bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A068: Targeting Akt reactivation following mTOR inhibition in breast cancer treatment
Authors: Alayev Anya , Snyder Rose B. , Holz Marina K. 
Published: May 2015

Abstract
Breast cancer is the second leading cause of cancer related deaths in women and up to 60% of diagnosed cases are estrogen receptor (ER)-positive. ER-positive status is associated with a poor prognosis. While ER-positive cancers could be targeted with endocrine therapy, such as aromatase inhibitors, resistance often develops. Therefore, there is a need to better understand molecular contributions of other signaling pathways with the goal of treating patients with personalized combination therapies.
The mechanistic target of rapamycin complex 1 (mTORC1) regulates cell cycle progression and proliferation and is a target of a naturally occurring inhibitor rapamycin. The 40S ribosomal S6 Kinase 1 (S6K1) is one of the best characterized downstream targets of mTORC1. The mTORC1/S6K1 pathway is often hyperactivated in breast cancer, promoting cell growth and proliferation. S6K1 is encoded by the RPS6KB1 gene, located on the 17q23 chromosomal region. While this region is amplified in several types of cancer, multi-copy amplicons are found specifically in breast cancer, underscoring the importance of S6K1 in this disease. Importantly, there is a direct link between the mTORC1/S6K1 and ER signaling pathways. S6K1 directly phosphorylates and activates ER, promoting ligand-independent ER activation and endocrine resistance. Based on this data, current FDA approved treatment of advaced ER-positive breast cancer combines mTORC1 inhibitors with endocrine therapy.
Some of the concerns that arise with the use of mTORC1 inhibitors (rapamycin analogs or rapalogs) is that they promote induction of autophagy and relieve the negative feedback signaling to Akt effected by S6K1, which promotes oncogenic Akt signaling, survival, and further stimulates mTORC1/S6K1 signaling, which may contribute to acquired drug resistance and patient relapse.
Our research focuses on identifying agents that could be combined with mTORC1 inhibitors to block S6K1 while maintaining negative feedback signaling to Akt. Our results show that such combination treatment does in fact prevent rapamycin-induced upregulation of Akt while maintaining inhibition of the S6K1 signaling pathway, as assayed by analysis of S6K1 targets PDCD4, eIF4B and S6. Moreover, the combination treatment inhibits autophagy and promotes apoptosis. Thus, the combined inhibition of S6K1 and Akt may prevent or reverse drug resistance in breast cancer.
Citation Format: Anya Alayev, Rose B. Snyder, Marina K. Holz. Targeting Akt reactivation following mTOR inhibition in breast cancer treatment. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research: Genetics, Biology, and Clinical Applications; Oct 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2013;11(10 Suppl):Abstract nr A068.
Abstract A094: The influence of pro-metastatic protein NEDD9 expression in supporting distant breast cancer metastasis
Authors: Ice Ryan J. , Mahavadi Sricharan A. , Pugacheva Elena N. 
Published: May 2015

Abstract
Although advances in treating early stage breast cancer have increased the overall survival rate, once the disease has metastasized treatment options become severely limited. Neural precursor cell expressed developmentally downregulated 9, NEDD9, is a pro-metastatic protein known to play a role during invasion and is increased in many tumor types including ductal breast carcinomas. The purpose of our study is to understand how NEDD9 contributes to the survival of metastatic disease and to establish via therapeutically relevant means the impact of reducing NEDD9 in metastatic breast cancer. Utilizing breast tumor xenograft models and in situ Zymography we were able to conclude that the reduction of NEDD9 led to a decrease in matrix metalloproteinase activity in the tumor cells in the primary site and distant lung metastasis thus reducing the number of invading cells. Additionally our study shows, via fluorescent immunohistochemistry analysis of lung metastasis, that by reducing the levels of NEDD9 in vivo the levels of active caspase 3 increased, along with decreasing Ki67 and phosphorylated Akt levels. These changes led to decreased proliferation and survival and increased cell death at distant metastatic sites and dramatically reduced number and size of lung metastasis. Finally, we have demonstrated that the application of NEDD9 Vivo-morpholinos is a valid method for targeting NEDD9 in a clinically relevant setting to reduce the levels of NEDD9 for treatment of metastatic breast cancer. Taken together our data suggests that not only does NEDD9 play a role in primary tumor invasion but is necessary for sustaining metastatic disease and can be reduced in a clinically viable manner resulting in less metastasis.
Citation Format: Ryan J. Ice, Sricharan A. Mahavadi, Elena N. Pugacheva. The influence of pro-metastatic protein NEDD9 expression in supporting distant breast cancer metastasis. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research: Genetics, Biology, and Clinical Applications; Oct 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2013;11(10 Suppl):Abstract nr A094.
Abstract A095: The microenvironmental basis of AXL regulation
Authors: Jokela Tiina , Stampfer Martha , Lorens James , LaBarge Mark 
Published: May 2015

