bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract P6-20-10: Role of GPR110 in breast cancer
Authors: Bhat R , Qin L , De Angelis C , Sahay D , Bhargava D , Creighton C , Yadav P , Yazdanfard S , Alrawi A , Yadav V , Vasaikar S , Nanda S , Sethunath V , Fu X , Zhang B , Narkar V , Schiff R , Trivedi M 
Published: May 2019

Abstract
Our long-term goal is to discover adhesion GPCR targets in breast cancer. Our previous studies have found GPR110 to be overexpressed in tumorigenic cell population as well as in anti-HER2 drug-resistant derivatives of HER2+ breast cancer cells. In subsequent studies, we found that GPR110 knockdown inhibited anchorage-independent cell growth, mammosphere formation, and invasion/migration of HER2+ breast cancer cells. Conversely, overexpression of GPR110 by lentiviral delivery of cDNA enhanced anchorage-independent cell growth, mammosphere formation, and invasion/migration in HER2+ breast cancer cells. In addition, GPR110 overexpression led to increase in the % of Aldefluor-positive tumorigenic cell population, further emphasizing the role of GPR110 as a mediator of tumorigenesis in addition to the metastatic processes in HER2+ breast cancer. Among various subtypes of breast cancer, GPR110 expression was higher in HER2+ and basal subtypes, most of which are triple-negative (negative for ER, PR, and HER2), compared to luminal A and B subtypes. GPR110 was either gene amplified or upregulated in 4% of all breast cancers based on the publicly available TCGA dataset. GPR110 overexpression predicted poorer recurrence-free survival in triple-negative breast cancer. Furthermore, GPR110 was overexpressed in brain metastatic lesions compared to mammary tumors in patient-derived xenograft models of triple-negative breast cancer (WHIM2 and WHIM30). Knocking down GPR110 reduced anchorage-dependent and -independent cell growth, mammosphere formation, and invasion/migration of triple-negative breast cancer cells. Overall, our results suggest that GPR110 may be a potential drug target in HER2+ and triple-negative breast cancer. Drug discovery efforts to identify GPR110 antagonists will provide useful pharmacological tools for validating GPR110 as a drug target in breast cancer. Since GPR110 is also overexpressed in various other types of cancer, understanding the mechanism of GPR110 upregulation and signaling in cancer is an important future direction.
This work was supported by the Department of Defense Grants W81XWH-14-1-0340 and W81XWH-14-1-0341 to Drs. Trivedi and Schiff, respectively.
Citation Format: Bhat R, Qin L, De Angelis C, Sahay D, Bhargava D, Creighton C, Yadav P, Yazdanfard S, Alrawi A, Yadav V, Vasaikar S, Nanda S, Sethunath V, Fu X, Zhang B, Narkar V, Schiff R, Trivedi M. Role of GPR110 in breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-20-10.
Abstract P6-20-12: FGFR1β is a driver isoform of FGFR1 alternative splicing in breast cancer cells
Authors: Zhao M , Zhuo M-L , Zheng X , Su X , Meric-Bernstam F 
Published: May 2019

Abstract
Background:Abnormal FGFR1 alternative splicing is correlated with tumorigenicity and poor prognosis in several tumor types. We sought to determine the roles of FGFR1α and FGFR1β variants in breast cancer. Methods: TCGA breast cancer samples and cell lines were analyzed for FGFR1α and FGFR1β expression. MCF-10A cells were used to overexpress these variants. Cell growth was assessed by SRB and colony formation assays. Cell transformation was assessed by 3D-Matrigel, soft agar, cell motility assays. Cell survival assay was used to determine drug IC50. Results: In the TCGA, compared to FGFR1 non-amplified samples, FGFR1-amplified samples had significantly higher FGFR1α, but not FGR1β levels. FGFR1β expression levels and FGFR1β/FGFR1α ratio were higher in basal subtype samples than in luminal samples in both the TCGA and in a panel of breast cancer cell lines. Both FGFR1α and FGFR1b induced transformation of MCF-10A cells. However, only FGFR1β-expressing cells, not FGFR1α, enhanced cell growth, cell motility, and FGFR signaling. Cells with higher FGFR1β levels and FGFR1β/FGFR1α ratio were more sensitive to FGFR inhibitor BGJ-398. Interestingly, in ER-negative cells, BGJ-398 decreased FGFR1β levels, likely by increasing expression of splicing repressor PTBP1. In ER-positive cells, estrogen treatment increased FGFR1β levels by decreasing PTBP1 expression, which was blocked by 4-OHT. Lastly, combination treatment with BGJ-398 and 4-OHT synergistically inhibited cell survival. Conclusions: These findings suggest that FGFR1 alternative splicing plays an important role in breast cancer, where FGFR1β functions as a driver isoform. Further work is needed to assess FGFR1β prognostic and predictive role.
Citation Format: Zhao M, Zhuo M-L, Zheng X, Su X, Meric-Bernstam F. FGFR1β is a driver isoform of FGFR1 alternative splicing in breast cancer cells [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-20-12.
Abstract PD1-07: Withdrawn
Authors: Howell SJ , Waters S , Twelves C , Joffe J , Moon S , Bale C , Venkitaraman R , Bezecny P , Casbard A , Wilhelm-Benartzi C , Carucci M , Butler R , Alchami F , Jones R 
Published: May 2019

