bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract BS3-1: Dominance of mitochondria in determining the malignant phenotype
Authors: Kaipparettu BA 
Published: May 2016

Abstract
Mitochondria are semiautonomous organelles within cells that play an important role in cellular energy metabolism, free radical generation, and apoptosis. Mitochondria contain their own genome (mtDNA), which encodes a number of proteins critical for energy metabolism, particularly in oxidative phosphorylation. They are also the major source of generating reactive oxygen species (ROS) in the cell. Advances in cancer metabolism research over the last decade have enhanced and modified our understanding on Warburg effect. It is now known that mitochondria in tumors are not always defective in their ability to carry out oxidative phosphorylation. Instead, in proliferating cells, mitochondrial energy pathways are reprogrammed to meet the challenges of macromolecular synthesis and to escape from apoptosis. Mitochondrial retrograde regulation (MRR) is a bidirectional communication between mitochondria and nucleus. MRR is triggered by mitochondrial functional demands and it responds in a continuous manner to the changing metabolic needs of the cell. At present, it is not clear whether mitochondrial genomic status or metabolomic reprogramming affect nuclear genome stability. Also, limited evidence is available on the significance of proteins involved in the inter-genomic cross talk in the regulation of tumorigenesis. Transmitochondrial cybrids (cybrids) are a great utility for the study of the functional effects of mitochondria in a defined nuclear background. Cybrids are constructed by fusing enucleated cells harboring mitochondria of interest with ρ0 cells (mtDNA-depleted cells). Our approach of discovering mitochondria regulated pathways using cybrid models and their in vitro and in vivo validation in different breast cancer cell lines and patient derived xenograft models suggest that mitochondrial metabolic character and retrograde signaling are playing important roles in oncogenic transformation and metastasis. Importantly, mitochondria-nuclear crosstalk is critical in the regulation of some of the major cancer pathways. Compared to hormone regulated/responsive breast cancers, triple negative breast cancer patients suffer from worse overall survival, significantly shorter disease-free and post-recurrence survival. Due to the lack of known oncogenic drivers for triple negative breast cancer, clinical benefit from currently available targeted therapies is limited, and new therapeutic strategies are urgently needed. Thus, understanding MRR and mitochondria mediated oncogenic signature is critical in understanding the currently limited known etiology and treatment resistance of certain subgroups of cancers like the triple negative breast cancer.
Citation Format: Kaipparettu BA. Dominance of mitochondria in determining the malignant phenotype. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr BS3-1.
Abstract ES2-3: Metabolic asymmetry in breast cancer: Implications for personlised medicine
Authors: Lisanti MP 
Published: May 2016

Abstract
Over the last decade, strong evidence has accumulated that the tumor micro-environment plays a key role in recurrence, metastasis and poor clinical outcome in breast cancer patients. In this context, more recent discoveries indicate that catabolic cancer-associated fibroblasts (CAFs) produce nutrients (lactate, ketone bodies and glutamine) to fuel anabolic mitochondrial metabolism in cancer cells. This new paradigm is known as metabolic-symbiosis or metabolic asymmetry and reflects the co-existence of multiple metabolic compartments in a given tumor. This type of metabolic co-operation in the tumor ecosystem underlies the metabolic heterogeneity found in human breast cancers, and can be used to more effectively predict tumor recurrence, metastasis, drug-resistance and poor clinical outcome, in breast cancer patients.
In my talk, I will highlight how this metabolic-symbiosis phenotype could be targeted from a therapeutic point of view, bringing us closer to the goal of personalized medicine.
For further information on this topic, please see the following references:
Caveolae and signalling in cancer.
Martinez-Outschoorn UE, Sotgia F, Lisanti MP.
Nat Rev Cancer. 2015 Apr;15(4):225-37.
Metabolic asymmetry in cancer: A balancing act that promotes tumor growth.
Martinez-Outschoorn UE, Sotgia F, Lisanti MP.
Cancer Cell. 2014 Jul 14;26(1):5-7.
Power surge: Supporting cells fuel cancer cell mitochondria.
Martinez-Outschoorn UE, Sotgia F, Lisanti MP.
Cell Metab. 2012 Jan 4;15(1):4-5.
Citation Format: Lisanti MP. Metabolic asymmetry in breast cancer: Implications for personlised medicine. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr ES2-3.
Abstract ES4-1: Longitudinal strategies in ER+ disease
Authors: Dickler M 
Published: May 2016

