bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3293: Leptin induces breast cancer metastasis through a Neuropilin-1 (NRP-1)/OBR complex
Authors: Belaid-Choucair Zakia , Dam Julie , Goudin Nicolas , Filhole Odile , Cochet Claude , lepelletier Yves , Coman Tereza , Courtois Geneviève , Colige Alain , Defresne Marie-Paule , Jockers Ralf , Hermine Olivier 
Published: May 2015

Abstract
Several studies have demonstrated Neuropilin-1 (NRP-1) implication in tumor progression independently of its known co-receptors. On the basis of growing connections between breast cancer and obesity, we postulated that leptin and its receptor OBR could be potential candidates. First, using NRP-1 over-expression in NRP-1 negative T47D or NRP-1 silencing in NRP-1 positive MDA-MB231 xenografts, we demonstrated that leptin induced metastasis in lymph node only in NRP-1 positive cells. Second, we demonstrated by co-immunoprecipitation, Proximity Ligation assay (duolink) and BRET analysis that NRP-1 is a co-receptor of OBR. Upon leptin exposure this complex is internalized to the nucleus. At this level, NRP-1 Chip-Seq analysis generated from MDA-MB-231 led to identify sequences of RNA polymerase II (Pol2) and transcription factor binding sites of genes implicated in breast cancer metastasis. This finding was confirmed by the detection of NRP-1/Pol2 interaction and by transcriptome analysis of RNA extracts from T47D-NRP-1 xenografts that shows modulation of these genes.
In conclusion, we have demonstrated that NRP-1 is a co-receptor of OBR and upon leptin exposure may play a role as a transcription factor regulating genes involved in cancer progression. Thus, NRP-1 might be a therapeutic target to prevent cancer metastasis induced by leptin
Citation Format: Zakia Belaid-Choucair, Julie Dam, Nicolas Goudin, Odile Filhole, Claude Cochet, Yves lepelletier, Tereza Coman, Geneviève Courtois, Alain Colige, Marie-Paule Defresne, Ralf Jockers, Olivier Hermine. Leptin induces breast cancer metastasis through a Neuropilin-1 (NRP-1)/OBR complex. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3293. doi:10.1158/1538-7445.AM2014-3293
Abstract 3294: Notch signaling is regulated by vacuolar ATPase in triple negative breast cancer
Authors: Pamarthy Sahithi , Beaman Kenneth D. 
Published: May 2015

Abstract
Triple Negative Breast Cancer (TNBC) constitutes 15 % of all diagnosed breast cancers. It is more common among African American and younger women. TNBC cells do not express Estrogen, Progesterone and Her2 receptors. As a result, patients have limited treatment options. To effectively treat TNBC, it is important to identify and target specific signaling pathways that contribute to TNBC tumorigenesis.
Notch signaling is an evolutionarily conserved juxtacrine pathway that is important in normal mammary development and has been shown to play a role in TNBC progression. Although there has been considerable research on role of Notch in TNBC, little is known about its regulation. Identifying novel molecules that can regulate Notch can lead to the development of effective combinatorial treatments.
The Vacuolar ATPase (V-ATPase) has been shown to regulate Notch Signaling in Drosophila. V-ATPase is an ATP driven proton pump, which is responsible for maintaining pH. Tumor cells increase expression of V-ATPase, which aids in cancer proliferation and metastasis.
Here, we report that the a2 isoform of V-ATPase regulates Notch Signaling in breast cancer. Among isoforms a1, a2, a3 and a4, breast cancer cell lines robustly expressed a2 V-ATPase on their surface. a2 V-ATPase is present towards the leading edge of cells and is higher in TNBC cell lines (MDA-MB-231, MDA-MB-468) as compared to normal chemically transformed cell line (184A1) and hormonal positive cell line (MCF7). Expression of Notch ligands, receptors and target genes was also higher in TNBC cell lines as compared to Non-TNBC cell lines. siRNA mediated knockdown of a2 V-ATPase resulted in an increase of Notch Signaling in the Triple Negative MDA-MB-231 cell line. To understand the molecular mechanism behind this regulation, we used Bafilomycin to inhibit V-ATPase activity. Following V-ATPase inhibition, the expression of Jagged1, a Notch ligand was increased. Our results suggest that Vacuolar ATPase can regulate Notch Signaling by affecting ligand internalization through endocytosis. We further assessed the effect of V-ATPase and Notch signaling inhibitors on cell proliferation of the breast cancer cell lines (184A1, MCF7, MDA-MB-231, MDA-MB-468). Combined inhibition of V-ATPase and Notch signaling caused significant cell death in all cell lines tested. Together our results identify a2 V-ATPase as a novel regulator of Notch signaling in Breast Cancer and that targeting both V-ATPase and Notch Signaling can be beneficial for Triple Negative Breast Cancer.
Citation Format: Sahithi Pamarthy, Kenneth D. Beaman. Notch signaling is regulated by vacuolar ATPase in triple negative breast cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3294. doi:10.1158/1538-7445.AM2014-3294
Abstract 3295: S6 kinase signaling in prognosis and tamoxifen response in two randomized breast cancer cohorts
Authors: Bostner Josefine , Karlsson Elin , Bivik Cecilia , Perez-Tenorio Gizeh , Fornander Tommy , Stål Olle 
Published: May 2015

