bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract P3-02-12: CAV1, MCT1, and MCT4 expression in ductal carcinoma in situ of the breast and its association with clinicopathologic features
Authors: Lee Ji Shin , Kim Nah Ihm , Park Min Ho 
Published: March 2020

Abstract
Background: Multicompartment tumor metabolism and metabolic coupling are markers of aggressive tumor behavior, clinically manifested as disease recurrence and progression. Loss of caveolin-1(CAV1) in stromal cells and upregulation of monocarboxylate transporters (MCTs), especially MCT1 and MCT4, in both stromal and cancer cells have been identified as playing an important role in the metabolic coupling necessary for release and uptake of metabolites. However, this phenomenon has only scarcely been described in ductal carcinoma in situ (DCIS) of the breast. The purpose of this study was to investigate the role of CAV1, MCT1, and MCT4 in DCIS carcinogenesis and its association with clinicopathologic factors.
Materials and methods: CAV1, MCT1, and MCT4 expression was examined in 9 pairs of DCIS tissues and matched normal adjacent tissues at mRNA and protein levels by qRT-PCR, RNAscope in situ hybridization (ISH) and immunohistochemistry. Immunohistochemical staining of CAV1, MCT1, and MCT4 was done in 79 DCIS samples with known hormone receptor (HR) and human epidermal growth factor 2 (HER2) expression using tissue microarray.
Results: CAV1 mRNA expression by qRT-PCR analysis was significantly decreased in DCIS tissues compared to their corresponding normal tissues. On the other hand, MCT1 and MCT4 mRNA expression in DCIS tissues were increased compared with corresponding normal tissues and the difference was statistically significant in MCT1. Compared with their corresponding normal tissues, DCIS tissues showed decreased stromal CAV1 mRNA and protein expression and increased epithelial MCT1 and MCT4 mRNA and protein expression by ISH and immunohistochemistry. Low stromal CAV1, high epithelial MCT1, and high epithelial MCT4 expressions were observed in 29 (36.7%), 51 (64.6%) and 15 (18.9%) cases with DCIS, respectively. Low stromal CAV1 expression was significantly associated with high nuclear grade (P &lt; 0.05). High epithelial MCT4 expression was associated with larger tumor size and HER2 positivity (P &lt; 0.05 and P &lt; 0.05, respectively). Although not statistically significant, low stromal CAV1 and high epithelial MCT4 expression tended to be associated with recurrence of DCIS. No associations were observed between stromal CAV1 expression and epithelial MCT 1 or MCT4 expression.
Conclusions: These results suggested that changes in CAV1, MCT1, and MCT4 are associated with carcinogenesis of DCIS, and further studies are needed for their clinical usefulness.
Keywords: Ductal carcinoma in situ; CAV1; MCT1; MCT4; Metabolism
Citation Format: Ji Shin Lee, Nah Ihm Kim, Min Ho Park. CAV1, MCT1, and MCT4 expression in ductal carcinoma in situ of the breast and its association with clinicopathologic features [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-02-12.
Abstract P3-02-15: Integrin a2 promotes stemness and lung metastasis in triple negative breast cancer
Authors: Adorno-Cruz Valery , Hoffmann Andrew , Liu Xia , Keri Ruth , Liu Huiping 
Published: March 2020

Abstract
Accumulating evidence demonstrates that cancer plasticity and stem cell properties (stemness) drive both tumorigenesis and metastasis, and how to eliminate metastasis remains one of the biggest challenges in the clinic. Here we report that the integrin receptor CD49b-encoding ITGA2 is an oncogenic target of miR-206 regulating cancer stemness and metastasis through pathways linked to lipid metabolism and cell cycle regulation in metastatic triple negative breast cancer (TNBC). ITGA2 knockdown suppressed self-renewal related mammosphere formation and pluripotency marker expression, inhibited cell cycling, compromised migration and invasion, and therefore decreased lung metastasis of TNBC. RNA sequencing analyses revealed that ITGA2 knockdown inhibits newly identified pathways such as lipid metabolism and protein kinase activity. ACLY-encoded ATP citrate lyase is one of the top targets in CD49b promoting lipid biosynthesis and self-renewal of breast cancer cells. Overexpression of CCND1 rescues the phenotype of ITGA2 knockdown-induced cell cycle arrest. High expression levels of the ITGA2/ACLY/CCND1 axis are associated with an unfavorable relapse-free survival of patients with high grade breast cancer, in both basal-like and other subtypes. This study identifies ITGA2 as a potential therapeutic target of TNBC stemness, metabolism, and metastasis.
Citation Format: Valery Adorno-Cruz, Andrew Hoffmann, Xia Liu, Ruth Keri, Huiping Liu. Integrin a2 promotes stemness and lung metastasis in triple negative breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-02-15.
Abstract P3-03-01: Double PIK3CA mutations in cis drive oncogene addiction and enhance sensitivity to PI3K alpha inhibitors in breast cancer
Authors: Vasan Neil , Razavi Pedram , Johnson Jared L , Shao Hong , Wilson Timothy , Schimmoller Frauke , Shah Hardik , Antoine Alesia , Ladewig Erik , Gorelick Alexander , Lin Ting-Yu , Toska Eneda , Xu Guotai , Kazmi Abiha , Chang Matthew T , Taylor Barry S. , Dickler Maura N. , Jhaveri Komal , Chandarlapaty Sarat , Rabadan Raul , Reznik Ed , Smith Melissa L , Sebra Robert , Friedman Lori , Cantley Lewis C , Scaltriti Maurizio , Baselga José 
Published: March 2020