Abstract
Endocrine therapy is a relatively well-tolerated treatment for hormone receptor-positive (HR+) breast cancer. This therapy can be offered as first-line treatment before initiation of chemotherapy in patients with manageable symptoms from their disease and no evidence of clinically significant compromise of visceral organ function. Targeting the estrogen receptor pathway with agents such as the aromatase inhibitors, tamoxifen and fulvestrant can provide effective therapy with a durable response to treatment for some patients. This presentation will review clinical trial data to guide choice of endocrine therapy and the sequential use of these agents in patients with endocrine-responsive disease. Within HR+ breast cancer, there is molecular diversity that can influence responsiveness to endocrine therapy. In addition, recent insight into the complex interactions between the estrogen receptor and cell cycle survival and/or growth factor signalling pathways have uncovered potential mechanisms of endocrine therapy resistance in HR+ breast cancer. This improved understanding has led to new options for treatment. We will review the clinical trial evidence that supports the addition of a cell cycle inhibitor, palbociclib, to first-line letrozole and second-line fulvestrant. We will also review evidence supporting the combination of an mTOR inhibitor, everolimus, to second- or third-line exemestane. These targeted agents increase progression-free survival when added to endocrine therapy, however at the present time, there is no benefit in overall survival. With this limitation in mind, we will review the side effects of these agents, weigh the toxicity and potential benefits, and examine if patient and/or tumor-based factors may help to determine which patients are best suited for these agents. Lastly, we will discuss the subset of patients with bone-only HR+ disease, and the complexities of assessing imaging and their response to therapy.
Citation Format: Dickler M. Longitudinal strategies in ER+ disease. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr ES4-1.
Abstract ES5-2: Circulating tumor DNA analysis for liquid biopsies: Current status and future opportunities
Authors: Diehn M 
Published: May 2016

Abstract
Circulating tumor DNA (ctDNA) represents a promising biomarker for sensitive, specific, and dynamic detection of disease burden in cancer patients. Additionally, ctDNA analysis allows non-invasive access to cancer genomes and therefore can be used for non-invasive tumor genotyping and monitoring of resistance mutations. In this presentation I will describe technical aspects of ctDNA detection and emerging clinical results from recent studies employing ctDNA analysis.
Citation Format: Diehn M. Circulating tumor DNA analysis for liquid biopsies: Current status and future opportunities. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr ES5-2.
Abstract OT1-03-09: FAIRLANE: A phase II randomized, double-blind, study of the Akt inhibitor ipatasertib (Ipat, GDC-0068) in combination with paclitaxel (Pac) as neoadjuvant treatment for early stage triple-negative breast cancer (TNBC)
Authors: Saura C , Isakoff SJ , Calvo I , Patt D , Andersen J , Gonzalez-Martin A , Fisher J , Ciruelos E , Gil-Gil M , De la Peña L , Choi Y , Jia S , Singel S , Patel PH , Baselga J , Oliveira M 
Published: May 2016