Abstract
AXL tyrosine kinase expression is a strong negative prognostic factor for survival of human breast cancer, and its expression is significant in metastases. Breast cancer metastasis is promoted by epithelial-mesenchymal transition (EMT), where epithelial cells lose their cell-to-cell contacts and polarity, resulting in transformation to a fibroblastic migratory phenotype. During EMT process, AXL is highly expressed, and knockdown of AXL completely prevents the invasion of breast cancer cells via EMT-based mechanisms. EMT is promoted by specific transcription factors like slug or oncogenes like Ras, but interestingly, without extracellular signaling feedback, cells will lose the EMT state and invasion capability.
In this study we characterize extracellular stimuli that stabilize AXL expression and the EMT-phenotype in human mammary epithelial cells. In Vitro studies were implemented with HMEC-derived cell lines, which have traceable origins and were derived through defined immortalization steps. Mammary epithelial cells were induced into an EMT phenotype by Slug-overexpression and exposure to different microenvironments. AXL and other EMT markers were monitored in each cell passage. Results have shown that with Slug-expressing cells lose the EMT phenotype after a few cell passages. When Slug induced HMECs were cultured on Micro Environment microArrays (MEArray), specific microenvironments were revealed that increased and stabilized AXL expression. Our results show that microenvironmental signals are essential to induce and maintain the EMT phenotype.
Citation Format: Tiina Jokela, Martha Stampfer, James Lorens, Mark LaBarge. The microenvironmental basis of AXL regulation. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research: Genetics, Biology, and Clinical Applications; Oct 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2013;11(10 Suppl):Abstract nr A095.
Abstract A109: A signal peptide as a putative tool against MMTV-associated breast cancers
Authors: Braitbard Ori , Bar-Sinai Allan , Roniger Maayan , Rajchman Dana , Hochman Nira , Hochman Jacob 
Published: May 2015

Abstract
Mouse Mammary Tumor Virus (MMTV) causes mammary carcinoma and lymphoma in mice. An increasing body of evidence from different laboratories suggests an association between MMTV and up to 38% of human breast cancers. This seems related to severity of the disease and geographical location. Signal peptides are N-terminal extensions of nascent secretory and membrane proteins (typically including 15-25 amino acid residues). They mediate translocation across, or insertion into the membrane of the endoplasmic reticulum (ER). The signal peptide of Mouse Mammary Tumor Virus (MMTV) envelop precursor (named MMTV-14 or p14 for short), in addition to being unusually long (98 a.a) demonstrates some unique characteristics: 1) It localizes to nucleoli; 2) It functions as a nuclear export factor for intron-containing viral transcripts; 3) It can function in a pro-oncogenic or anti-oncogenic capacity depending on its phosphorylation by the kinases CK2 (at serine 65) or PKC (at serine 18), respectively. We report that, in addition to its nucleolar localization, p14 is expressed on the cell surface of murine lymphomas and mammary carcinomas that harbor MMTV, as well as on the surface of MCF-7 human breast cancer cells ectopically expressing p14. Cell surface expression allows p14 to play the role of a tumor associated antigen. Indeed, priming and boosting of mice with recombinant p14, using different adjuvants, induces specific anti-p14 antibodies, as well as immunizes these mice against malignant tumor cells that harbor MMTV. This immunity is adoptively transferred to naïve mice. Thus, MMTV-p14 is a multi-faceted signal peptide with immune modulating characteristics that can be used for developing both preventive and therapeutic approaches towards MMTV-associated breast cancers.
Supported in part by a Kamin grant from the Office of the Chief Scientist.
Citation Format: Ori Braitbard, Allan Bar-Sinai, Maayan Roniger, Dana Rajchman, Nira Hochman, Jacob Hochman. A signal peptide as a putative tool against MMTV-associated breast cancers. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research: Genetics, Biology, and Clinical Applications; Oct 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2013;11(10 Suppl):Abstract nr A109.
Abstract A114: Differential gene expressions in breast cancer epithelia of African American and European American women: Health disparity at the molecular level
Authors: Bagasra Omar , Howard Khirston , Johnson Leslie 
Published: May 2015