Abstract
This abstract was withdrawn by the authors.
Citation Format: Howell SJ, Waters S, Twelves C, Joffe J, Moon S, Bale C, Venkitaraman R, Bezecny P, Casbard A, Wilhelm-Benartzi C, Carucci M, Butler R, Alchami F, Jones R. Withdrawn [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr PD1-07.
Abstract PD4-02: Withdrawn
Authors: Wong MJ , Patel R , DeMartini WB , Todderud JE , Okamoto S , Ikeda DM 
Published: May 2019

Abstract
This abstract was withdrawn by the authors.
Citation Format: Wong MJ, Patel R, DeMartini WB, Todderud JE, Okamoto S, Ikeda DM. Withdrawn [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr PD4-02.
Abstract PD4-06: A clinical model for assessing the individual breast cancer risk in mammography screening
Authors: Eriksson M , Czene K , Pawitan Y , Hall P 
Published: May 2019

Abstract
Background. Mammography screening reduces breast cancer mortality, but is suboptimal for the breast cancers that are not detected by the screening. These women are identified as symptomatic interval cancers with more aggressive tumors and worse pronosis. To efficiently screen for breast cancer the individual breast cancer risk should be determined. We describe a model that is suited for bi-annual screening programs and estimates the 2-year risk of breast cancer. The risk model could be used at most mammography screening units without adding substantial cost.
Methods. The study was based on the population based prospective KARMA cohort including 70,877 participants. Mammograms were collected up to five years following baseline mammogram. A prediction model was developed using mammographic features (density, microcalcifications and masses), use of hormone replacement therapy (HRT), family history of breast cancer, menopausal status, and body mass index. Relative risks were calculated using conditional logistic regression and 2-year absolute risks were calculated
Results. Comparing women at highest and lowest mammographic density yielded a 5-fold higher risk of breast cancer for women at highest density. When adding microcalcifications and masses to the model, high-risk women had a nearly 9-fold higher risk of breast cancer compared to those at lowest risk. In the full model, taking HRT use, family history of breast cancer and menopausal status into consideration, area under the curve (AUC) reached 0.73.
We calculated the absolute 2-year risk of breast cancer based on national incidence and mortality rates. We also stratified women into risk groups using the NICE guidelines adapted to 2-year risks. The 20% women with moderate or high breast cancer risk were 7.6 times more likely to develop breast cancer compared to the general risk. Also 18% of the women showed 4 times reduced risk compared to the average population.
Conclusions. This risk model can improve mammography screening by identifying women that are in need of additional examination procedures. There is also a substantial proportion of women with low breast cancer risk who will have little benefit from screening.
Citation Format: Eriksson M, Czene K, Pawitan Y, Hall P. A clinical model for assessing the individual breast cancer risk in mammography screening [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr PD4-06.
Abstract PD4-08: Relationship between FDG-uptake and expression level of PD-L1 in primary ER positive/HER2 negative breast cancer
Authors: Hirakata T , Fijii T , Kaira K , Kurozumi S , Katayama A , Yajima R , Obayashi S , NaKazawa Y , Tokuda S , Yanai K , Shirabe K 
Published: May 2019

