bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4648: Differential regulation of estrogen metabolizing CYP1A1 and CYP1B1 enzymes by novel resveratrol analogs in breast cancer cells
Authors: Ronghe Amruta Mukund , Chatterjee Anwesha , Padhye Subhash , Bhat Hari K. 
Published: August 2015

Abstract
Evidence from epidemiological and experimental studies suggest an association between diets rich in phytoestrogens and reduced risk of breast cancer. Resveratrol, a bioflavonoid, found naturally in grapes, fruits and nuts, has been shown to be a potent chemopreventive agent in vitro. However, poor bioavailability, rapid metabolism and poor specificity limit its use as the preferred anticancer agent. In an attempt to improve the anticancer properties of resveratrol, we synthesized several analogs of resveratrol with appropriate chemical modifications. Of the compounds that were screened for anticancer activity towards breast cancer cells, two analogs, namely, HPIMBD and TIMBD showed better potency and selectivity in inhibiting the growth of breast cancer cell lines while they did not significantly affect the growth of non-neoplastic breast epithelial cell lines. In this study, we investigated the ability of resveratrol and resveratrol analogs in the regulation of estrogen metabolizing genes, cytochrome P450 (Cyp) 1A1, 1B1 and their upstream regulator AhR in breast cancer and non-neoplastic breast epithelial cells.
Non-neoplastic breast epithelial cell line MCF-10A and breast cancer cell lines T47D and MDA-MB-231 were treated with resveratrol, HPIMBD or TIMBD. From cells in culture, mRNA and protein was isolated and expression analyses of CYP1A1, CYP1B1 and AhR carried out by PCR and western blot analyses. Unlike resveratrol, HPIMBD and TIMBD significantly induced the mRNA and protein expression levels of CYP1A1 and AhR while they inhibited that of CYP1B1. Also, HPIMBD and TIMBD induced the expression of CYP1A1 in an AhR-dependent fashion while they inhibited CYP1B1 expression of CYP1B1 by a proteosomal degradation pathway. Cyp1A1 preferentially metabolizes estradiol to 2-hydroxyestradiol and Cyp1B1 to 4-hydroxyestradiol. While, 2-hydroxyestradiol and its methylated product are suggested to be chemo-protective, 4-hydroxyestradiol is regarded as a carcinogenic metabolite of estradiol. Taken together, our findings indicate that novel resveratrol analogs HPIMBD and TIMBD differentially regulate the expressions of CYP1A1 and CYP1B1 in breast cancer cells that may have implications in chemoprevention of breast cancer by these analogs.
Note: This abstract was not presented at the meeting.
Citation Format: Amruta Mukund Ronghe, Anwesha Chatterjee, Subhash Padhye, Hari K. Bhat. Differential regulation of estrogen metabolizing CYP1A1 and CYP1B1 enzymes by novel resveratrol analogs in breast cancer cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4648. doi:10.1158/1538-7445.AM2015-4648
Abstract 4650: Novel resveratrol-analog HPIMBD inhibits breast cancer cell metastasis by reversal of epithelial-mesenchymal transition
Authors: Chatterjee Anwesha , Ronghe Amruta , Padhye Subhash , Bhat Hari K. 
Published: August 2015

Abstract
Epithelial-mesenchymal transition (EMT) is a biological process that mediates a phenotypical change in the polarized epithelial cells to mesenchymal cells. The process of EMT increases a cell's migratory and invasive properties. It is well documented that the process of EMT plays a very critical role in cancer metastasis. The objective of this study was to characterize the role of a novel Resveratrol analog 4-(E)-{4-hydroxyphenylimino)-methylbenzene, 1,2-diol} (HPIMBD) on EMT in human breast cancer cells.
Human breast cancer cells MDA-MB-231 were treated with Resveratrol (Res) and HPIMBD for up to 48 hours. Protein expression levels of E-cadherin, matrix metalloproteases (MMPs), snail, slug, zeb1/2 and nuclear migration of β-catenin were quantified after treatment with Res or HPIMBD and compared with that of the vehicle-treated control cells. mRNA expression levels of β-catenin and wnt-7b were also quantified. Migration MDA-MB-231 cells was determined after treatment with Res or HPIMBD by wound healing assay.