Abstract
Background: TNBC often exhibits activation of PI3K/Akt signaling, associated with loss of PTEN expression, low INPP4B expression, and/or increased AKT3 amplification. Inhibition of the PI3K/Akt pathway in diverse cancers leads to radiosensitization and/or chemosensitization. Ipat is an oral, potent ATP-competitive small molecule inhibitor of all three isoforms of Akt. The combination of ipat with taxanes in preclinical models resulted in enhanced efficacy relative to either ipat or chemotherapy alone. In a Phase Ib clinical study, the combination of ipat with diverse chemotherapy regimens was well-tolerated and resulted in RECIST responses, particularly pts with tumors having PI3K/Akt activation.
Methods: FAIRLANE is a randomized, double-blind, placebo controlled, multicenter, neoadjuvant Phase II study designed to estimate the efficacy of ipat combined with pac versus placebo combined with pac in women with Stage Ia  IIIa TNBC. Approximately 150 pts (Pts) will be enrolled, randomized in a 1:1 ratio, and stratified by PTEN status, node involvement, and tumor size. Pts will receive 3 cycles of ipat 400 mg or placebo orally once daily on Days 1 to 21 of each 28-day cycle, along with pac 80 mg/m2 every 7 days for a total of 12 doses. All pts will undergo pretreatment and Day 8 tumor tissue acquisition to evaluate pathway biomarkers. Following three cycles of treatment, pts will undergo surgery. The primary efficacy endpoint, pCR within the breast and axilla (ypT0/Tis ypN0) in all pts and in pts with PTEN low tumors, will be assessed by local pathology evaluation following completion of neoadjuvant therapy and surgery. Additional endpoints include objective response rate, safety, BCS rate, pharmacokinetics, and pathway biomarkers. Following surgical resection of primary tumor, pts are expected to continue post-operative treatment with a standard adjuvant chemotherapy regimen at physician's discretion. The study is open for accrual. Clinical trial information: NCT02301988.
Citation Format: Saura C, Isakoff SJ, Calvo I, Patt D, Andersen J, Gonzalez-Martin A, Fisher J, Ciruelos E, Gil-Gil M, De la Peña L, Choi Y, Jia S, Singel S, Patel PH, Baselga J, Oliveira M. FAIRLANE: A phase II randomized, double-blind, study of the Akt inhibitor ipatasertib (Ipat, GDC-0068) in combination with paclitaxel (Pac) as neoadjuvant treatment for early stage triple-negative breast cancer (TNBC). [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr OT1-03-09.
Abstract OT3-02-01: Randomized phase II study of Hangeshashinto (TJ-14) for chemotherapy induced oral mucositis in patients with breast cancer (Hangesha-B study)
Authors: Iwamoto M , Umezaki N , Matsuda J , Kawaguchi K , Terasawa R , Sato N , Fyjioka H , Kimura K , Tanaka S , Uchiyama K 
Published: May 2016

Abstract
Background: Oral mucositis is a common complication of systemic chemotherapy for cancer, and is associated with higher risk of infection, pain, chemotherapy dose reduction. Severe mucositis impairs oral function and seriously affects nutrition and quality of life of the patients.
Hangeshashinto (TJ-14) is a traditional Japanese herbal (Kampo) medicine reduces the level of prostaglandin E2 and affects the cyclooxygenase activity, and alleviates chemotherapy induced oral mucositis. We conducted a randomized phase II trial to investigate whether Hangeshashinto (TJ-14) prevents or controls chemotherapy induced oral mucositis.
Patients and Methods: Patients who develop moderate to severe chemotherapy induced oral mucositis (WHO grade&gt;1) during any cycle of chemotherapy are randomly assigned to receive either Hangeshashinto (TJ-14) (n=25) or placebo (n=25). Patients receive the administration of Hangeshashinto (TJ-14) or placebo for 3 weeks at the beginning of the next course of chemotherapy. The patients are advised to dissolve 2.5g of Hangeshashinto (TJ-14) or placebo in 50ml drinking water, and divide it into twice or three times in an oral cavity. Patients rinse their oral cavity with it three times daily. The signs of oral mucositis is assessed by the investigator during the screening cycle. The CTCAE v4.0 grading is used to assess the severity of oral mucositis. The primary endpoint is duration time of oral mucositis, and secondary endpoints include incidence of oral mucositis, incidence of diarrhea, blood levels of CRP, The change of body weight, and blood levels of albumin.
Accrual: This study began in June 2015. The expected end of accrual of 50 patients will be the last quarter 2017.
Citation Format: Iwamoto M, Umezaki N, Matsuda J, Kawaguchi K, Terasawa R, Sato N, Fyjioka H, Kimura K, Tanaka S, Uchiyama K. Randomized phase II study of Hangeshashinto (TJ-14) for chemotherapy induced oral mucositis in patients with breast cancer (Hangesha-B study). [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr OT3-02-01.
Abstract P1-03-06: Leptin as a mediator of tumor-stromal interactions promotes breast cancer stem cell activity
Authors: Giordano C , Panza S , Chemi F , Barone I , Bonofiglio D , Cordella A , Hashim A , Györffy B , Simões BM , Clarke RB , Weisz A , Catalano S , Andò S 
Published: May 2016