Abstract
Mortality rates from breast cancer (BC) remain higher in African-American (AA) women despite a lower incidence when compared to European American (EA) women. Multiple factors including differences in access to health care, disparate utilization of screening tools as well as biologic factors are being explored as causative agents. We are addressing this concern by studying the expressions of BC signaling pathway genes in paired BC cell lines from AA and EA patients. The total mRNAs from the primary cell lines from both ethnic groups were analyzed by utilizing gene array for breast cancer signaling pathways (SABioSciences). The array analyses showed that there were nine genes which were commonly regulated in both races including: BAD, BAG1, CCNE1, IL6R, IL6ST, ITGB4, MAP2K7, PLAU and PTGS2. Overall, estrogen receptor (BAG1, CYP19A1), inflammation (C3) or metastasis and cell integrity (COL6A1, ID2) or apoptosis (BAD) genes were represented. However, there were numerous genes that were differentially expressed between the two racial groups. In AA, the following genes were down regulated: CDKN2A, CLDN7, CTNNB1, CTSD, EGFR, ESR1, HMGB1, KRT18, STC2 and TP53. One of the most significantly genes was ESR1, the estrogen receptor 1 gene which was down regulated in the AA as compared to EA and may play an important role in AA BC development. There were eight genes that were differentially expressed in EA. These include: CCD1, FOSL1, GSN, IL2RA, IL6, ITGA6, NFYB and SLC7A. Some of these differentially expressed genes may play a protective role in EA. These findings may help us uncover that the molecular basis of high BC mortality in AA and may help in the development of biomarkers for the early diagnosis of BC.
Citation Format: Omar Bagasra, Khirston Howard, Leslie Johnson. Differential gene expressions in breast cancer epithelia of African American and European American women: Health disparity at the molecular level. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research: Genetics, Biology, and Clinical Applications; Oct 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2013;11(10 Suppl):Abstract nr A114.
Abstract B024: Comprehensive biomarker profiling of matched primary and metastatic estrogen receptor positive breast cancers
Authors: Spoerke Jill M. , Schleifman Erica B. , Desai Rupal , Xiao Yuanyuan , Wong Cheryl , Abbas Ilma , O'Brien Carol , Patel Rajesh , Sumiyoshi Teiko , Fu Ling , Tam Rachel , Koeppen Hartmut , Wilson Timothy , Raja Rajiv , Hampton Garret M. , Lackner Mark R. 
Published: May 2015

Abstract
Patients with newly diagnosed, early stage estrogen receptor positive (ER+) breast cancer often show disease free survival in excess of five years following surgery and systemic adjuvant therapy. As such, an important question is whether diagnostic tumor tissue from the primary lesion offers an accurate molecular portrait of the cancer post recurrence and thus may be used for predictive diagnostic purposes for patients with relapsed, metastatic disease. To address this question, we performed detailed biomarker analyses on matched, asynchronous primary and metastatic tumors from 77 patients with ER+ breast cancer.
The class I phosphatidylinositol 3' kinase (PI3K) is thought to be an important driver in ER+ breast cancer and has been linked to acquired resistance to hormonal therapy. We thus examined whether mutations in PIK3CA and loss of PTEN showed differences in primary and metastatic samples. We also sought to look more broadly at markers reflective of proliferation, molecular subtype, and key receptors and signaling pathways. To accomplish this, we developed an analysis platform using the Fluidigm BioMark™ microfluidics system to measure the relative expression of 90 breast cancer related genes in formalin-fixed paraffin-embedded (FFPE) tissue.
Application of this panel of assays to matched tumor pairs showed a very high concordance between primary and metastatic tissue, with generally few changes in mutation status, proliferative markers, or gene expression between matched samples. Thus, archival primary tumor tissue may still provide an accurate portrait of biomarker status in patients with disease recurrence.
Citation Format: Jill M. Spoerke, Erica B. Schleifman, Rupal Desai, Yuanyuan Xiao, Cheryl Wong, Ilma Abbas, Carol O'Brien, Rajesh Patel, Teiko Sumiyoshi, Ling Fu, Rachel Tam, Hartmut Koeppen, Timothy Wilson, Rajiv Raja, Garret M. Hampton, Mark R. Lackner. Comprehensive biomarker profiling of matched primary and metastatic estrogen receptor positive breast cancers. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research: Genetics, Biology, and Clinical Applications; Oct 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2013;11(10 Suppl):Abstract nr B024.
Abstract B064: Anti-phospho-estrogen receptor alpha (Ser305), clone 124.9.4, is a potential clinical antibody marker for tamoxifen-resistant breast cancer
Authors: Speckmann Wayne , Brockett Robert , Yang Chun , Solache Alejandra 
Published: May 2015