Abstract
Detecting signals in the mammalian target of rapamycin (mTOR), and the estrogen receptor (ER) pathways for prediction of treatment response may be a future clinical tool in primary breast cancer. Here, we investigated the validity and value of the mTOR targets p70-S6 kinase (S6K) 1 and 2 as biomarkers for tamoxifen sensitivity in vitro and in two independent tamoxifen randomized postmenopausal breast cancer cohorts. In addition, the prognostic value of the S6Ks was evaluated.
We found S6K1 to correlate with HER2 and cytoplasmic Akt activity, whereas S6K2 and phosphorylated S6K were closer connected with ER positivity, low proliferation and nucleic p-Akt. Treatment prediction and prognosis were evaluated by immunohistochemical staining. Nuclear accumulation of S6K1 was indicative of a reduced tamoxifen treatment effect, compared with a significant benefit from tamoxifen treatment in patients without tumor S6K1 nuclear accumulation. Patients with a combination of S6K1 nuclear accumulation and S6K2 cytoplasmic accumulation in the tumor cells had no tamoxifen benefit. Also, S6K1 and S6K2 activation, indicated by p-S6K-t389 expression, was associated with low benefit from tamoxifen compared with untreated patients. In addition, high protein expression of S6K1, independent of localization, predicted worse prognosis. This was not evident for variations in S6K2 or p-S6K-t389 expression.
In conclusion, the mTOR targeted kinases S6K1 and S6K2 interfere with proliferation and response to tamoxifen. Monitoring their activity and intracellular localization may provide biomarkers for breast cancer treatment, allowing for identification of a group of patients less likely to benefit from tamoxifen and thus in need of an alternative or additional treatment.
Citation Format: Josefine Bostner, Elin Karlsson, Cecilia Bivik, Gizeh Perez-Tenorio, Tommy Fornander, Olle Stål. S6 kinase signaling in prognosis and tamoxifen response in two randomized breast cancer cohorts. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3295. doi:10.1158/1538-7445.AM2014-3295
Abstract 3300: Estrogen stimulates cell cycle progression dependent on Src kinase activity and IMP1 stabilization of myc mRNA in estrogen receptor-positive breast cancer cells
Authors: Abdullah Christopher , Korkaya Hasan , Courtneidge Sara A. 
Published: May 2015