Abstract
Activating mutations in PIK3CA, the gene coding for the catalytic subunit (p110α) of phosphoinositide-3-kinase (PI3K), are the most frequent oncogenic alterations in estrogen receptor-positive (ER+) breast cancer and are also prevalent in other tumor types. PI3Kα inhibitors including alpelisib have recently been shown to be clinically active in ER+ PIK3CA mutant breast cancer. To characterize determinants of sensitivity to these agents, we undertook a comprehensive analysis of PIK3CA mutant cancer genomes and observed the presence of double PIK3CA mutations in 12-15% of breast cancer and other tumor types. These double PIK3CA mutations are clonal, located in cis on the same allele, and are composed of a single hotspot mutation combined with a recurrent second-site mutation. Double PIK3CA mutations in cis result in increased PI3K activity and downstream signaling together with enhanced cell proliferation and tumor growth compared to single hotspot mutations. The biochemical mechanisms underlying this increased oncogenicity include increased disruption of p110α binding to the inhibitory subunit p85α, which relieves its catalytic inhibition, and increased membrane lipid binding. Finally, these double PIK3CA mutations predict for increased sensitivity to PI3Kα inhibitors compared to single hotspot mutations (e.g. E545K or H1047R) in experimental models and in patients with ER+ PIK3CA mutant metastatic breast cancer from the SANDPIPER randomized phase III clinical trial. These findings implicate double PIK3CA mutations in cis as a novel mechanism of oncogene addiction relative to single hotspot mutations, providing a rationale to develop PI3Kα inhibitors for the therapy of double PIK3CA mutant cancers.
Citation Format: Neil Vasan, Pedram Razavi, Jared L Johnson, Hong Shao, Timothy Wilson, Frauke Schimmoller, Hardik Shah, Alesia Antoine, Erik Ladewig, Alexander Gorelick, Ting-Yu Lin, Eneda Toska, Guotai Xu, Abiha Kazmi, Matthew T Chang, Barry S. Taylor, Maura N. Dickler, Komal Jhaveri, Sarat Chandarlapaty, Raul Rabadan, Ed Reznik, Melissa L Smith, Robert Sebra, Lori Friedman, Lewis C Cantley, Maurizio Scaltriti, José Baselga. Double PIK3CA mutations in cis drive oncogene addiction and enhance sensitivity to PI3K alpha inhibitors in breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-03-01.
Abstract P3-03-12: Obesity promotes the activation of genes and pathways in tumor associated breast fat
Authors: Infante Niel , Coad James , Primerano Don , Denvir James , Vona-Davis Linda 
Published: March 2020