Abstract
Resistance to tamoxifen is one of the major challenges in breast cancer treatment. Different mechanisms related to tamoxifen sensitivity have been widely investigated, including the phosphorylation of ERα. It has been shown experimentally that phosphorylation of estrogen receptor alpha at serine 305 (ERαS305-P) by protein kinase A (PKA) leads to an activation of ERα and to transcription of ERα-responsive gene after tamoxifen treatment [EMBO J 26:3534-3544][EMBO J 21:5437-5447], leading to tamoxifen resistance. More recently, clinical studies also show that ERαS305-P may be a good biomarker to identify patients unlikely to respond to tamoxifen [J Pathol 217:372-379][Breast Cancer Res Treat 125(1):1-12]. Here we developed and validated a rabbit monoclonal anti-phospho-estrogen receptor alpha (Ser305) antibody, EMD Millipore 05-922R., with immunohistochemistry (IHC) validation on different breast cancer patient samples and other non-breast cancer tissue micro array (TMA) samples.
Citation Format: Wayne Speckmann, Robert Brockett, Chun Yang, Alejandra Solache. Anti-phospho-estrogen receptor alpha (Ser305), clone 124.9.4, is a potential clinical antibody marker for tamoxifen-resistant breast cancer. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research: Genetics, Biology, and Clinical Applications; Oct 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2013;11(10 Suppl):Abstract nr B064.
Abstract B067: Taxonomy of breast cancer based on normal cell phenotype and ontology
Authors: Thakkar Ankita , Santagata Sandro , Ergonul Ayse , Wang Bin , Woo Terri , Hu Rong , Harrell J. Chuck , McNamara George , Schwede Matthew , Culhane Aedin C. , Kindelberger David , Rodig Scott , Richardson Andrea , Schnitt Stuart J. , Tamimi Rulla M. , Ince Tan A. 
Published: May 2015

Abstract
The classification of lymphoma and leukemia is successfully done by using normal cell types as a reference point which is one of the many reasons that better therapies are available for their treatment. In case of breast cancer, clinically it is classified as Estrogen Receptor positive, Human Epidermal Growth Factor Receptor 2 (Her2) positive and triple negative breast cancer while in the research settings, it has been classified by mRNA expression profiling but these classification systems are still evolving. Our laboratory attempted to classify breast cancer by examining the expression of different keratin isoforms and Hormone Receptors (HR) studied through immunostaining in 36 normal breast samples and later in 1731 breast tumors from the Nurses' Health Study (NHS) cohort with a patient follow up extending beyond 25 years. Among the various receptors tested, three of these receptors: Androgen Receptor, Estrogen Receptor and Vitamin D Receptor were capable of identifying four major subgroups being designated as HR0-3, depending on the number of hormone receptors present. More importantly, radically different survival outcomes were observed between these HR sub-groups through Kaplan Meier curve analysis; which highlights their usefulness as vital biological markers as wells as targets for breast cancer treatment. Furthermore, the characterization of these HR was carried out in 20 different breast cancer cell lines and the combination of different receptor modulators alone or in combination was attempted with better anti-proliferative effects being observed in the combinatorial group than either treatment alone. Thus, our new classification not only re-classifies breast cancer but also gives insight on how patients could be treated through targeting hormone receptors.
Citation Format: Ankita Thakkar, Sandro Santagata, Ayse Ergonul, Bin Wang, Terri Woo, Rong Hu, J. Chuck Harrell, George McNamara, Matthew Schwede, Aedin C. Culhane, David Kindelberger, Scott Rodig, Andrea Richardson, Stuart J. Schnitt, Rulla M. Tamimi, Tan A. Ince. Taxonomy of breast cancer based on normal cell phenotype and ontology. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research: Genetics, Biology, and Clinical Applications; Oct 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2013;11(10 Suppl):Abstract nr B067.
Abstract B077: Breast tumor kinase (Brk/PTK6) is a mediator of hypoxia/HIF-associated breast cancer progression
Authors: Seagroves Tiffany N. , Lange Carol A. 
Published: May 2015