Abstract
Estrogen (E2) stimulation promotes proliferation in estrogen receptor-positive (ER+) breast cancer, which accounts for 60-75% of all breast cancer. E2 signals through the ER via three pathways: the classical genomic pathway involving transcriptional activation of the ER, crosstalk between ER and other transcription factors, and “non-genomic” signaling cascades, which do not involve the transcriptional activity of the ER. This “non-genomic” pathway likely involves Src family kinases (SFKs) and has been implicated in cell cycle progression in fibroblasts engineered to express the ER (Castoria 1999). While not typically amplified or mutationally activated in ER+ breast cancer, Src is hyperactive in most breast cancers.
To test whether SFK activity is required for G1/S cell cycle progression in breast cancer cells, we pretreated quiescent ER+ MCF7 cells with a selective SFK inhibitor (SU11333) prior to stimulation with E2. Inhibition of SFK activity blocked progression from G1 to S phase. Previous data from our laboratory has demonstrated that G1/S progression in response to peptide growth factor stimulation of quiescent fibroblasts is dependent upon SFK-mediated stabilization of myc mRNA (Bromann 2005). We therefore tested whether SFK activity also regulates myc expression in breast cancer cells. Our data suggest that SFK activity is required for accumulation of myc mRNA in quiescent MCF7s after E2 stimulation, and that E2 stimulated stabilization of myc mRNA is dependent on SFK activity.
One potential myc mRNA stabilizer is IMP1 (IGF2BP1, ZBP1, CRDBP) an RNA binding protein that is primarily expressed during development and in stem cells, and re-expressed in some cancer types, including breast cancer. IMP1 has previously been shown to stabilize myc mRNA in stem cells as well as osteosarcoma cells. While the signaling pathways that mediate this stabilization have not been well studied, previous work has identified a Src phosphorylation site on IMP1 which regulates IMP1 function (Sasaki 2010). We hypothesized that IMP1 may play a role in E2-mediated stabilization of myc mRNA. Indeed, MCF7 cells require IMP1 to accumulate myc mRNA after E2 stimulation. In summary, E2 stimulation activates SFKs, which then promote G1/S cell cycle progression in part by stabilizing myc mRNA levels, through the activity of IMP1.
Bromann et al JBC, 2005
Castoria et al. EMBO J, 1999
Sasaki et al. J Neurosci, 2010
Citation Format: Christopher Abdullah, Hasan Korkaya, Sara A. Courtneidge. Estrogen stimulates cell cycle progression dependent on Src kinase activity and IMP1 stabilization of myc mRNA in estrogen receptor-positive breast cancer cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3300. doi:10.1158/1538-7445.AM2014-3300
Abstract 3301: Inhibition of the secretory pathway calcium ATPase 1 (SPCA1) in MDA-MB-231 breast cancer cells and the effect on protein expression
Authors: Lee Jane M. , Ross Diana G. , Monteith Gregory R. , Roberts-Thomson Sarah J. 
Published: May 2015

Abstract
SPCA1 is a Ca2+ pump located on the membrane of the Golgi apparatus and is involved in controlling calcium levels within the Golgi. We have previously shown that SPCA1 is upregulated in some basal-like breast cancers. Given the role of the Golgi in protein trafficking and processing, we hypothesised that SPCA1 may be involved in regulating the expression of proteins important in cancer. To address this hypothesis we used 2D-DIGE to identify proteins that are altered when SPCA1 is silenced in MDA-MB-231 basal cancer cells. MDA-MB-231 cells were seeded into 6-well plates (75,000 cells/well) and treated with SPCA1 or non-targeting siRNA. Protein was isolated 72 h post siRNA treatment, and SPCA1 silencing was confirmed by immunoblotting. 2D-DIGE and MS/MS were used to identify proteins with differential expression with SPCA1 silencing. Heat shock protein 60 (HSP60) was identified as a protein potentially sensitive to SPCA1 silencing using 2D-DIGE. Immunoblotting and real time RT-PCR showed that SPCA1 silencing reduced HSP60 protein and mRNA expression by 81±2% and 60±7% (n=3, P&lt;0.05), respectively. Given the role of HSP60 in cell death pathways, we also assessed the consequences of SPCA1 silencing on heat shock and staurosporine-induced cell death. SPCA1 silencing had no effect on heat shock-induced cell death but reduced the sensitivity of MDA-MB-231 breast cancer cells to staurosporine. Although further studies are required to fully characterize the functional consequences of HSP60 downregulation upon SPCA1 silencing, this work suggests that SPCA1 is a complex regulator of proteins important in cancer pathways.
Citation Format: Jane M. Lee, Diana G. Ross, Gregory R. Monteith, Sarah J. Roberts-Thomson. Inhibition of the secretory pathway calcium ATPase 1 (SPCA1) in MDA-MB-231 breast cancer cells and the effect on protein expression. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3301. doi:10.1158/1538-7445.AM2014-3301
Abstract 3307: Angiomotin regulates the Hippo pathway to increase prostate cancer cell growth
Authors: Ortiz Angelica , Zeng Hao , Lin Sue-Hwa 
Published: May 2015

