Citations

Abstract Background: Nulliparity is an established endometrial cancer risk factor, but whether this association is related to infertility is unclear. Although there are many underlying causes of infertility, few studies have assessed risk relationships according to specific causes. Despite concerns that most treatments induce ovulation and that the endometrium is highly hormonally-responsive, previous studies have provided conflicting results on treatment associations. Methods: To address these issues, we conducted a pooled analysis of 8,151 cases and12,471 controls from 2 cohort and 12 case-control studies conducted in 1982 to 2009 (N. America, Europe, Australia, Asia). All studies provided self-reported infertility, causes and treatments, except for 1 study that relied on data from national registries. Study-specific exposures and covariate data were harmonized across studies. Logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI), adjusted for study, age, interview year, race, parity, oral contraceptive and menopausal hormone use, and body mass index. If data were not reported for a particular variable, that study was excluded from the variable-specific analysis. Results: Nulliparous women had an elevated endometrial cancer risk compared with parous women (adjusted OR=1.73; 95% CI: 1.58-1.90).Women with self-reported infertility also had an increased risk (adjusted OR=1.22; 95% CI: 1.13-1.32) compared with those without infertility issues, even after adjusting for parity; the strongest associations was seen among studies that defined infertility as unsuccessfully trying to conceive for 2+ years (adjusted OR=1.31; 95% CI: 1.07-1.60). Infertility was associated with similar risks among nulliparous (1.22; 1.10-1.48) and parous (1.22; 1.12-1.34) women, although there was no increased risk associated with infertility among those who had given birth to 3+ children. Two infertility causes associated with risk elevation were endometriosis (adjusted OR=2.08; 95% CI: 1.46-2.95 compared with women no infertility problems) and anovulation (adjusted OR=1.40; 95% CI: 1.16-1.70). Based on relatively small numbers, none of the individual treatments (in vitro fertilization, selective estrogen response modulators, gonatropins, progestins, estrogens) were substantially related to risk. Conclusion: Based on mainly self-reported infertility data, we found that parity and infertility independently contribute to endometrial cancer risk, with parity seemingly being the predominant risk predictor. Understanding residual endometrial cancer relationships related to causes of infertility and infertility treatment may benefit from documented medical information on causes of infertility and treatment parameters. Citation Format: Hannah P. Yang, Linda S. Cook, Elisabete Weiderpass, Hans-Olov Adami, Kristin E. Anderson, Hui Cai, James R. Cerhan, Tess Clendenen, Ashley S. Felix, Christine Friedenreich, Montserrat Garcia-Closas, Marc T. Goodman, Xiaolin Liang, Jolanta Lissowska, Lingeng Lu, Anthony M. Magliocco, Susan E. McCann, Kristen B. Moysich, Sara H. Olson, Malcolm C. Pike, Silvia Polidoro, Fulvio Ricceri, Harvey Risch, Carlotta Sacerdote, V. Wendy Setiawan, Xiao Ou Shu, Amanda B. Spurdle, Britton Trabert, Penelope M. Webb, Nicolas Wentzensen, Yong-Bing Xiang, Youming Xu, Herbert Yu, Anne Zeleniuch-Jacquotte, Louise A. Brinton. Infertility and risk of incident endometrial carcinoma: a pooled analysis from the Epidemiology of Endometrial Cancer Consortium. [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 2167. doi:10.1158/1538-7445.AM2014-2167

Significance We have identified a lethal subtype of gastric cancer (GC) that is characterized by high levels of clonal heterogeneity and TP53 (tumor protein P53) mutation. We have also uncovered key novel mutations in the targetable NRG1 (neuregulin-1) and ERBB4 (V-Erb-B2 avian erythroblastic leukemia viral oncogene homolog 4) ligand-receptor pair and identified BRCA2 (breast cancer 2, early onset) mutations as new genetic markers to predict better survival for GC. Our study represents a novel approach for GC personalized medicine and identified novel clinical actionable therapies for GC therapy.