Abstract
Background: 18F-Fluorodeoxyglucose-positron emission tomography (FDG-PET) is used to evaluate the glucose metabolic rates of cancers. Several studies have reported that high FDG uptake is predictive of poor prognosis and aggressive features in patients with breast cancer (BC). FDG-uptake is influenced by many factors including inflammation. In this study, we investigated the relationship between FDG uptake and immunological factors, including degrees of stromal tumor-infiltrating lymphocytes (TILs), CD8 and programmed cell death ligand 1 (PD-L1) in ER positive/HER2 negative (ER+/HER2-) BC. No published study, to our knowledge, has assessed the association between FDG uptake and PD-L1 in BC cases, even though both represent prognosis. Methods: Invasive carcinoma tissues of 79 ER+/HER2- BC patients who underwent surgery without preoperative therapy were examined. PD-L1, CD8 and TILs expression were evaluated by immunohistochemically (IHC) method. The evaluation of PET was determined by standardized uptake value max (SUVmax). Multivariate linear regression analysis, including expression of PD-L1, CD8 and TILs, was performed to identify independent variable correlation with SUVmax. Results: Among the 79 ER+/HER2- BC (T1-4, N0-2, M0) patients, the analysis revealed that PD-L1 (P=0.005), lymphovascular invasion (P=0.011), large tumor size (p=0.001), lymph node meatstasis (P=0.010), and high nuclear grade (P=0.011) and premenopasal status (P=0.014) were significantly associated with high SUVmax in the primary tumor. To define predictive value for the expression of PD-L1, SUVmax cut offwas determined using receiver operating characteristic (ROC) analysis; low (&lt;3.0) and high (≥3.0). Among the 30 cases with high SUVmax, 10 cases (33.3%) had PD-L1 positive expression in the primary tumor, while only 2 (4.1%) of the 49 cases with low SUVmax had PD-L1 positive expression in the primary tumor. Conclusions: The present study demonstrated that the finding of preoperative FDG uptake is associated with the expression of PD-L1 in ER+/HER2- BC. In light of our results, FDG uptake may be predictive of the expression of PD-L1 and may be reflective of immunological features as well as prognostic features among patients with ER+/HER2- BC.
Citation Format: Hirakata T, Fijii T, Kaira K, Kurozumi S, Katayama A, Yajima R, Obayashi S, NaKazawa Y, Tokuda S, Yanai K, Shirabe K. Relationship between FDG-uptake and expression level of PD-L1 in primary ER positive/HER2 negative breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr PD4-08.
Abstract PD6-05: Withdrawn
Authors: Kehm RD , Phillips K-A , Daly MB , Andrulis IL , Liao Y , Ma X , Zeinomar N , MacInnis RJ , Dite GS , John EM , Buys SS , Milne RL , Hopper JL , Terry MB 
Published: May 2019

Abstract
This abstract was withdrawn by the authors.
Citation Format: Kehm RD, Phillips K-A, Daly MB, Andrulis IL, Liao Y, Ma X, Zeinomar N, MacInnis RJ, Dite GS, John EM, Buys SS, Milne RL, Hopper JL, Terry MB. Withdrawn [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr PD6-05.
Abstract TS2-2: Clinical development of inhibitors of the PI3K pathway
Authors: Saura Manich C 
Published: May 2019

Abstract
The activation of the PI3K-AKT-mTOR pathway as a mechanism of resistance to different breast cancer treatments has been well described for years at the preclinical level. This observation, together with the high frequency of alterations of this pathway in patients with breast tumors (especially in the luminal subtype such as PI3KCA mutations, loss of PTEN function or AKT mutations) makes this pathway a highly desirable in inhibiting the growth of these tumor types.
The first clinical evidence that inhibition of the PI3K-AKT-mTOR pathway leads to increased progression-free survival in metastatic breast cancer came from the BOLERO-2 trial with the mTORC1-targeting agent everolimus, the only PI3K-AKT-mTOR pathway inhibitor approved to date in breast cancer. Potentially better drugs have subsequently been developed and tested. PI3K inhibitors were designed to potentiate the inhibition of the pathway to optimize treatment efficacy and improve the toxicity profile.
The first to be developed were the pan-PI3K inhibitors buparlisib and pictilisib. Results from pivotal clinical studies combining fulvestrant demonstrated increased efficacy but at the cost of increased toxicity that was considered clinically unacceptable. None of them consequently eceived approval for breast cancer treatment. It was hoped that Isoform-specific PI3K inhibitors (alpha or beta-sparing) would improve the toxicity profile and increase efficacy, especially in patients with molecular alterations in the PI3K-AKT-mTOR pathway. We are now witnessing interesting times for these drugs since we have seen the results of the two phase III studies with specific pathway inhibitors, taselisib and alpelisib. During this session we will carefully review the results of both studies in terms of efficacy and toxicity profile as well as those from other phase I-II clinical trials with these and other agents.
Representing the main challenges in the future, we still have to determine the best strategy to select those patients who will likely derive greater benefit from these therapies as well as establish the context in which they are most effective, taking into account the mechanisms of resistance that PI3K inhibitors can overcome or those that emerge during treatment with these drugs.
Citation Format: Saura Manich C. Clinical development of inhibitors of the PI3K pathway [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr TS2-2.
Abstract A05: Targeting the EMT-immunosuppression loop in lung cancer as a strategy to prevent metastasis
Authors: Chen Limo , Lou Yanyan , Heymach John , Wistuba Ignacio , Ullrich Stephen , Qin Xiao-Feng , Gibbons Don 
Published: May 2019