Abstract
Breast cancer stem cells (BCSCs) play crucial roles in tumor initiation, metastasis and resistance to anticancer therapies. These cells rely for their properties on complex interactions with the tumor microenvironment through networks of cytokines and growth factors. In this study, we investigated how leptin, as a mediator of tumor-stromal interactions, may affect BCSC activity using breast cancer cell lines and patient-derived samples. We found that conditioned media (CM) from cancer associated fibroblasts and breast adipocytes significantly increase mammosphere formation in breast cancer cells. Depletion of leptin from stromal cell-CM as well as inhibition of leptin signaling by using a full leptin receptor antagonist peptide LDFI completely abrogated this effect. Accordingly, mammosphere cultures exhibited increased leptin receptor expression and leptin exposure enhanced mammosphere formation. Microarray analyses revealed a similar expression profile of genes involved in stem cell biology in mammosphere cells treated with stromal cell-CM and leptin. Interestingly, leptin is able to increase the mammosphere formation in metastatic breast cancer cells isolated from patients (n = 10) and this can be blocked by using peptide LDFI. In addition, leptin receptor (OBR) mRNA expression, analyzed in cells from metastatic fluids, directly correlated with mammosphere formation activity ex vivo (r=0.68, p= 0.05; n = 8). Finally, Kaplan–Meier survival curves indicated that OBR expression correlated with reduced overall survival in breast carcinomas (HR=1.9, p=0.022). Together, our results suggest that leptin/leptin receptor may represent a potential therapeutic target that can block the stromal-tumor interactions that drive BCSC-mediated disease progression.
Citation Format: Giordano C, Panza S, Chemi F, Barone I, Bonofiglio D, Cordella A, Hashim A, Györffy B, Simões BM, Clarke RB, Weisz A, Catalano S, Andò S. Leptin as a mediator of tumor-stromal interactions promotes breast cancer stem cell activity. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P1-03-06.
Abstract P1-03-08: Tartrate-resistant acid phosphatase (TRAcP) dependent polarization of breast cancer-promoting macrophages
Authors: Dai M-S , Janckila A , Lo H-C , Wu C-C , Chao T-Y , Yu J-C 
Published: May 2016

Abstract
Background:
Breast cancer associated macrophages often promote tumor growth and metastasis by conditioning the tumor microenvironment and suppressing adaptive immune responses. Tartrate-resistant acid phosphatase (TRACP) is a novel serum biomarker associated with systemic macrophage burden in a variety of chronic inflammatory diseases and is strongly expressed by tumor-associated macrophages. We tested the hypothesis that TRACP is required for M2 macrophage polarization.
Methods:
Macrophage cell lines were polarized in vitro and tested for TRACP, iNOS and Arg-1 expression and their ability to promote or repress breast cancer cell growth and invasion in vitro and in vivo. A novel TRACP deficient, Acp5 mutant mouse was used as a macrophage source and as a breast cancer host to confirm a role for TRACP for macrophages to support cancer growth.
Results:
TRACP was up-regulated in concert with M2 polarization and down-regulated in M1 polarized cells. TRACP expression correlated with macrophage promotion of tumor growth and invasion in vitro. Although TRACP-deficient macrophages could be induced to express Arg-1 when stimulated with IL-4 plus IL-13 (M2 phenotype), the TRACP deficient macrophages behaved like M1 cells suppressing tumor growth and invasion compared to than WT cells. Tumor xenografts grew slower in primary subcutaneous grafts and metastasized less extensively in intravenous grafts in TRACP deficient mice compared to WT. Furthermore, the tumor metastatic patterns could be reversed in WT animals by co-grafting TRACP-deficient macrophages and in TRACP deficient hosts by co-grafting WT macrophages.
Conclusions:
TRACP expression is normally a phenotypic marker for alternatively activated macrophages, but not necessary for expression of Arg-1. In a host environment of TRACP deficiency, Arg-1 positive macrophages can be generated by cytokine stimulation in vitro and by tumor in vivo, however, TRACP deficiency still conveyed a tumor suppressive phenotype in cell based studies and in intact animals. TRACP plays a role in functional polarization of M2 macrophages and their ability to promote breast cancer growth and metastasis.
Citation Format: Dai M-S, Janckila A, Lo H-C, Wu C-C, Chao T-Y, Yu J-C. Tartrate-resistant acid phosphatase (TRAcP) dependent polarization of breast cancer-promoting macrophages. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P1-03-08.
Abstract P1-04-01: Breast milk exosomes promote breast cancer progression
Authors: Sauter ER , Qin W , Dasgupta S 
Published: May 2016

