2017

Abstract
Estrogen receptor positive (ER+) breast cancer accounts for 70% of all breast cancers and is primarily treated with endocrine therapy. Approximately 40% of patients on endocrine therapy will become resistant via a number of mechanisms. There is evidence that in many cases ER continues to play a central role, including mutations in ER leading to a constitutively active receptor. Estrogen receptor degraders like fulvestrant are effective in shutting down ER signaling; however, poor pharmaceutical properties limit fulvestrant clinical activity and prevent it from achieving maximum receptor blockade.
We describe the discovery of SAR439859, a novel, orally bioavailable SERD that is a potent antagonist and degrader of ER both in vitro and in vivo. SAR439859 has robust activity in multiple ER+ breast cancer cell lines including cells that are resistant to tamoxifen as well as cell lines harboring ER mutants. Across a large panel of ER+ cells, SAR439859 demonstrated broad and superior ER degradation activity than most SERDs undergoing clinical testing. This leads to a profound inhibition of ER signaling, better inhibition of cell growth and results in improved in vivo efficacy. SAR439859 demonstrated tumor regression in all ER+ BC models including MCF7-ESR1 mutant-Y537S model, as well as patient-derived xenograft model that is resistant to endocrine therapies. Furthermore, SAR439859 displays limited cross-resistance with other class of SERDs.
Taken together, these results suggest that SAR439859 would be of therapeutic benefit in metastatic BC setting for patients harboring wild type or mutant ER. SAR439859 is being advanced toward the clinic.
Citation Format: Shomali M, Cheng J, Koundinya M, Weinstein M, Malkova N, Sun F, Hebert A, Cindachao M, Hoffman D, McManus J, Levit M, Pollard J, Vincent S, Besret L, Adrian F, Winter C, El-Ahmad Y, Halley F, Hsu K, Lager J, Garcia-Echeverria C, Bouaboula M. Identification of SAR439859, an orally bioavailable selective estrogen receptor degrader (SERD) that has strong antitumor activity in wild-type and mutant ER+ breast cancer models [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P3-04-05.
Abstract P3-04-23: Combination therapy of targeted anticancer pathways and estrogen receptor ligands and their responses in de novo andtamoxifen resistant cell models
Authors: Gutgesell LM , Xiong R , Thatcher GRJ , Tonetti DA 
Published: March 2017

Abstract
Approximately 75% of breast cancers are classified as Estrogen Receptor positive (ER+). Tamoxifen, a selective estrogen receptor modulator (SERM), is the standard of care for many of these ER+ breast cancer patients. Unfortunately, tamoxifen resistance occurs in almost 50% of patients within 5 years of treatment, and endocrine-independence accompanying resistance also negates the effects of aromatase inhibitors. Combination therapy is increasingly used in non-cytotoxic therapeutic approaches in many types of cancer. The potential exists that endocrine resistance can be lessened, eliminated, or overcome through targeted therapy in combination with endocrine therapy. Inhibition of kinase signaling (e.g. via CDK4/6 or PI3K) and other pathways (e.g. HSP90) are expected to be effective in combination with endocrine therapy. We have discovered a variety of ER ligands with potential as endocrine therapeutic agents, based upon a single chemical scaffold with a diverse set of pharmacological responses: including SERMs, selective ER downregulators (SERDs), selective estrogen mimics (SEMs), and selective human ER partial agonists (ShERPAs). To predict which agents in combination with these endocrine-targeted ligands would be of potential therapeutic benefit it was necessary to develop 3D spheroidal cultures of ER+ breast cancer cell lines: including endocrine-dependent lines; and cell lines made endocrine-independent either by extended exposure to tamoxifen or extended deprivation of estradiol. In contrast to 2D cultures, drug response in 3D spheroidal cell cultures was predictive of response to treatment in mouse xenograft studies. Growth of endocrine-dependent cell lines was, as expected, inhibited by SERDs; and endocrine-independent, tamoxifen-resistant cell lines were also sensitive to SERD treatment, although one cell line was largely resistant. Growth of all three tamoxifen-resistant cell lines was inhibited by SEMs/ShERPAs. Importantly, regardless of the type of endocrine therapeutic agent studied, concentrations leading to saturation of the target (ER) did not cause cell death. Equally, all endocrine therapies studied benefited from combination treatment with other agents, leading to enhanced cell death.
Citation Format: Gutgesell LM, Xiong R, Thatcher GRJ, Tonetti DA. Combination therapy of targeted anticancer pathways and estrogen receptor ligands and their responses in de novo andtamoxifen resistant cell models [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P3-04-23.
Abstract P3-04-27: Delineating novel molecular pathways driving endocrine resistance in breast cancer
Authors: Bosch A , Staaf J , Akrap N , Kaminska KK , Borgquist S , Borg Å , Honeth G 
Published: March 2017