Treatment with HPIMBD significantly up-regulated E-cadherin protein expression levels. The up-regulation of E-cadherin by HPIMBD was associated with suppression of snail, slug and Zeb1 protein levels. HPIMBD significantly down-regulated mRNA expression levels of β-catenin and wnt-7b. Furthermore, HPIMBD restricted nuclear migration of β-catenin. Treatment of breast cancer cells with HPIMBD resulted in down-regulation of MMP3 and MMP9 but not MMP2 protein expression levels. Treatment with HPIMBD also prevented breast cancer cell migration.
Our studies demonstrtae that HPIMBD decreases the metastatic properties of breast cancer cells by inhibition of EMT and down-regulation of wnt/β catenin pathway. These findings suggest that HPIMBD may have a potential in inhibtion of EMT and may be explored as as a potential therapy to prevent breast cancer metastasis.
Note: This abstract was not presented at the meeting.
Citation Format: Anwesha Chatterjee, Amruta Ronghe, Subhash Padhye, Hari K. Bhat. Novel resveratrol-analog HPIMBD inhibits breast cancer cell metastasis by reversal of epithelial-mesenchymal transition. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4650. doi:10.1158/1538-7445.AM2015-4650
Abstract 4653: Modulation of mTOR and p53 signaling using rapamycin plus CP-31398 inhibits growth and progression of urothelial carcinoma in-vivo
Authors: Madka Venkateshwar , Mohammed Altaf , Li Qian , Zhang Yuting , Biddick Laura , Patlolla Jagan M.R. , Lightfoot Stanley , Wu Xue-Ru , Steele Vernon , Kopelovich Levy , Rao Chinthalapally V. 
Published: August 2015

Abstract
Bladder cancer is the second most common genitourinary cancer worldwide. Despite multidisciplinary treatment advances, muscle-invasive bladder cancer continues to have high mortality. Since dysregulation of p53 and mTOR signaling in urothelium is associated with tumor initiation, growth and invasiveness, we investigated whether up-regulation of TP53 plus inhibition of mTOR additively or synergistically inhibits tumor growth and progression in vivo. Transgenic UPII-SV40T male mice (n = 15/group) were generated, genotyped and fed control or experimental diets containing the mTOR inhibitor rapamycin (8 or 16 ppm) and/or the p53 stabilizing agent CP31398 (150 ppm) starting at 6 weeks of age. After 34 weeks, control diet fed transgenic mice developed urothelium-specific high-grade, invasive transitional cell carcinoma (TCC) with significant increase in bladder weights (140.2 ± 9.8 mg; p&lt;0.0001) compared with wild type (27.3 ± 0.8 mg). Rapamycin (8 or 16 ppm) reduced tumor weight by ∼ 67% or 77% and CP31398 decreased it by &gt;70%. The combination of CP31398 with 8 ppm rapamycin decreased tumor weight by ∼83% (16.47 ± 5.4 mg; p&lt;0.0001). Rapamycin (8 or 16 ppm) suppressed tumor invasion by 53% (p&lt;0.005) or 66% (p&lt;0.0005). CP-31398 alone failed to inhibit tumor invasion; however its combination with low-dose rapamycin inhibited tumor invasion &gt;71% (p&lt;0.0001). Molecular analysis of tumors via real-time PCR, IHC and western blotting showed synergistic inhibition by the drug combination of tumor growth and invasion with suppression of mTOR signaling (mTOR, pmTOR, raptor, rictor, Akt, pAkt); induction of p53 expression; and decreased expression of proliferation (PCNA), cell cycle regulators (cyclin D1, cyclin A), pro-survival molecules (Hif1a, Vegf) and androgen receptor. The combination of CP-31398 and rapamycin appears to be a promising approach for preventing urothelial TCC invasion. (Supported in part by NCI-CN53300)
Note: This abstract was not presented at the meeting.