Abstract
Angiomotin (AMOT) is a member of the motin family that consists of three members, AMOT, AMOTL1, and AMOTL2, which function as either positive or negative regulators of cell growth depending on interacting proteins and cellular context. The role of AMOT in prostate cancer (PCa) has not been studied. AMOT is expressed as two isoforms, AMOTp80 and AMOTp130. The AMOTp130 isoform has an extended 409 aa N-terminal domain that is absent in AMOTp80. Both AMOTp80 and AMOTp130 are expressed in LNCaP and C4-2B4, but at a very low level in PC3-mm2 PCa cells. We found that expression of AMOTp130 and AMOTp80 have distinct functions in PCa cells. While AMOTp80 functions as a tumor promoter by enhancing PCa cell proliferation, AMOTp130 did not. We further show that AMOTp80 affects the Hippo tumor suppressor pathway by inhibiting LATS1 and YAP phosphorylation, resulting in nuclear translocation of YAP. Once in the nucleus, YAP increases transcription of the target protein BMP4. Moreover, inhibition of BMP receptor activity by LDN-193189 abrogates AMOTp80-mediated proliferation. These observations suggest that AMOTp80 induces the expression of BMP4, which functions in an autocrine manner to promote PCa cell proliferation. Together, our studies identify AMOTp80-MST-LATS1-YAP-BMP4 as a novel signal pathway that regulates PCa cell proliferation.
Citation Format: Angelica Ortiz, Hao Zeng, Sue-Hwa Lin. Angiomotin regulates the Hippo pathway to increase prostate cancer cell growth. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3307. doi:10.1158/1538-7445.AM2014-3307
Abstract 3311: The cholesterol/ 27-hydroxycholesterol axis is a novel therapeutic target in castrate resistant prostate cancer
Authors: Alfaqih Mahmoud A. , Nelson Erik R. , Safi Rachid , Jasper Jeff , Chang Ching-yi , Freedland Stephen J. , McDonnell Donald P. 
Published: May 2015

Abstract
The most recent estimates indicate that men have a seventeen percent chance of developing invasive prostate cancer (PCa) over their lifetime. This makes PCa the most commonly diagnosed malignancy among men in industrialized countries, accounting for the second leading cause of cancer-related deaths. Although PCa almost always develops resistance to androgen-deprivation therapy, both androgen receptor (AR) itself and the processes downstream of the receptor remain active and are necessary for cancer progression and thus continue to be viable targets for therapeutic intervention. In this regard, it is of significance that several independent studies demonstrate a link between elevated intra-prostatic levels of cholesterol and the presence of malignancy. This puts into context our current finding that 27-hydroxycholesterol (27HC), a primary metabolite of cholesterol, regulates pathways and processes that oppose AR action. For example, AR activation results in a net uptake of cholesterol by PCa cells and enhances denovo lipogenesis, while 27HC down-regulates genes involved in cholesterol uptake and activates those involved in its efflux. More importantly, we show that treatment of PCa cell lines with 27HC inhibits their proliferation, an activity that is reversed upon supplementing the cells with an exogenous source of cholesterol or upon over-expression of low density lipoprotein receptor (LDLR), a membrane protein that mediates the uptake of cholesterol. In prostatic tissues, 27HC is synthesized directly from cholesterol by the cytochrome P450 enzyme, CYP27A1. To further highlight the above axis as a novel therapeutic target, using data mining approaches from clinical databases, we show that (1) transcript levels of CYP27A1 are dramatically down-regulated during PCa progression and (2) patients whose tumors express high levels of CYP27A1transcript exhibit longer disease free survival. Most notably, we were able to show that over-expression of CYP27A1 inhibits the proliferation of PCa cell lines in vitro and delays the growth of xenografts in castrated immune-deficient mice. In summary, our data thus far strongly implicates that CYP27A1 is a potential tumor suppressor in PCa and highlights the cholesterol/27HC axis as a target for the development of novel therapeutics for castrate resistant disease.
Citation Format: Mahmoud A. Alfaqih, Erik R. Nelson, Rachid Safi, Jeff Jasper, Ching-yi Chang, Stephen J. Freedland, Donald P. McDonnell. The cholesterol/ 27-hydroxycholesterol axis is a novel therapeutic target in castrate resistant prostate cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3311. doi:10.1158/1538-7445.AM2014-3311
Abstract 3313: 17β-Estradiol-ERβ axis confers proliferation and migration through IGF-1R-dependent expression of TMPRSS2 in castration-resistant PC-3 cells
Authors: Kim Hogyoung , Datta Amrita , Elmageed Zakaria Y. Abd , Abdel-Mageed Asim B. 
Published: May 2015