Abstract
Tumor-associated adipocytes play an active role in breast tumor progression. Moreover, obesity has been established as a risk factor in cancer-related mortality. The altered expression of genes and signaling pathways in breast adipose as a result of obesity may create a more favorable microenvironment for tumor progression. To this end, we analyzed transcriptome profiles of human adipose tissue from lean and obese women with invasive breast cancer using RNA sequencing (n=10/group). Within individuals, adipose tissue was sampled proximal and distal (2 cm) to the breast tumor. A heat map of normalized expression values was generated with unsupervised clustering for the most informative genes. A cluster heat map was obtained by the analysis of the express of 35 DEGs with the most significant differences (adjusted p-value P&lt; 0.01 and fold change &gt; 2) recorded. Starting with a list of genes marked as significant in the analysis of lean vs obese, we queried the STRING database. Using ClusterMaker2 and MCL clustering, we performed enrichment analysis and found KEGG pathway hsa05224 breast cancer was enriched with an FDR of 2.7e-40. Using KEGGParser, we over-layed fold changes from lean vs obese data. In examining obese women, there were 16 Hallmark pathways that were statistically significant (adjusted p-value P&lt; 0.10); whereas a subset of these (11 pathways) were significant in lean women. Pathways that were significant in both lean and obese individuals were pathways that regulate EMT, adipogenesis and TGF-β signaling. EMT transcription factors and TGF-β signaling are known to regulate cancer adipogenesis. The results underscore the link between obesity and altered gene expression in mammary fat associated with breast cancer. (Supported by NIH P20GM103434 and NIGMS U54GM104942)
Citation Format: Niel Infante, James Coad, Don Primerano, James Denvir, Linda Vona-Davis. Obesity promotes the activation of genes and pathways in tumor associated breast fat [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-03-12.
Abstract P3-05-05: Imipramine, an FDA approved anti-depressant, suppresses triple negative breast cancer growth and progression through inhibition of FOXM1 and DNA repair pathways
Authors: Timilsina Santosh , Rajamanickam Subapriya , Jatoi Ismail , Chen Yidong , Vadlamudi Ratna , Kaklamani Virginia , Rao Manjeet K 
Published: March 2020

Abstract
Triple Negative Breast Cancer (TNBC) is an aggressive subtype of breast cancer that lacks effective targeted therapies with the main therapeutic option being cytotoxic chemotherapies, which have toxic side effects on patient’s health. Less toxic alternatives that could target key pathways that are altered in TNBCs could lead to better outcomes for the patients. Important distinguishing traits of TNBCs is the high amounts of genomic instability and high number of alterations in key proteins in DNA repair and cell proliferation that helps the cancer grow, survive and progress. Previous findings from our lab indicate that Imipramine Blue, a derivative of anti-depressant imipramine, is a potent inhibitor of proliferation and DNA repair pathways in TNBC. Therefore, we tested the therapeutic efficacy of Imipramine on TNBCs using various in vitro assays for viability, migration, invasion as well as in vivo xenograft assays for tumor growth. Our results demonstrate that Imipramine inhibits cancer cell viability and progression in vitro. Similarly, in vivo xenograft assays showed reduced tumor growth in pre-clinical models upon imipramine treatment. Importantly, at the molecular level, Imipramine treatment suppressed key players in both cell proliferation, and DNA repair pathways, including FOXM1; a proto-oncogene that is a master regulator of both cell proliferation and DNA Repair pathways. These findings suggest that Imipramine may be a potential therapeutic option for TNBC patients. A clinical trial is ongoing to test the efficacy of Imipramine in Triple Negative Breast Cancer patients.
Citation Format: Santosh Timilsina, Subapriya Rajamanickam, Ismail Jatoi, Yidong Chen, Ratna Vadlamudi, Virginia Kaklamani, Manjeet K Rao. Imipramine, an FDA approved anti-depressant, suppresses triple negative breast cancer growth and progression through inhibition of FOXM1 and DNA repair pathways [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-05-05.
Abstract P3-06-12: Autophagy-mediated survival mechanism to c-Src inhibitor therapy in triple negative breast cancer
Authors: Jung Kwanghwa , Park Junhyoung , Sirupangi Tirupataiah , Jia Dongya , Gandhi Nishant , Pudakalakatti Shivanand , Elswood Jessica , Porter Weston , Putluri Nagireddy , Zhang Xiang H.-F , Chen Xi , Bhattacharya Pratip K. , Creighton Chad J. , Lewis Michael T. , Rosen Jeffrey M. , Wong Lee-Jun C. , Das Gokul M. , Osborne C. Kent , Rimawi Mothaffar F , Kaipparettu Benny Abraham 
Published: March 2020

