bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5547: A genetic variant near KLK3 gene is associated with aggressive prostate cancer and can stratify Gleason score 7 patients
Authors: Gu Jian , He Yonggang , Strom Sara S. , Logothetis Christopher J. , Kim Jeri , Wu Xifeng 
Published: May 2015

Abstract
Purpose: Gleason score (GS) 7 prostate cancer is a heterogeneous disease with significant differences in aggressiveness and prognosis. We sought to identify genetic biomarkers that may predict the aggressiveness of GS 7 diseases. Experimental Design: We genotyped 72 prostate cancer susceptibility single nucleotide polymorphisms (SNPs) identified in genome-wide association studies in 1827 white men with histologically confirmed prostate adenocarcinoma. SNPs associated with disease aggressiveness were identified by comparing high-aggressive (GS ≥8) and low-aggressive (GS ≤6) cases. The significant SNPs were then tested to see whether they could further stratify GS 7 prostate cancer. Results: Three SNPs_rs2735839, rs10486567, and rs103294_were associated with biopsy-proven high-aggressive (GS ≥8) prostate cancer (P &lt; 0.05). Rs2735839 and rs10486567 were also associated with high D'Amico risk groups. Furthermore, the frequency of the variant allele (A) at rs2735839 was significantly higher in patients with biopsy-proven GS 4+3 disease than in those with GS 3+4 disease (P = 0.003). In multivariate logistic regression analysis, patients carrying the A allele at rs2735839 exhibited a 1.85-fold (95% 1.31-2.61) increased risk of being GS 4+3 compared to those with GS 3+4. Rs2735839 is located 600 base pair downstream of KLK3 gene (encoding PSA) on 19q13.33 and has been shown to modulate PSA level, providing strong biological plausibility for its association with prostate cancer aggressiveness. Conclusions: We showed the association of the rs2735839 with high-aggressive prostate cancer (GS ≥8). Moreover, we reported for the first time that rs2735839 can stratify GS 7 patients, which would be clinically important for more accurately assessing the clinical behavior of the intermediate-grade prostate cancer and for tailoring personalized treatment and post-treatment management.
Citation Format: Jian Gu, Yonggang He, Sara S. Strom, Christopher J. Logothetis, Jeri Kim, Xifeng Wu. A genetic variant near KLK3 gene is associated with aggressive prostate cancer and can stratify Gleason score 7 patients. [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 5547. doi:10.1158/1538-7445.AM2014-5547
Abstract 5549: Recipient-donor contradictory genotype with impact on anticancer drug pharmacogenetics after liver transplant: A deadly gift
Authors: Serdjebi Cindy , Fanciullino Raphaelle , Fina Frederic , Verschuur Arnaud , Roquelaure Bertrand , Lacarelle Bruno , Ouafik L'Houcine , Ciccolini Joseph , André Nicolas 
Published: May 2015

Abstract
A 5-year old girl with liver transplant was scheduled for a therapy including high-dose cytarabine for her Burkitt lymphoma. Cytarabine pharmacogenetics focus on cytidine deaminase (CDA) , the polymorphic liver enzyme responsible for its detoxification. Preliminary double testing for her CDA status on DNA lymphocytes showed none of the germline polymorphisms usually associated with CDA deficiency (ie, 79A&gt;C (K27Q), 208G&gt;A), but surprisingly with a functional mild deficiency syndrom. Despite 30% reduction in cytarabine dosing, life-threatening toxicities showed quickly and treatment was discontinued. Genetic HRM-based investigations performed in the patient on liver biopsy failed in generating a clear genotype. Further HRM+sequencing retrospective investigations on liver biopsy collected from the donor showed that he was actually bearing the homozygous CDA*2 allelic variant (ie, 79AA), a genotype usually associated with severe CDA deficiency. Based upon the donor liver genotype, and not the recipient genotype, treatement was resumed with further dose reduction, close monitoring and better tolerance eventually. The patient is now in complete remission more than a year after completion of the treatment. This case report illustrates the limits and risks of searching germline polymorphisms in patients with liver transplant when the story plays in the liver.
Citation Format: Cindy Serdjebi, Raphaelle Fanciullino, Frederic Fina, Arnaud Verschuur, Bertrand Roquelaure, Bruno Lacarelle, L'Houcine Ouafik, Joseph Ciccolini, Nicolas André. Recipient-donor contradictory genotype with impact on anticancer drug pharmacogenetics after liver transplant: A deadly gift. [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 5549. doi:10.1158/1538-7445.AM2014-5549
Abstract 5553: Monotherapy efficacy of catalytic and allosteric inhibitors of AKT in breast cancer models with AKT1E17K mutations
Authors: Davies Barry R. , Guan Nin , Logie Armelle , Palmer Amy , Jacobs Vivien , James Neil , Jenkins Emma L. 
Published: May 2015