Abstract
Background
Estrogen receptor (ER) is a main driver of tumor progression in ER+ metastatic breast cancer (MBC). The use of endocrine therapy can effectively control the disease in a large proportion of patients. However, the majority of MBC eventually become resistant and progress. To elucidate the mechanisms of acquired resistance to endocrine treatment is key in order to better select therapeutic partners and delay disease progression.
Methods
A panel of ER+ breast cancer cell lines initially sensitive to the selective estrogen receptor degrader (SERD) fulvestrant was exposed to increasing concentrations of this drug over several months to induce resistance. Cell proliferation was determined with the xCELLigence system. Protein expression was measured by phospho-kinase array and western blotting. RNA expression was evaluated by gene expression microarray analysis (Illumina) and validated by RT-qPCR. Cell cycle distribution was analyzed by flow cytometry.
Results
Using an unbiased approach to identify pathways that drive endocrine resistance, both the parental and the resistant cell models were studied. As expected, fulvestrant treatment resulted in G1-cell cycle arrest in the parental cell lines.
In stark contrast, resistant cells bypassed fulvestrant-induced proliferation block despite a lower expression of genes driving mitotic progression compared to untreated parental cells. This gene expression pattern was coupled with a reduction of ER protein level in the resistant cells, which was in line with a significant decrease in the expression of ER-target genes. Our phospho-screen analysis showed a genotype specific down-modulation of p53 and up-regulation of several signaling components of mitogenic pathways in resistant cells compared to parental cells.
Conclusions
Our results suggest that acquired endocrine resistance is driven by multiple cell-specific mechanisms rather than a common molecular underpinning. Strikingly, there is one unique feature in our models, which is a cellular switch towards an ER-independent gene expression program. Ongoing in vitro and in vivo studies, aimed at further characterizing these cellular models, will provide valuable insights into the heterogeneity underlying the response to endocrine treatment observed in MBC patients.
Citation Format: Bosch A, Staaf J, Akrap N, Kaminska KK, Borgquist S, Borg Å, Honeth G. Delineating novel molecular pathways driving endocrine resistance in breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P3-04-27.
Abstract P3-06-08: HDAC6 deacetylates HMGN2 to regulate Stat5a activity and breast cancer growth
Authors: Clevenger CV , Craig JM , Fiorillo AA , Feeney YB , Harrell JC , Medler TR 
Published: March 2017

Abstract
Stat5 is a transcription factor utilized by several cytokine/hormone receptor signaling pathways that promotes transcription of genes associated with proliferation, differentiation, and survival of cancer cells. However, there are currently no clinically approved therapies that target Stat5, despite ample evidence that it contributes to breast cancer pathogenesis. Previous research in our lab has shown that the high mobility group nucleosome binding domain 2 (HGMN2) protein serves as a Stat5 co-activator. The activity of HMGN2 has been previously shown to be regulated by acetylation. Here, we show that deacetylation of HMGN2 on lysine residue K2 by histone deacetylase 6 (HDAC6) promotes Stat5-mediated transcription and breast cancer growth. Conversely, in vitro HDAC6 inhibition by pharmacologic and knock-down approaches enhanced HMGN2 acetylation with a concomitant reduction of in vitro Stat5-mediated signaling and global gene expression, and breast cancer growth. In vitro and in vivo treatment of traditional and patient-derived xenograft models with HDAC6 inhibitors resulted in a highly significant reduction of tumor growth. Translationally, it was also found that high levels of acetylated K2 were present in normal human breast tissue, which was lost in primary breast cancers and lymph node metastases. This suggests that blockade of HMGN2 deacetylation as described above is a novel treatment for breast cancer, given that existing HDAC6 inhibitors have a favorable toxicity profile in Phase I trials of other tumor types. Altogether, these results reveal a novel mechanism through which HDAC6 regulates the transcription of Stat5 target genes and demonstrates the utility of HDAC6 inhibition as a potential breast cancer therapeutic.
Citation Format: Clevenger CV, Craig JM, Fiorillo AA, Feeney YB, Harrell JC, Medler TR. HDAC6 deacetylates HMGN2 to regulate Stat5a activity and breast cancer growth [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P3-06-08.
Abstract P3-06-09: Selection of presumed CD49f antagonists and their biological evaluation in breast cancer cells
Authors: Velasco-Velázquez M , Velázquez-Quesada I , Aguirre-Alvarado C , Guerrero-Rodríguez S , Ruiz-Moreno A , Ramirez-Salinas G , Segura-Cabrera A , Pérez-Tapia M 
Published: March 2017