Abstract
c-Src (Src) is a proto-oncogene involved in signaling that culminates in the control of multiple biological functions. Src is also one of the most frequently upregulated pathways in triple negative breast cancer (TNBC). Dysregulation of Src has been detected in TNBC and is strongly associated with tumor metastasis and poor prognosis. However, even after promising preclinical studies, Src inhibitors did not show major clinical advantage in unselected TNBC populations. We have previously published that metastatic TNBC has high energy-dependency to mitochondrial fatty acid beta-oxidation (FAO) and FAO activates Src by inducing autophosphorylation at Y419. However, our recent analysis suggests that as observed with the Src inhibitors, TNBC tumors treated with FAO inhibitors also develop drug-resistance and exhibit continuous tumor growth. Evaluation of their drug resistance mechanism revealed that while short-term inhibition of FAO or Src induces autophagic and apoptotic cell deaths, long-term inhibition results in autophagy-mediated drug resistance and survival. Further analyses suggest that FAO/Src inhibitors promote interferon regulatory factor 1 (IRF1) expression and activate mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) pathway via the induction of cellular reactive oxygen species (ROS) in TNBC. Activated MEK/ERK then suppresses IRF1 expression and induces survival pathways for drug resistance and tumor survival. Validation of in vitro findings using in vivo TNBC models confirmed that combination of FAO/Src inhibitors with MEK/ERK inhibitor or ROS scavenger provide significant benefit to overcome the therapeutic resistance of TNBC. These findings open-up new therapeutic opportunities to manage TNBC patients with currently non-targetable metastatic tumors.
Citation Format: Kwanghwa Jung, Junhyoung Park, Tirupataiah Sirupangi, Dongya Jia, Nishant Gandhi, Shivanand Pudakalakatti, Jessica Elswood, Weston Porter, Nagireddy Putluri, Xiang H.-F Zhang, Xi Chen, Pratip K. Bhattacharya, Chad J. Creighton, Michael T. Lewis, Jeffrey M. Rosen, Lee-Jun C. Wong, Gokul M. Das, C. Kent Osborne, Mothaffar F Rimawi, Benny Abraham Kaipparettu. Autophagy-mediated survival mechanism to c-Src inhibitor therapy in triple negative breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-06-12.
Abstract P3-06-14: Inhibition of PRKCQ enhances chemosensitivity of triple negative breast cancer by regulating EMT and Bim
Authors: Irie Hanna Yoko , Byerly Jessica H. , Port Elisa R. 
Published: March 2020

Abstract
Background/Rationale: While some patients with triple negative breast cancer (TNBC) achieve long-term remission with standard-of-care chemotherapy, many have cancers that are chemotherapy resistant, putting them at risk for metastatic recurrence. There is also a lack of targeted therapies for TNBC, highlighting the need for novel therapeutic strategies for this subtype. PRKCQ, a member of the novel protein kinase C family, is preferentially expressed in TNBC compared to other breast cancer subtypes and we previously reported that PRKCQ expression is sufficient to promote oncogenic activities (growth-factor independent growth, anoikis resistance and migration). In addition, PRKCQ suppression inhibits growth of TNBC tumor xenografts. We sought to determine if PRKCQ expression modulation impacts sensitivity of triple negative breast cancer cells to standard of care chemotherapy and whether PRKCQ inhibition could be a strategy to enhance chemosensitivity of drug-resistant TNBC. Methods: We determined the effects of modulating PRKCQ expression, using PRKCQ cDNA or shRNA vectors, on sensitivity of TNBC cells to the apoptotic effects of standard-of-care chemotherapy, including those cancers that are relatively chemotherapy resistant at baseline. We also determined the mechanisms by which PRKCQ regulates sensitivity to chemotherapy. Results: Increased PRKCQ expression in non-transformed MCF-10A breast epithelial cells promotes resistance to the apoptosis-inducing effects of Doxorubicin or Paclitaxel treatment. These effects are dependent on PRKCQ kinase activity as a catalytically inactive PRKCQ failed to promote resistance. Downregulation of PRKCQ or inhibition of its kinase activity enhanced sensitivity of TNBC cells to chemotherapy. PRKCQ impacts chemotherapy sensitivity of TNBC by regulating epithelial-mesenchymal transition (EMT) and expression of Bim, a pro-apoptotic Bcl2 family protein. Conclusions. PRKCQ promotes resistance of TNBC to standard of care chemotherapies by promoting EMT and suppressing pro-apoptotic Bim. Inhibiting PRKCQ expression or activity sensitizes TNBC cells to chemotherapy and could be an effective strategy to overcome chemotherapy resistance of a subset of triple negative breast cancers, thereby improving patient outcomes.
Citation Format: Hanna Yoko Irie, Jessica H. Byerly, Elisa R. Port. Inhibition of PRKCQ enhances chemosensitivity of triple negative breast cancer by regulating EMT and Bim [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-06-14.
Abstract P3-07-11: BRCA mutations and association with discordance in a large oncotype database
Authors: Blanter Julia , Zimmerman Brittney , Tharakan Serena , Cascetta Krystal , Ru Meng , Tiersten Amy 
Published: March 2020