Abstract
AKT1E17K mutations occur at low frequency in a variety of solid tumors, including those of the breast and urinary bladder. Although this mutation has been shown to transform rodent cells in culture, it was found to be less oncogenic than PIK3CA mutations in breast epithelial cells. Moreover, the therapeutic potential of AKT inhibitors in human tumors with an endogenous AKT1E17K mutation is not known. Expression of exogenous copies of AKT1E17K in MCF10A breast epithelial cells increased phosphorylation of AKT and its substrates, and induced colony formation in soft agar. These effects were inhibited by the allosteric and catalytic AKT inhibitors MK-2206 and AZD5363, respectively. We identified two breast cancer explant models with AKT1E17K mutation (HBC-x2 and HBCx-31). Dosing of AZD5363 at 150 mg/kg twice daily or MK-2206 at 120 mg/kg 3 times a week significantly inhibited tumor growth in both models, but AZD5363 was significantly more active than MK-2206 at the dosing schedules employed, in both models. Pharmacodynamics were assessed in the HBC-x2 model at 2 h after the final dose. Both compounds significantly inhibited phosphorylation of PRAS40 and S6, caused relocalisation of FOXO3a to the nucleus, and reduced Ki67 staining. The data indicate that breast cancers with AKT1E17K mutations are rational targets for monotherapy treatment with AKT inhibitors.
Citation Format: Barry R. Davies, Nin Guan, Armelle Logie, Amy Palmer, Vivien Jacobs, Neil James, Emma L. Jenkins. Monotherapy efficacy of catalytic and allosteric inhibitors of AKT in breast cancer models with AKT1E17K mutations. [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 5553. doi:10.1158/1538-7445.AM2014-5553
Abstract 5563: Docetaxel-induced mucositis in breast cancer patients: Association with plasma alpha-1-acid glycoprotein level and SLCO1B3 genotype
Authors: Jabir Rafid S. , HO Gwo F. , Anuar Muhammad Azrif A. , Stanslas Johnson 
Published: May 2015

Abstract
Mucositis is one of the major non-hematological adverse effects (AEs) of docetaxel, besides fatigue, nausea, vomiting, diarrhea and rash which limit its use in cancer patients. Alpha-1-acid glycoprotein (AAG) is an acute phase reactant glycoprotein and is a primary carrier of docetaxel in the blood. Docetaxel demonstrates extensive binding to plasma proteins (&gt;98%) including AAG, lipoproteins and albumin. However, there is a remarkable inter-individual variation of AAG level among cancer patients. Low plasma AAG levels will result in excessive free drug in the circulation, which in turn causes more AEs. Consequently, either the dose is reduced or treatment modality is diverted. In addition, single nucleotide polymorphisms (SNPs) of genes encoding for proteins involved in the transport of docetaxel (SLCO1B3) could lead to reduced clearance and accumulation in the circulation and subsequent AEs. Hence, we investigated 91 Malaysian breast cancer patients receiving docetaxel as a single agent chemotherapy at 90-100 mg/m2 and 75 mg/m2 in the adjuvant and metastatic settings respectively, to determine the association between the SNP (SLCO1B3 334TG), plasma AAG level and docetaxel AEs. The plasma AAG level was determined using Enzyme Linked Immunosorbent assay (ELISA) technique, while the SNPs were analyzed using PCR-RFLP technique followed by DNA sequencing of selected samples. The patients consisted of 49 Chinese (54%), 34 Malays (37%) and 8 Indians (9%). We found a significant difference in plasma AAG level between patients with mucositis and those without (178±74 mg/dl vs 225±97 mg/dl,P&lt;0.05). Moreover, patients with mutant SLCO1B3 334GG who developed diarrhea also had mucositis (p&lt;0.05). In conclusion, patients with lower plasma AAG level are more susceptible to develop mucositis. In addition, patients carrying mutant SLCO1B3 334GG who have diarrhea tend to develop mucositis concurrently. Plasma AAG level and SNPs could serve as potential predictive biomarkers of docetaxel-induced mucositis.We would like to thank Malaysian Ministry of Higher Education (MOHE) and University Malaya for funding this project through FRGS (04-04-10-848FR) and HIR (UM.C/625/1/HIR) grants.
Citation Format: Rafid S. Jabir, Gwo F. HO, Muhammad Azrif A. Anuar, Johnson Stanslas. Docetaxel-induced mucositis in breast cancer patients: Association with plasma alpha-1-acid glycoprotein level and SLCO1B3 genotype. [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 5563. doi:10.1158/1538-7445.AM2014-5563
Abstract 5567: Impact of progesterone receptor (PR) isotype-specific immunohistochemistry (IHC) on the diagnosis of triple negative breast cancer (BC)
Authors: Gilles Erard , Bosq Jacques , Caplier Laura , Bexon Alice , Zukiwski Alexander , Bonneterre Jacques 
Published: May 2015