Citation Format: Venkateshwar Madka, Altaf Mohammed, Qian Li, Yuting Zhang, Laura Biddick, Jagan M.R. Patlolla, Stanley Lightfoot, Xue-Ru Wu, Vernon Steele, Levy Kopelovich, Chinthalapally V. Rao. Modulation of mTOR and p53 signaling using rapamycin plus CP-31398 inhibits growth and progression of urothelial carcinoma in-vivo. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4653. doi:10.1158/1538-7445.AM2015-4653
Abstract 4658: Resveratrol aspirinate derivatives as novel chemopreventive agents for colon cancer
Authors: Sang Shengmin , Zhu Yingdong , Fu Junsheng , Shurlknight Kelly 
Published: August 2015

Abstract
In more than a century of use, the benefits of aspirin have been exploited in different therapeutic areas, from inflammation to cardiovascular diseases and cancer prevention. However, the major limitation to the use of aspirin is its side effect to cause ulceration and bleeding in the gastrointestinal tract. The present study found that resveratrol, a natural chemopreventive agent from grapes and berries, and its methylated derivatives can react with acetylsalicyloyl chloride to form resveratrol aspirinate (RAS) and related derivatives. Among all the synthesized derivatives, we found that RAS is the most active component and have much stronger growth inhibitory effect on human colon cancer cells (HCT-116 and HT-29) than resveratrol and aspirin along, as well as the combination of resveratrol and aspirin. In addition, we found that RAS can be hydrolyzed to regenerate resveratrol and aspirin in mice and in human colon cancer cells. Therefore they serve as prodrugs of aspirin and resveratrol and its derivatives. Compared to simply combining aspirin and resveratrol, RAS has not only greater growth inhibitory effects on human colon cancer cells, but also can prevent the damage of gastric epithelial cells caused by direct contact between aspirin and gastric mucosa. Further mechanistic studies found that RAS inhibited cell growth through regulating cell cycle arrest via down-regulation of cyclins D1 and E, and inducing cancer cell apoptosis via mitochondrial pathway. In addition, two stable RAS analogues, for the first time, were successfully synthesized to demonstrate the importance of the scaffold composed of resveratrol and aspirin in the anti-cancer activity of RAS. Our results demonstrated for the first time that resveratrol based aspirin derivatives represent a brand-new, safer and improved alternative to aspirin in anti-cancer and anti-inflammatory therapies.
Note: This abstract was not presented at the meeting.
Citation Format: Shengmin Sang, Yingdong Zhu, Junsheng Fu, Kelly Shurlknight. Resveratrol aspirinate derivatives as novel chemopreventive agents for colon cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4658. doi:10.1158/1538-7445.AM2015-4658
Abstract 4664: Impact of TP53 mutations, single nucleotide variants and global methylation patterns on pre-menopausal breast cancer risk
Authors: Samuel Nardin , Lemire Mathieu , Novokmet Ana , Hudson Thomas J. , Malkin David 
Published: August 2015

Abstract
INTRODUCTION: Li-Fraumeni Syndrome (LFS) is a cancer predisposition syndrome that confers a high lifetime risk of developing malignancies, including pre-menopausal breast cancer. Over 80% of LFS patients harbor germline mutations of the TP53 tumor suppressor gene.
OBJECTIVE: We sought to determine if the spectrum of TP53 variants, as well as global methylation methylation patterns, correlates with the presence of TP53 mutations or influences cancer risk in pre-menopausal breast cancer patients.
METHODS: Constitutional DNA was obtained from peripheral blood lymphocytes (PBL) of 10 patients with pre-menopausal breast cancer harboring germline TP53 mutations, 10 patients diagnosed with pre-menopausal breast cancer that are non-mutation carriers, 15 TP53 mutation carriers who do not have cancer, and 15 healthy female controls. Genome-wide methylation analysis of PBL-derived DNA was performed using the Illumina 450K array. Sanger sequencing of exons 2-11, and flanking intron regions of the TP53 gene was performed.
RESULTS: The most commonly observed single nucleotide polymorphism (SNP) in TP53 across all samples was at c.215C&gt;G (p.Pro72Arg) in exon 4 (rs1042522). We observed a G allele frequency of 66.0% in our study group. Three additional low-frequency variants in TP53 were observed: the exon 4: c.108G&gt;A (p.Pro36Pro) variant was found in 2 patients, exon 6: c.639A&gt;G (p.Arg213Arg) was found in 9 patients and intron 9: c.993+12T&gt;C was found in 4 patients. Methylation patterns were not associated with a specific TP53 mutation or variant; however, distinct methylation patterns were observed in TP53 mutation carriers when compared to either TP53 wild-type healthy individuals or patients with early-onset breast cancer.