Abstract
BACKGROUND: BRCA mutated tumors have been shown to be associated with higher recurrence scores as compared to BRCA negative breast cancer patients. Prior studies have demonstrated 7-19% discordance between oncotype RS and tumor grade (TG) in breast cancer patients. We developed a large oncotype database to determine if BRCA mutation status is associated with discordance.
METHODS: We identified 723 patients (32 (4%) BRCA positive patients and 691 (96%) BRCA negative patients) with early-stage, hormone positive BC treated between 2006-2018, with tumor characteristics available for analysis.
Discordance was defined as one or two-step difference between RS (low, intermediate, high risk) and TG (well (WD), moderately (MD) and poorly (PD) differentiated).
BRCA status was defined as BRCA 1 deleterious mutation, BRCA 2 deleterious mutation, BRCA mutation of unknown type, BRCA variant of undetermined significance (VUS) or other mutation.
N(%) or median were used to describe patients’ characteristics between groups and compared by Mann-Whitney U test at the confidence level of 5%.
RESULTS: Among these patients, there were 32 patients (4% of total) who had any documented mutation or VUS. 16% had documented deleterious mutation in BRCA 1, 22% BRCA 2, 6% BRCA unknown type, 25% BRCA VUS, and 31% other VUS (most commonly CHEK2 and ATM).
Median RS was 23.5 in patients with deleterious BRCA mutations (1, 2 or unknown) vs. 16 in patients in the BRCA negative database which was statistically significant (p&lt;0.01).
One step and two-step discordance was present in 46% and 8% respectively of patients with deleterious BRCA mutations vs. 53% and 11% respectively in the BRCA negative database.
CONCLUSIONS: Patients with deleterious BRCA mutations demonstrated no difference in rates of discordance as compared to BRCA negative patients. We further demonstrated that patients with BRCA positive tumors display higher recurrence scores than patients with BRCA negative tumors.
Citation Format: Julia Blanter, Brittney Zimmerman, Serena Tharakan, Krystal Cascetta, Meng Ru, Amy Tiersten. BRCA mutations and association with discordance in a large oncotype database [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-07-11.
Abstract P3-07-13: Neoadjuvant composite score as a prognostic marker in early and locally advanced triple negative breast cancer
Authors: Dubashi Biswajit , Kayal Smita , Matta Kirankumar , Thumaty Divya bala , Yadav Nisha , Kadambari D , ch Toi Pampa , Gunaseelan K , Ganesan Prasanth 
Published: March 2020

Abstract
Aim Triple negative subtype (TNBC) is an aggressive breast cancer with inferior survival. Pathological CR (pCR) is a good surrogate endpoint for survival among patients receiving neoadjuvant chemotherapy (NACT). We attempted to validate the composite score(CPS) (Jaccqueline et al, J Clin Oncol 26:246-252) combining clinical and pathological variables among TNBC patients receiving NACT at our center. Methodology Data of patients with TNBC who underwent NACT between January 2014 to July 2017 was retrospectively analysed. The composite CPS score included cTN stage and y pTN stage, and ranged from 0 to 4. This was calculated using an online software (http://www3.mdanderson.org/app/medcalc/index.cfm?pagename=bcnt). The scores obtained from the calculator was used to develop a risk grouping into low risk (0,1) and High risk (2,3,4). Overall survival (OS)and disease free survival (DFS) were calculated using the Kaplan-Meier method and differences was examined using the log rank test. Results Seventy-eight patients with TNBC [median age: 45 (24-75)] had received NACT (anthracyclines and taxanes). Early and locally advanced breast cancer constituted 17 (21.8 %) and 61 (78.2%) respectively and 22 (28.2 %) achieved pCR. After a median follow up of 28 months (5-62), 3-yr DFS and OS were 59% and 82% respectively for the entire population. The 3-yr DFS in low (n=18) and high risk (n=60) patients was 85.7% and 51.4% respectively (p=0.032). The 3-yr OS in the low and high risk was 93% and 79% respectively(p=0.28, NS). Conclusion Our study supports the use of the composite clinical pathological score (CPS) as a prognostic marker in patients with non-metastatic triple negative breast cancer. The risk stratification developed may help identify patients who may require additional adjuvant therapy.
Citation Format: Biswajit Dubashi, Smita Kayal, Kirankumar Matta, Divya bala Thumaty, Nisha Yadav, D Kadambari, Pampa ch Toi, K Gunaseelan, Prasanth Ganesan. Neoadjuvant composite score as a prognostic marker in early and locally advanced triple negative breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-07-13.