Abstract
Background: Given the poor therapeutic outcomes for triple negative BC, diagnostic accuracy is vital. In routine IHC, PR is measured using bispecific antibodies (Ab) that recognize epitopes common to PRA and PRB. PR A and B expression is imbalanced in BC. Relative expression of the PR isotypes appears to be prognostic in tumors evaluated with a bispecific Ab (Hopp 2004). Tumors can express PRA or PRB on different cells in the same tumor (Mote 2008), which differ from those expressing ERα (Zukiwski 2013). A true triple negative phenotype might escape detection with the use of one single Ab to detect both PR A and B epitopes, depending on its sensitivity/specificity. This study evaluated the use of two isotype-specific PR Abs to fully characterize PR status.
Methods: 312 archived BC specimens with clinical data came from Oscar Lambret Cancer Center, Lille. HER2 status was previously determined. IHC was performed using anti-ERα, anti-PRA and PRB Abs. ERα and PR tumor positivity was defined as ≥ 1% stained tumor cells.
Results: 276 cases had complete data. Table 1 shows ERα, PRA and PRB status. 38/276 cases (14%) were ERα and HER2 negative: 22 were PR A or B negative, 9 were PR A and B positive, 2 were positive only for PRA and 5 only for PRB. Discussion: Bispecific PR Abs rarely report PRA and PRB similarly (Mote 2001). PR Phosphorylation and activation may vary across tumors. Potentially only one PR isotype may drive BC tumor growth. Triple-negative BC status determination could be PR Ab-dependent. These cases are currently being tested with a standard bispecific PR Ab to understand which would be considered triple-negative with routine IHC.
Conclusion: Further evaluation of IHC with specific PRA and PRB Abs is warranted to determine if certain patients, currently classified as having triple-negative BC, could respond to antiprogestins, which have shown activity in BC.
Table 1% of276 casesPR (PRA or PRB)PRAPRBERαNegativePositiveTotalNegativePositiveTotalNegativePositiveTotalNegative148221742115722Positive77178146579106868Total217910031691002575100
Citation Format: Erard Gilles, Jacques Bosq, Laura Caplier, Alice Bexon, Alexander Zukiwski, Jacques Bonneterre. Impact of progesterone receptor (PR) isotype-specific immunohistochemistry (IHC) on the diagnosis of triple negative breast cancer (BC). [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 5567. doi:10.1158/1538-7445.AM2014-5567
Abstract 5568: CYP17A1 and abiraterone: Implications for breast cancer endocrine therapy
Authors: Capper Cameron P. , Johnson Michael D. , Larios José M. , Rae James M. 
Published: May 2015

Abstract
The cytochrome P450 17A1 (CYP17A1) inhibitor abiraterone, which blocks synthesis of all steroid hormones including androgens and estrogens, is an effective treatment for castrate resistant prostate cancer. Its utility for treating hormone receptor-positive breast cancer has yet to be established. In prostate cancer, the anti-proliferative effects of abiraterone are mediated by inhibiting CYP17A1 activity resulting in a significant reduction in circulating concentrations of the sex steroids dehydroepiandrosterone (DHEA), androstenedione, testosterone, and dihydrotestosterone (DHT). Recently, it has been proposed that the reduction in aromatizable androgens by abiraterone may make this drug useful for the management of hormone-dependent breast cancer. However, data from our lab suggests that abiraterone has estrogenic properties and can induce proliferation in breast cancer cells expressing the estrogen receptor (ER). Crystal violet assays were used to assess abiraterone-induced proliferation in the ER-positive, estrogen-dependent breast cancer cell lines MCF-7 and T47D. We show that abiraterone induced a dose dependent increase in cell proliferation with an IC50 of 3.7 μM and maximal stimulation (200%) observed at 8μM, compared to vehicle treated cells. Abiraterone also induced the expression of the ER response gene, GREB1. Abiraterone-induced proliferation and gene expression was blocked by increasing doses of the selective estrogen receptor down-regulator (SERD) fulvestrant. Abiraterone induced the dose-dependent expression of luciferase in MCF-7 cells transfected with an estrogen responsive luciferase reporter construct. In conclusion, our data suggest that abiraterone can induce ER-positive breast cancer cell proliferation in vitro by acting as a weak ER agonist. Further studies are underway to determine whether estrogenic effects of abiraterone are also observed using in vivo models of ER response. If abiraterone exhibits estrogenic effects in vivo then these data would suggest that abiraterone should be combined with an ER antagonist if used for the clinical management of women with ER+ tumors.
Citation Format: Cameron P. Capper, Michael D. Johnson, José M. Larios, James M. Rae. CYP17A1 and abiraterone: Implications for breast cancer endocrine therapy. [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 5568. doi:10.1158/1538-7445.AM2014-5568
Abstract 5569: Ki67 is an independent prognostic marker in breast cancer even after accounting for molecular subtype
Authors: Mahmoud Abeer M. , Macias Virgilia , Al-alem Umaima , Kresovich Jacob K. , Khramtsova Galina , Kajdacsy-Balla Andre , Wiley Elizabeth L. , Rauscher Garth H. 
Published: May 2015