Abstract
Breast cancer is the second cause of cancer death in women and the large majority of those deaths are due to drug resistance and/or recurrence. The cancer stem cell (CSC) model suggests that tumor stem-like cells play key roles in resistance and recurrence in breast cancer patients. Thus, CSCs have been pointed as targets for new anti-cancer therapies. CD49f is an integrin subunit that participates in the CSC-niche interaction. Knock-down of CD49f in breast cancer cells impairs mammosphere formation in vitro and tumorigenesis in vivo, suggesting that this protein is needed for maintenance of stemness.
Aiming to target breast CSC, we used consensus docking to select potential CD49f antagonists from a collection of 13,000+ drugs with previous clinical evaluations. Seven compounds with the lowest consensus Z score were selected for in vitro biological validation. Cell adhesion assays showed that four of the selected drugs (5193, 1382, 7631, and 12723) decrease the binding of CD49f+ MDA-MB-231 breast cancer cells to laminin, suggesting that those compounds antagonize the receptor. Mammosphere formation assays showed that compounds 5193, 1382, and 12723 limit the clonogenic capability of CD49f+ breast cancer cells in vitro. Compound 5193 was highly toxic in 2D cell viability assays. On the other hand, the clonogenic impairment produced by compounds 1382 and 12723 is independent of bulk cell line cytotoxicity, suggesting a direct impact on the CSC pool. The analyses of the effect of these drugs on the expression of breast CSC markers and CD49f-activated pathways are on their way.
Thus, we have identified some drugs that might be repurposed to target breast CSC. Since the pharmacokinetics and toxicology of those drugs is known, they could easily be ready for clinical trials. We demonstrated that in silico screening is useful to identify antagonists of receptors with relevant roles in breast CSC biology.
This work was supported by CONACYT 221105, PAPIIT-UNAM IN228616, and Red temática de células troncales y medicina regenerativa.
Citation Format: Velasco-Velázquez M, Velázquez-Quesada I, Aguirre-Alvarado C, Guerrero-Rodríguez S, Ruiz-Moreno A, Ramirez-Salinas G, Segura-Cabrera A, Pérez-Tapia M. Selection of presumed CD49f antagonists and their biological evaluation in breast cancer cells [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P3-06-09.
Abstract P3-07-16: ZBTB2 is a novel therapeutic target for cisplatin-resistance in metastatic breast cancer
Authors: Shin V , Siu MT , Cheuk I , Ho J , Chen J , Kwong A 
Published: March 2017