DISCUSSION: This study represents an epigenome-wide analysis and targeted genetic survey of germline TP53 in early-onset, pre-menoupausal breast cancer. As a result of the mutation frequency observed, germline mutations in TP53 may need to be included in the genetic work-up of patients with early-onset breast cancer. Parallel studies of genome-wide methylation demonstrate these patterns may serve as an independent biomarker of early-onset breast cancer risk.
Note: This abstract was not presented at the meeting.
Citation Format: Nardin Samuel, Mathieu Lemire, Ana Novokmet, Thomas J. Hudson, David Malkin. Impact of TP53 mutations, single nucleotide variants and global methylation patterns on pre-menopausal breast cancer risk. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4664. doi:10.1158/1538-7445.AM2015-4664
Abstract 4673: Parity and short-term estradiol treatment confers protection against breast cancer by suppressing cell survival and migration
Authors: Arumugam Arunkumar , Subramani Ramadevi , Nandy Sushmita , Do Duy , Lakshmanaswamy Rajkumar 
Published: August 2015

Abstract
Early pregnancy is the only natural phenomenon known to confer protection against breast cancer. We have earlier demonstrated that short-term treatment with pregnancy levels of estradiol (STET) is very effective in preventing mammary carcinogenesis. The underlying mechanisms behind the protective effect of parity and STET remain unclear. In the current study, we attempted to delineate the influence of the mammary gland microenvironment on mammary carcinogenesis among parous and STET compared to age matched virgin rats. Parous, STET, and virgin (control) Sprague Dawley rats were administered N-methyl-N-nitrosourea (50mg/kg BW) at 15 weeks of age. Mammary cancer development was monitored by weekly palpations for 9 months post carcinogen treatment. A subset of rats (n = 4) were euthanized five weeks post carcinogen treatment. Mammary gland samples were surgically excised and used for histological and molecular analysis. Our analysis demonstrated that parity and STET resulted in reduced expression of cell survival markers (pAKT, pmTOR), extracellular matrix mediated signaling proteins (ERK1/2, pFAK, Itgb1) hormonal (ER, PR, GHR) and growth factor receptors (pEGFR, pIGFR1) compared to age matched virgin group. Further, expression of EMT markers and regulators of cell migration were significantly reduced in parous and STET mammary glands. MicroRNA analysis disclosed that both parity and STET differentially regulated the expression of 23 microRNAs. Among these 18 microRNAs were down regulated and 5 microRNAs were up regulated in both parous and STET treatment. In silico analysis revealed that several of the differentially regulated microRNAs are direct regulators of the cell survival and cell migratory proteins. Parity and STET by altering microRNA expression influences cell survival, cell migration and cell death signaling pathways reduces the cancer promoting microenvironment in the mammary gland.
Citation Format: Arunkumar Arumugam, Ramadevi Subramani, Sushmita Nandy, Duy Do, Rajkumar Lakshmanaswamy. Parity and short-term estradiol treatment confers protection against breast cancer by suppressing cell survival and migration. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4673. doi:10.1158/1538-7445.AM2015-4673
Abstract 4677: Control of androgen receptor function by the genomic action of the cochaperone Bag-1L
Authors: Cato Laura , Neeb Antje , Adelmant Guillaume , Ficarro Scott , Westerling Thomas , Marto Jarrod A. , Cato Andrew C. , Brown Myles 
Published: August 2015

Abstract
The androgen receptor (AR) is an important determinant of normal and malignant prostate growth and its function is regulated by many factors, including molecular chaperones, cochaperones and coregulators. One such factor is the nuclear-resident cochaperone Bag-1L. Overexpression of Bag-1L and the amplification of its gene have been reported in the hormone-refractory and metastatic stages of prostate cancer and in androgen-independent prostate cancer cells. However the exact mechanism of Bag-1L-mediated regulation of AR action in prostate cancer remains unclear.