Abstract
Triple negative (basal type) breast cancers (TNBC) are aggressive and difficult to treat relative to luminal type breast cancers. These tumors frequently express abundant Met receptors and are enriched for transcriptional targets regulated by hypoxia inducible factor 1-alpha (HIF-1α), a principal mediator of cell stress that independently predicts cancer relapse and increased risk of metastasis. We recently showed that breast tumor kinase (Brk/PTK6) is a critical downstream effector of Met signaling. Herein, we examined the regulation of Brk by HIFs in TNBC cell lines and mouse models. Brk mRNA and protein levels are strongly upregulated by hypoxia, low glucose and reactive oxygen species in vitro. HIF knockdown demonstrated that BRK expression is dependent upon both HIF-1α; and HIF-2α; and chromatin-immunoprecipitation (ChIP) assays revealed that Brk is a direct transcriptional target of HIF-1α/α. Notably, knockdown of HIF-1α/2α in MDA-MB-231 cells significantly diminished xenograft growth; Brk re-expression reversed this effect. Finally, we crossed WAP-Brk (FVB) transgenic mice into the METmut knock-in (FVB) model. Expression of the Brk transgene augmented METmut-induced mammary tumor formation and metastasis. Surprisingly, mouse mammary tumors that arose in either METmut or WAP-Brk X METmut mice expressed abundant Sik, the mouse homolog of Brk, which conferred markedly increased tumor formation and decreased survival. These results identify HIF-1α/2α as novel regulators of Brk expression and suggest that Brk is a key mediator of hypoxia-induced breast cancer progression. Targeting Brk expression or activity may provide an effective means to block the progression of aggressive breast cancers (supported by NIH R01 CA107547 (C.A.L.) and NIH R01 CA138488 (T.N. S.).
Citation Format: Tiffany N. Seagroves, Carol A. Lange. Breast tumor kinase (Brk/PTK6) is a mediator of hypoxia/HIF-associated breast cancer progression. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research: Genetics, Biology, and Clinical Applications; Oct 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2013;11(10 Suppl):Abstract nr B077.
Abstract B089: The suppression of ERa activity promotes the mitochondrial deficient CD133hi/Notch3hi/ERalow cancer stem cell phenotype via autocrine IL6 in luminal breast cancer
Authors: Sansone Pasquale , Bonafe Massimiliano , Ceccarelli Claudio , Berishaj Marjan , Bromberg Jacqueline 
Published: May 2015

Abstract
The inhibition of ERa pathway (hormonal therapy -HT-) is the most effective therapeutic strategy for metastatic luminal breast cancer. However, the efficacy of HT is time-limited, suggesting that metastatic disease will eventually employ an ERa-independent biochemistry. Here we demonstrated that CD133hi/CD44low tumor initiating cells arise following ERa lack of function via oxidative phosphorylation (OXPHOS) dysfunction. These cells display a remarkable migrating and metastatic phenotype, which associate with the downregulation of ERa and the increased expression of Notch3. Chronic lack of ERa activity by tamoxifen generates CD133hi/Notch3hi/ERalow via the up-regulation of tumor-derived IL6. We then showed that IL6 confers resistance to ERa lack of function by up-regulating glycolysis/OXPHOS. Finally, higher expression of CD133, Notch3 and IL6 identifies ERalow luminal breast cancers endowed with metastatic and self-renewal potentials. In conclusion, our data demonstrate that oxidative phosphorylation dysfunction and autocrine IL6 are key molecular triggers of intra-tumor heterogeneity and tumor initiating capabilities in luminal breast cancer refractory to anti ERa target therapy.
Citation Format: Pasquale Sansone, Massimiliano Bonafe, Claudio Ceccarelli, Marjan Berishaj, Jacqueline Bromberg. The suppression of ERa activity promotes the mitochondrial deficient CD133hi/Notch3hi/ERalow cancer stem cell phenotype via autocrine IL6 in luminal breast cancer. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research: Genetics, Biology, and Clinical Applications; Oct 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2013;11(10 Suppl):Abstract nr B089.