Abstract
This abstract is being presented as a short talk in the scientific program. A full abstract is printed in the Proffered Abstracts section (PR01) of the Conference Proceedings.
Citation Format: Limo Chen, Yanyan Lou, John Heymach, Ignacio Wistuba, Stephen Ullrich, Xiao-Feng Qin, Don Gibbons. Targeting the EMT-immunosuppression loop in lung cancer as a strategy to prevent metastasis. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Metastasis; 2015 Nov 30-Dec 3; Austin, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(7 Suppl):Abstract nr A05.
Abstract A13: Macrophage FLT1 mediated inflammatory response determines breast cancer distal metastasis
Authors: Qian Bin-Zhi , Zhang Hui , Li Jiufeng , Yeo Eun-Jin , Carragher Neil O. , Bresnick Anne R. , Lang Richard A. , Pollard Jeffrey W. 
Published: May 2019

Abstract
Macrophages are abundantly found in the tumor microenvironment and enhance malignancy. At distal metastatic sites, our previous studies identified a distinct population of metastasis associated macrophages (MAMs) that promotes tumor cell extravasation, seeding and persistent growth. These macrophages were derived from circulating inflammatory monocytes recruited by CCL2/CCR2 chemokine signaling and directly promote tumor cell extravasation and metastatic seeding in vivo through VEGF production. Our recent studies identified that MAMs express high levels of cell surface FMS-like tyrosine kinase 1 (FLT1, also known as VEGFR1) after their recruitment. Blockade of FLT1 signaling using specific inhibitory antibodies significantly inhibited the metastatic seeding and persistent growth. Using several genetic models of Flt1 deficiency, we show that macrophage specific FLT1 signaling is critical for breast tumor distal metastatic potential. FLT1 is not expressed by other hematopoietic cells and its inhibition did not affect the recruitment of MAMs, which indicated that specific FLT1 signaling in MAMs are important for their metastasis promoting functions. Indeed, we identified that FLT1 regulates a set of inflammatory response genes including Colony Stimulating Factor 1 (CSF1) a central regulator of macrophage biology. Using a genetic gain-of-function approach we show that CSF1 mediated autocrine signaling in MAMs is downstream of FLT1 and can restore the tumor-promoting activity in MAMs even when FLT1 has been inhibited. Together, our data established a link between inflammation and cancer metastasis and suggested the therapeutic potential of targeting these pathways in treating metastatic disease.
Citation Format: Bin-Zhi Qian, Hui Zhang, Jiufeng Li, Eun-Jin Yeo, Neil O. Carragher, Anne R. Bresnick, Richard A. Lang, Jeffrey W. Pollard. Macrophage FLT1 mediated inflammatory response determines breast cancer distal metastasis. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Metastasis; 2015 Nov 30-Dec 3; Austin, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(7 Suppl):Abstract nr A13.
Abstract A15: SMC2 role in regulating tumor angiogenesis via FGF signaling
Authors: Sharif Ghada M. , Schmidt Marcel O. , Shuptrine Casey , Louis Weiner M. , Riegel Anna T. , Wellstein Anton 
Published: May 2019