Here we show that Bag-1L and AR directly interact with one another through two distinct domains in both proteins. While the N-terminus of Bag-1L binds to the AR BF-3 domain via a conserved GARRPR motif, the C-terminal Hsp70/Hsc70-binding domain (BAG) of Bag-1L binds to the tau5 region in the intrinsically disordered AR AF1. The latter interaction is of particular significance as tau5 is a region crucial for the ligand-independent transcriptional activity of the receptor. Understanding the details of this interaction will therefore provide new opportunities of controlling AR action for therapeutic purposes outside of targeting the LBD.
We have identified the exact amino acids (K231, K232 and K279) in the BAG domain that are required for the interaction with AR. Amino acid substitution of these residues destroy the interaction of Bag-1L and AR but do not affect the binding to Hsp70/Hsc70. We also observed significant reduction in androgen-dependent cell growth when the BAG-domain mutant is overexpressed in prostate cancer cells in culture and in xenograft mouse models. We further tested the consequence of the BAG-domain mutation on AR transactivation by microarray analysis. We observed repressed expression of multiple genes, including the AR coactivator NCoA2. Correspondingly, we observed multiple changes in the Bag-1L interactome when comparing the wild-type with the BAG mutant; this includes the loss of interaction with the heat shock protein Hsp27 for the mutant Bag-1L protein. Combined these results demonstrate the importance of Bag-1L for AR function and the potential of this protein for therapeutic intervention in prostate cancer.
Citation Format: Laura Cato, Antje Neeb, Guillaume Adelmant, Scott Ficarro, Thomas Westerling, Jarrod A. Marto, Andrew C. Cato, Myles Brown. Control of androgen receptor function by the genomic action of the cochaperone Bag-1L. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4677. doi:10.1158/1538-7445.AM2015-4677
Abstract 468: Delayed tumor growth in breast cancer is associated with reduced activity of the a2 isoform of vacuolar ATPase
Authors: Katara Gajendra K. , Kulshrestha Arpita , Gilman-Sachs Alice , Beaman Kenneth D. 
Published: August 2015

Abstract
In cancer cells, vacuolar ATPase (V-ATPase), a multi-subunit enzyme, is expressed on the plasma as well as vesicular membranes and critically influences metastatic behavior. The soluble, cleaved N-terminal domain of a2 isoform of V-ATPase (a2NTD) is associated with in vitro induction of both tumor associated macrophages (TAMs) phenotype and activity in macrophages. This activity caused us to further investigate the role of a2NTD in cancer progression. We evaluated the effects of the knock down of a2 isoform (a2V) in tumor cells and the concomitant tumor microenvironment in the 4T-1 mouse breast cancer model. In vitro experiments showed that macrophages co-cultivated with a2V knocked down (sh-a2) tumor cells produced lower amounts of tumorigenic factors and have a reduced ability to suppress T cell activation and proliferation compared to control tumor cells. Furthermore, sh-a2 4T1 or control 4T-1 cells were inoculated into female Balb/c mice to generate mammary tumors. Data analysis showed that tumor growth in mice inoculated with sh-a2 4T-1 cells was delayed up to ten fold compared to control (mean±SD: 1.3 ± 1.15 vs 13.96 ± 4.06, P&gt;0.01) at day 8 after inoculation. The expression of TAM associated molecules like mannose receptor-1 or CD206, IL-10, Arginase-1, matrix metalloproteinase and vascular endothelial growth factor were significantly down regulated in tumors from sh-a2 inoculated mice compared to control (P&lt;0.01). Additionally, a significant reduction in the number of TAMs (F4/80+CD206+: mean = 6) and increase in macrophage with anti-tumor activity (F4/80+CD11c+: mean = 10.4) was also observed in these tumors which contributed towards delay in tumor growth. Further, we successfully deleted a2V gene in mice and its effect on tumor generation and microenvironment is evaluated. These findings demonstrated that in the absence of a2V in tumor cells, the resident TAM population in the tumor microenvironment is altered, which affected in vivo tumor growth. The data show that by involving the host innate immune system, tumor growth can be control through targeting of a2V and other related factors in tumor cells.
Citation Format: Gajendra K. Katara, Arpita Kulshrestha, Alice Gilman-Sachs, Kenneth D. Beaman. Delayed tumor growth in breast cancer is associated with reduced activity of the a2 isoform of vacuolar ATPase. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 468. doi:10.1158/1538-7445.AM2015-468