Abstract
Background: The stimulation of extant neoplastic cells vs. their inhibition during breast involution is a key concept in whether pregnancy and lactation decrease or increase breast cancer risk. The time of weaning, a period of breast involution and remodeling, appears critical to future breast cancer risk, as during involution the breast microenvironment becomes tumor promotional. Both matrix metalloproteinases (MMPs) and transforming growth factor (TGF)β isoforms have been implicated in this process. We previously reported that TGFβ2 (but not TGFβ1) expression was significantly higher in milk collected from the cancer containing (vs. matched clinically normal) breast of women diagnosed with cancer during lactation.
Hypothesis: TGFβ2 in milk exosomes from healthy lactating women modulates the development and progression of breast cancer.
Methods: Matched (early, mature and wean-early involution) milk samples were collected from 13 lactating women, exosomes isolated and the levels of five (MMP2, 3, 9; TGFβ1, 2) proteins measured. Based on the results, additional wean samples were analyzed for TGFβ2 expression and samples divided based on their TGFβ2 expression. The highest and lowest TGFβ2 expressing milk exosome samples were co-cultured with MCF-7 breast cancer cells grown in exosome-depleted media. Cell proliferation was measured after 24h. Confocal microscopy was performed after 72h to evaluate epithelial to mesenchymal transition (EMT) in the cells. A TGFβ2 neutralizing blocking antibody was applied after 72 h co-culture.
Results: The greatest increase in expression (four-fold) at the time of involution was in TGFβ2. Confocal microscopy performed 24h after co-culture confirmed the uptake of the exosomes (both those expressing hi and lo TGFβ2) in the MCF-7 cells. There was a significant increase in cell proliferation compared to control (p&lt;0.001) in cells treated with hi TGFβ2 milk exosomes. 72h after co-culture, bright field microscopy demonstrated that MCF-7 cells treated with hi TGFβ2 underwent EMT including the formation of filopodia, whereas those treated with low TGFβ2 did not. A TGFβ2 blocking antibody reversed the EMT phenotype and filopodia formation.
Impact: Pregnancy has a lasting influence on breast cancer risk, and pregnancy associated breast cancers (PABCs) diagnosed after delivery are generally aggressive, with a poor prognosis. Part of the reason for the development of PABCs, and the aggressive nature of PABCs may be the influence of high-expressing TGFβ2 exosomes in the milk on the breast ductal epithelium.
Citation Format: Sauter ER, Qin W, Dasgupta S. Breast milk exosomes promote breast cancer progression. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P1-04-01.
Abstract P1-05-02: The N-terminus of Twist1 is responsible for interacting with transcriptional repressors to promote EMT and metastasis of breast cancer cells
Authors: Yu X , He T , Xu J 
Published: May 2016

Abstract
Twist1, a basic helix-loop-helix transcription factor, plays a key role to mediate epithelial-mesenchymal transition (EMT) and promote breast cancer metastasis. However, knowledge about Twist1 structure-function relationships to cancer-related phenotypes is limited. Therefore, we studied the requirement of Twist1 N-terminus in Twist1-dependent breast cancer metastasis. We showed that the amino-terminus of Twist1 was the dominant negative mutant of Twist1. Overexpression of Twist1 N-terminus exhibited different cell morphology and motility in vitro. Inoculation of Twist1 N-terminus overexpression cells into SCID mice showed delayed tumor formation and reduced lung metastasis. Furthermore, Twist1 N-terminus overexpression induced expression change of EMT markers, including E-cadherin, β-catenin, vimentin and Twist1 both in vivo and in vitro. Co-immunoprecipitation and mass spectrometry revealed that Twist1 N-terminus interacted with several members of the Mi2/nucleosome remodeling and deacetylase (Mi2/NuRD) complex, HDAC2, 3 and 7, MTA1 and 2, RbAp46/48, and many corepressors including NCoR1 and 2, which released them from the proximal region of E-cadherin promoter for transcriptional activation. These data suggest that Twist1 N-terminus is required for Twist1-mediated transcriptional programs and breast cancer metastasis.
Citation Format: Yu X, He T, Xu J. The N-terminus of Twist1 is responsible for interacting with transcriptional repressors to promote EMT and metastasis of breast cancer cells. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P1-05-02.