Abstract
Background: Zinc finger and BTB/POZ domain containing proteins (ZBTB) belong to a class of DNA-binding proteins that involved in development, differentiation and carcinogenesis. Our earlier findings showed that ZBTB2 expression was upregulated in cisplatin-resistant cells when compared with naïve cells. Increase in ZBTB2 expression was associated with ABCG2 drug transporter in drug resistance. However, the molecular mechanism of ZBTB2 in drug resistance and breast cancer metastasis remain largely unclear.
Methods: A cisplatin-resistant triple-negative breast cancer (TNBC) cell line, MDA-MB-231/cis, was used to examine the involvement of drug transporter genes and the drug resistance pathway. Stem cell related genes were studied by RNA-sequencing. Characterization of ZBTB2 on cell proliferation, invasion and epithelial-mesenchymal transition (EMT) process were performed in ZBTB2 siRNA transfected cells. Stem-like cells properties were validated using aldehyde dehydrogenase (ALDH) activity, tumorsphere formation ability and stem cell markers. Metastatic animal model was used to study the genetic changes during metastasis and associated with the findings in clinical samples.
Results: ZBTB2 has a higher expression in TNBC than other breast cancer subtypes. Also, the ZBTB2 expression is more prominent in primary breast tumor tissues when compared with non-tumor counterparts from TNBC patients. Silencing of ZBTB2 significantly reduced cell proliferation, invasion and sensitized cells to cisplatin through induction of apoptosis. Induction of ZBTB2 has been associated with breast cancer metastasis in mice model, where higher expression was seen in metastatic tumors when compared with primary tumors from tumor xenografts. ABCG2 and some epithelial-mesenchymal transition (EMT) markers (Twist 1, Snai2 and MMP-9) have been increased in metastatic tumors. Further, RNA sequencing analysis showed that ABCG2, IL6ST and FGFR1 were upregulated in MDA-MB-231/cis cells and downregulated in ZBTB2 siRNA transfected cells. Silencing of ZBTB2 reduced ALDH activity and tumorsphere formation ability. Treatment with inhibitor of NFkB (Bay11-7085) further decreased cell proliferation in cisplatin-resistant cells when compared with siZBTB2 alone. Expression of Stat3 and b-catenin were reduced upon knockdown of ZBTB2.
Conclusion: Taken together, silencing of ZBTB2 sensitize cancer cells to cisplatin through regulation of EMT markers and stem-like cell properties in TNBC. These findings suggest a novel molecular pathway targeting ZBTB2/stat3/NFkB signaling to combat drug resistance in metastatic TNBC.
Citation Format: Shin V, Siu MT, Cheuk I, Ho J, Chen J, Kwong A. ZBTB2 is a novel therapeutic target for cisplatin-resistance in metastatic breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P3-07-16.
Abstract P3-07-17: Squalene epoxidase is a potential metabolic oncogene by amplification with clinical implications in breast carcinoma: An in silico pan-cancer study with i
n vitro evidence
Authors: Zoppoli G , Brown D , Caffa I , Garuti A , Piras D , Gallo M , Isnaldi E , Nencioni A , Ballestrero A 
Published: March 2017

Abstract
This abstract was withdrawn by the authors.
Abstract P3-07-19: Dual inhibition of the MEK5 and PI3K pathways synergistically reduces proliferation and viability in triple negative breast cancer cells
Authors: Wright TD , Raybuck C , Wendekier K , Cavanaugh JE 
Published: March 2017

Abstract
Aberrations in the MAPK/extracellular signal-regulated kinase (MEK/ERK) and phosphoinositide-3-kinase (PI3K) pathways have been linked to increased proliferation and survival in triple negative breast cancer (TNBC) cells. It has been proposed that these survival characteristics are enhanced through compensatory signaling and crosstalk mechanisms. Promising combinations of MEK and PI3K inhibition have been evaluated in phase I clinical trials for various cancer types. However, these clinical trials have had limited efficacy and have yet to encompass the MEK5/ERK5 pathway, which has been shown to promote cell survival. The goal of this study was to examine the crosstalk between the MEK1/2, MEK5, and PI3K pathways and determine the most promising combination of the MEK1/2, ERK5, and PI3K inhibitors, U0126, XMD8-92, and LY294002, respectively, in a diverse panel of triple negative breast cancer cell lines: BT549, MDA-MB-231, and MDA-MB-468. Our results indicate that dual inhibition of the MEK5 and PI3K pathways significantly reduced proliferation (45.53%) in MDA-MB-231 TNBC cells. Also, the combination of MEK5 and PI3K inhibition was shown to be synergistic. In contrast, inhibition of ERK1/2 alone or in combination with PI3K or ERK5 inhibition yielded mixed responses. Additionally, treatment with LY294004 in MDA-MB-231 (ERK 5 KO) was more potent (IC50= 2.5 uM) than treatment in the native MDA-MB-231 cell line (IC50= 13.7 uM). These data suggest that crosstalk between these kinases occurs and dual inhibition of PI3K and ERK5 may be a novel therapeutic approach for treating TNBC.
Citation Format: Wright TD, Raybuck C, Wendekier K, Cavanaugh JE. Dual inhibition of the MEK5 and PI3K pathways synergistically reduces proliferation and viability in triple negative breast cancer cells [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P3-07-19.