Abstract
Ki67 labeling index (LI) has been demonstrated to be a prognostic marker in invasive breast cancer; a high Ki67 LI is associated with poorer survival among breast cancer patients. The goal of these analyses was to examine the extent to which Ki67 was associated with specific breast cancer subtypes, and whether it could serve as an additional prognostic marker above and beyond breast cancer subtype, in an ethnically diverse sample of 287 patients (86 Non-Hispanic White, 84 Hispanic and 116 African American).
IHC analysis was performed on tissue microarrays constructed from invasive breast cancer samples obtained from the Breast Cancer Care in Chicago study (patients diagnosed between 2005-2008). Tissue samples were tested for the expression of estrogen receptor (ER), progesterone receptor (PR), HER2, EGFR and CK5/6. From these results, breast cancers were classified as Luminal A (ER+/PR+/HER2-), Luminal B (ER+/PR+/HER2+), HER2 enriched (ER-/PR-/HER2+), and triple negative (TN) (ER-/PR-/HER2-). TN tumors were subclassified into basal like (BL) if they expressed either EGFR or CK5/6 or otherwise classified as unspecified (US) if negative for both EGFR and CK5/6. Ki67 LI was classified as low (&lt;14%) or high (≥14%). We used multivariable logistic regression to examine associations between Ki67, breast cancer subtype, and histological grade, controlling for race/ethnicity and age at diagnosis in all models.
In adjusted models, the proportion of tumors with a high Ki67 LI was much lower for luminal A (28%) than for luminal B, HER2, TN-US, and TN-BL subtypes (91,66, 77 and 89%, respectively, p&lt;0.0001). The proportion of tumors that were high histologic grade was also much lower for luminal A (29%) than for luminal B, HER2, TN-US, and TN-BL subtypes (85, 86, 94 and 68%, respectively, p&lt;0.0001). Before accounting for subtype, 68% of high Ki67 tumors were high grade, compared with only 26% of low Ki67 tumors (p&lt;0.0001); after controlling for breast cancer subtype these percentages were 58% and 37%, respectively, p=0.001).
In this multi-ethnic sample of breast cancer patients, we found that Ki67 was a significant independent predictor of more aggressive, higher grade disease, even after accounting for molecular subtype. Ki67 might serve as a useful additional marker for the classification of breast cancer into molecular subtypes.
Citation Format: Abeer M. Mahmoud, Virgilia Macias, Umaima Al-alem, Jacob K. Kresovich, Galina Khramtsova, Andre Kajdacsy-Balla, Elizabeth L. Wiley, Garth H. Rauscher. Ki67 is an independent prognostic marker in breast cancer even after accounting for molecular subtype. [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 5569. doi:10.1158/1538-7445.AM2014-5569
Abstract 5571: Genome-wide crosstalk of estrogen and progesterone signaling in breast cancer
Authors: Singhal Hari , Greene Geoffrey 
Published: May 2015