Abstract
Prostate cancer (PCa) is the most common and the second leading cause of cancer-related death among males in the Western world. TMPRSS2, a gene that encodes serine-protease type II transmembrane domain, has been shown to be frequently prevalent as a TMPRSS2-ERG gene fusion during early event in the genesis of PCa. However, TMPRESS2 function remains largely unknown, especially in castration-resistant PCa cells. While TMPRESS2 has previously been shown to be an androgen-regulated gene, TMPRSS2-ERG expression is regulated by a novel ERβ-dependent mechanism. The objectives of this study are to determine the mechanisms of expression and the functional significance of TMPRSS2 in growth and migration of castration-resistant AR-null PC-3 cells. 17β-Estradiol (E2; 10nM) induced TMPRSS2 expression (4-fold higher) in an ERβ-dependent manner as evidenced by shRNA silencing, but not by ERα-specific shRNA, in PC-3 cells. Intriguingly, the E2-induced TMPRSS2 expression was blocked by AG1024 (IGF-1R inhibitor) or knockdown of IGF-1R by siRNA, but not by AG1478 (EGFR inhibitor), suggesting that IGF-1R mediates expression of TMPRESS2 by the E2-ERβ axis in PC-3 cells. Moreover, TMPRSS2-specific siRNA markedly attenuated E2-induced cell growth and migration of PC-3 cells, suggesting that TMPRSS2 may be pivotal to E2-mediated progression of castration-resistant disease in vivo. The effects of TMPRSS2 silencing seem to be mediated through inhibition of E2-induced activation of NF-κB-signaling in these cells. Taken together, our results unraveled the underlying mechanisms that govern the expression and function of TMPRSS2 in mediating E2-induced growth and migration of castration-resistant PC-3 cells. Delineation of such critical players may culminate in identifying therapeutic targets to selectively circumvent castration-resistant outgrowth in PCa patients.
Citation Format: Hogyoung Kim, Amrita Datta, Zakaria Y. Abd Elmageed, Asim B. Abdel-Mageed. 17β-Estradiol-ERβ axis confers proliferation and migration through IGF-1R-dependent expression of TMPRSS2 in castration-resistant PC-3 cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3313. doi:10.1158/1538-7445.AM2014-3313
Abstract 3315: RON-mediated hijacking of AR signaling in androgen-independent prostate cancer
Authors: Batth Izhar Singh , Meng Peng , Bedolla Roble , Reddick Robert E. , Kumar Addanki Pratap 
Published: May 2015

Abstract
Despite significant progress in developing effective strategies for management of localized prostate cancer, the 5-year survival for metastatic castrate-resistant disease is less than 30%. Previous studies from our own and other laboratories showed the anti-tumorigenic potential of 2-Methoxyestradiol (2-ME2) in various tumor models. Although variety of mechanisms including anti-angiogenic, pro-apoptotic, cell cycle deregulation has been reported to contribute to 2-ME2-mediated biological effects, the precise mechanism is unclear. To explore the role of 2-ME2, we carried out gene expression array analysis and discovered Recepteur d’Origine Nantais (RON) as one of the most significantly down regulated gene in response to 2-ME2 treatment. Subsequently, RON was found to be significantly upregulated in advanced-stage PCA cell lines, which do not express androgen receptor (AR); and high-grade human prostate tumors. Stable silencing of RON in androgen independent, PTEN-/- PC3 cells showed noticeable changes in cell morphology, actin filament organization, as well as markers of epithelial-to-mesenchymal transition (EMT). In PTEN wild type DU145 cells, RON knockdown caused an increase in AR expression and promoter activity but decreased the transcriptional activation and expression of AR target genes such as PSA. In contrast, RON overexpression in androgen-responsive LNCAP cells leads to a suppression of the transcriptional activation of both AR and its downstream targets, including PSA. Furthermore, we found that RON silencing decreases expression and promoter activity of the anti-apoptotic protein FLICE-like inhibitory protein (FLIP) that is accompanied by the induction of apoptosis. In addition, intervention with 2-ME2 reduced tumor growth that is accompanied with decreased RON expression in the prostate in transgenic adenocarcinoma of mouse prostate (TRAMP) model. These observations implicate RON as a hijacker of AR signaling that contributes in part to PCA growth. Therefore, restoration of native AR signaling via RON targeting could possibly be exploited in combination with antiandrogenic therapy to prevent recurrence of castrate-resistant prostate cancer. Supported by CA135451 (APK).
Citation Format: Izhar Singh Batth, Peng Meng, Roble Bedolla, Robert E. Reddick, Addanki Pratap Kumar. RON-mediated hijacking of AR signaling in androgen-independent prostate cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3315. doi:10.1158/1538-7445.AM2014-3315