Abstract
Fibroblast growth factors (FGFs) play a crucial role during embryonic development, tissue homeostasis, wound healing and angiogenesis. FGF-binding protein 1 (FGFBP1) is a secreted protein that binds FGFs stored in the extracellular matrix and transports them to their receptor, therefore they can modulate FGF signaling. FGFBP1 contributes to the progression of many cancers including colon, pancreas and squamous cell cancer. It acts as an angiogenic switch during tumor development. E0771 cells, a murine mammary carcinoma cell line, was subcutaneously injected into syngeneic C57BL/6 mice. While these cells form aggressive tumors within two weeks and metastasize to the lungs in wild type FGFBP1 (FGFBP1+/+) mice, there was no tumor growth or metastasis in FGFBP1 knock out (FGFBP1-/-) mice. A genome-wide shRNA library screen revealed a novel role for structural maintenance of the chromosome 2 (SMC2) in compensating for the loss of FGFBP1 in the stroma of FGFBP1-/- mice. E0771 cells with SMC2 knock down (KD) or CRISPR targeting SMC2 formed aggressive tumors in FGFBP1-/- mice and metastasized to the lungs. Surprisingly, FGFBP1 expression level was 32 folds lower in SMC2 KD E0771 cells yet FGF2 was 16 folds up in the tumors from SMC2 KD E0771 cells. Tumor histology shows impaired and leaky angiogenesis in FGFBP1-/- compared to FGFBP1+/+ mice. Furthermore, higher levels of GM-CSF and G-CSF were detected in the conditioned media (CM) of SMC2 KD E0771 cells compared to control cells suggesting differential immune cell recruitment. Also, an endothelial monolayer exposed to CM from SMC2 KD E0771 cells showed delayed wound closure and loose junctions suggesting a tendency for endothelium disintegration and initiation of blood vessel formation. Interestingly, the CM effect was blocked using PD173074, a pan FGFR inhibitor. In conclusion, SMC2 demonstrate a role in regulating FGF signaling which affects the course of angiogenesis during tumor development.
Note: This abstract was not presented at the conference.
Citation Format: Ghada M. Sharif, Marcel O. Schmidt, Casey Shuptrine, Weiner M. Louis, Anna T. Riegel, Anton Wellstein. SMC2 role in regulating tumor angiogenesis via FGF signaling. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Metastasis; 2015 Nov 30-Dec 3; Austin, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(7 Suppl):Abstract nr A15.
Abstract A29: Gram-negative bacterial infection enhances the potential of gastric adenocarcinoma peritoneal metastasis via TNFR1 dependent manner
Authors: Alzahrani Malak , Giannias Betty , Bourdeau France , Kayano Rafael , Ferri Lorenzo 
Published: May 2019

Abstract
Adenocarcinoma of the proximal stomach is the fastest rising malignancy in North America, and is associated with a high rate of recurrence to the peritoneum. As part of cancer treatment, the majority of patients undergo at least one invasive surgical procedure. Recent clinical data has linked postoperative infection complications with adverse oncologic outcomes; however, the underlying mechanisms are unclear. Emerging evidence suggests that the release of TNFa, a key inflammatory cytokine during infection facilitates cancer progression. The role and mechanisms the gram-negative bacterial infections play in facilitating the metastatic potential of gastric cancer to the peritoneum is entirely unknown. We hypothesized that incubation of gastric cancer cells and MC with heat-inactivated E. Coli or LPS can augment gastric cancer cell adhesion and invasion via TNFR1 signaling and increase the potential of peritoneal metastasis. Incubation of human gastric cancer cells or/and MC with heat inactivated E. coli, LPS or TNFa significantly increased in vitro adhesion 3-4 folds to MC and enhanced in vitro invasion. These enhanced cell adhesion and invasion phenotypes following incubation with LPS or E. coli were attenuated at three levels: inhibition of TLR4 (Eritoran), inhibition of TNFR1 (anti-TNFR1/isotype control antibodies) or p38 MAPK inhibitor (BIRB0796). TNFa treatment also increases CD54, CD44 and CD29 expression on cancer cells and MC. To further validate in vitro results, a novel ex-vivo murine peritoneal metastasis model is developed. We report that ex vivo gastric cancer cells adhesion to murine peritoneum is augmented by overnight LPS, E. Coli and TNFa treatments and this effect was abrogated when TNFR1-/- mouse peritoneum is used or in the presence of TNFR1 monoclonal or isotype control antibodies. These findings implicate TNFa in the process of gastric cancer metastasis to peritoneum in the context of systemic infection and identify TNFa as potential therapeutic targets.
Citation Format: Malak Alzahrani, Betty Giannias, France Bourdeau, Rafael Kayano, Lorenzo Ferri. Gram-negative bacterial infection enhances the potential of gastric adenocarcinoma peritoneal metastasis via TNFR1 dependent manner. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Metastasis; 2015 Nov 30-Dec 3; Austin, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(7 Suppl):Abstract nr A29.