Abstract
Estrogen receptor alpha (ER) and progesterone receptor (PR) are established biomarkers in breast cancer and receptor-targeted therapies are routinely used in breast cancer treatment. Estrogen receptor exists as two subtypes, ERα and ERβ, and PR has two isoforms PRA and PRB. Furthermore, millions of women worldwide use estrogen and progesterone formulations as oral contraceptives and hormone replacement therapies. Although critical crosstalk occurs between estrogen and progesterone signaling, the global nature and mechanistic details of this interaction are not known. Our central hypothesis is that there is genome-wide dominance of progesterone over estrogen signaling in breast cancer. This hypothesis is based on our novel findings that gene expression and proliferation of T47D and ZR75 breast cancer cells upon co-treatment with estrogen and progesterone is similar to progesterone-only treatment and is significantly different from estrogen-only treatment. Furthermore, four derivative T47D sublines that lack either of the PR isoforms, both the isoforms of PR or ER along with PR are being used to study ERα-, PRA- and PRB-specific regulatory networks. ER- and PR-regulated gene networks are defined by correlating ER and PR genome binding data obtained from ChIP-seq with gene expression data of T47D cells acquired using RNA-seq. For instance, genes that are known to be important in breast carcinogenesis, such as GATA3, GREB1, PDZK1, FOXA1 are found to be co-regulated by ER and PR. Subsequently the intersection of identified ER- and PR-regulated gene networks will be studied and their clinical value will be assessed. Transcription cofactors FOXA1 and NF1C are critical for transactivation by ER and PR. Knockdown of these cofactors in T47D cells alters the ER/PR crosstalk in these cells. To validate the clinical value of genes co-regulated by ER and PR in breast cancer, meta-analysis for their enrichment in established breast cancer signatures will be done. Cluster analysis of the expression of these genes in patient tumor samples that differ in clinical outcomes will also be performed. Finally, a Kaplan-Meier survival analysis will be done to study a correlation between expression of these genes and patient survival. These innovative studies will determine the global influence of progesterone over estrogen signaling in breast cancer. The resulting map of ER- and PR-regulated gene networks will lead to the optimization of breast cancer treatments, hormonal contraceptives and hormone replacement therapies.
Citation Format: Hari Singhal, Geoffrey Greene. Genome-wide crosstalk of estrogen and progesterone signaling in 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 5571. doi:10.1158/1538-7445.AM2014-5571
Abstract 5580: TGF-β1 enhanced cell migration involving pluripotent transcription factor OCT4 in endometriosis
Authors: Chang Te-Sheng , Au Heng-Kien , Ling Thai-Yen , Chi Ching-Chi , Tzeng Chii-Ruey , Chang Jui-Hung , Huang Yen-Hua 
Published: May 2015

Abstract
Endometriosis is the eutopic and/or ectopic growth of endometrial tissues. High levels of TGF-β in peritoneal fluid and increased expression of OCT4 have been well documented in endometriosis. However, the molecular mechanism between TGF-β and OCT4 expression in endometriosis still remains largely unknown. In this study, we examined the roles of OCT4 in TGF-β-induced endometrial cell migration and the progression of human ectopic endometriosis. We analyzed the plasma levels of TGF-β (n = 80) and gene expression levels of TGF-βR1 in patient tissues (n = 60) by an ELISA assay and quantitative real-time RT-PCR. The serum TGF-β and tissue TGF-βR1 expressions were significantly increased in the ectopic endometriotic tissues (n = 54, 29 for adenomyosis tissues and 25 for chocolate cysts) comparing with the normal endometrium (n = 5). The TGFβR1 transcriptional level in endometriotic tissues was positively correlated with expressions of OCT4 and genes associated with cell migration, such as VIMENTIN, TWIST, SNAIL and SLUG. TGF-β dose-dependently increased the OCT4 expression both in gene and protein levels in human endometriotic stromal cells and, at a less intensity, in HEC1A endometrial carcinoma cell line. Additionally, TGF-βincreased the expression of migration-associated genes and proteins (SNAIL and N-CAD) dose-dependently both in gene and protein levels in human endometriotic stromal cells. Knockdown of OCT4 significantly suppressed the TGF-β-induced the expressions of migration-associated genes and proteins (N-CAD and SNAIL), and promoted the migration of endometrial cells as evidenced by wound-closure and transwell assays. Conclusions: TGF-β,TGF-βRI, and OCT4 are significantly upregulated in human ectopic endometriotic tissues. The significant OCT4 expression may be involved in the pathology of ectopic endometrial growth through TGF-β-induced migration of endometrial cells.
Citation Format: Te-Sheng Chang, Heng-Kien Au, Thai-Yen Ling, Ching-Chi Chi, Chii-Ruey Tzeng, Jui-Hung Chang, Yen-Hua Huang. TGF-β1 enhanced cell migration involving pluripotent transcription factor OCT4 in endometriosis. [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 5580. doi:10.1158/1538-7445.AM2014-5580