Platelet-derived growth factor (PDGF) and transforming growth factor-β (TGF-β) signaling are required for hepatic stellate cell (HSC) activation under pathological conditions such as liver metastatic tumor growth. These two signaling pathways are functionally divergent; PDGF signaling promotes proliferation and migration of HSCs, and TGF-β induces transdifferentiation of quiescent HSCs into myofibroblasts. Although PDGF signaling is implicated in TGF-β-mediated epithelial mesenchymal transition of tumor cells, the role of PDGF receptors in TGF-β activation of HSCs has not been investigated. Here we report that PDGF receptor-α (PDGFR-α) is required for TGF-β signaling of cultured human HSCs although HSCs express both PDGF-α and -β receptors. PDGFR-α knockdown inhibits TGF-β-induced phosphorylation and nuclear accumulation of SMAD2 with no influence on AKT or ERK phosphorylation associated with noncanonical TGF-β signaling. PDGFR-α knockdown suppresses TGF-β receptor I (TβRI) but increases TβRII gene transcription. At the protein level, PDGFR-α is recruited to TβRI/TβRII complexes by TGF-β stimulation. PDGFR-α knockdown blocks TGF-β-mediated internalization of TβRII and induces accumulation of TβRII at the plasma membrane, thereby inhibiting TGF-β phosphorylation of SMAD2. Functionally, knockdown of PDGFR-α reduces paracrine effects of HSCs on colorectal cancer cell proliferation and migration in vitro. In mice and patients, colorectal cancer cell invasion of the liver induces upregulation of PDGFR-α of HSCs. In summary, our finding that PDGFR-α knockdown inhibits SMAD-dependent TGF-β signaling by repressing TβRI transcriptionally and blocking endocytosis of TGF-β receptors highlights a convergence of PDGF and TGF-β signaling for HSC activation and PDGFR-α as a therapeutic target for liver metastasis and other settings of HSC activation.

Abstract BACKGROUND Metformin, a widely used anti-diabetic drug, is being considered as a highly promising agent for treatment and prevention of many types of cancer, including breast cancer. Although the exact mechanism of action of metformin is unknown, it is thought that metformin is an AMPK activator. To better individualize metformin therapy and explore additional underlying molecular mechanism associated with metformin action, we conducted a metformin pharmacogenomic study using 266 genomic data-enriched lymphoblastoid cell lines (LCLs). METHODS Genome-wide microarray data were generated for all LCLs, including 1.3 million SNPs, 485K DNA methylation probes and 54K mRNA expression probe sets. Metformin cytotoxicity assay was performed using MTS assay. Genome-wide association (GWA) analyses and integrated analyses using all the genomic data and metformin cytotoxicity (IC50 value) were performed to identify top candidate genes for functional validation in breast cancer cell lines, MDA-MB 231 and Hs578T, using siRNA screening approach. Further mechanistic study was performed to investigate the role of candidates in regulation of AMPK activity. RESULTS GWA analyses in LCLs identified 198 mRNA expression probe sets and 210 DNA methylation probes associated with metformin IC50 with p-value <10-4, respectively. Analysis of 1.3 million SNPs found 12 loci (a region containing at least 1 SNP of p-value <10-5 and 1 SNP of p-value <10-3 within 50kb) that were associated with metformin IC50. Integrated SNP loci-mRNA expression-IC50 analysis indicated that the SNP loci on chromosome 16 was associated with metformin IC50 through a trans-regulation of expression of 7 genes with p-value <10-4. Integrated methylation-mRNA expression-IC50 analysis showed that 15 DNA methylation probes in 6 genes were associated with metformin IC50 through both cis- and trans-regulation of expression of 48 genes with p-value <10-4, including 4 methylation probes in 3 of those 6 genes that were cis-correlated with its own gene expression. Ingenuity pathway analysis of top 62 candidate genes identified four major pathways and 55 genes within those pathways were selected for functional validation in breast cancer cell lines. The knockdown experiment showed that down regulation of 25 genes significantly altered metformin sensitivity in MDA-MB231, and 14 of them also showed the same effect in Hs578T. Preliminary mechanistic experiment indicated that knockdown of 7 genes significantly reduced AMPK activity in MDA-MB231 and 3 of them had same effect in Hs578T. CONCLUSIONS GWAS using a genomic data-enriched LCL model system, together with functional validation in breast cancer cell lines, could help us to identify novel genetic and epigenetic biomarkers involved in metformin response and help us to better understand the mechanisms of metformin in cancer treatment. Citation Format: Nifang Niu, Xianglin Tan, Brooke L. Fridley, Daniel J. Schaid, Ryan P. Abo, Anthony Batzler, Erin E. Carlson, Gregory Jenkins, Sebastian Moran, Holger Andrea Heyn, Manel Esteller Badosa, Liewei Wang. Metformin pharmacogenomics: A genome-wide associate study to identify genetic and epigenetic biomarkers involved in metformin response. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2271. doi:10.1158/1538-7445.AM2013-2271

Abstract Purpose: This phase I, multicenter, open-label, single-arm, dose-escalation, and dose-expansion study evaluated the safety, tolerability, and antitumor activity of MEDI-573 in adults with advanced solid tumors refractory to standard therapy or for which no standard therapy exists. Experimental Design: Patients received MEDI-573 in 1 of 5 cohorts (0.5, 1.5, 5, 10, or 15 mg/kg) dosed weekly or 1 of 2 cohorts (30 or 45 mg/kg) dosed every 3 weeks. Primary end points included the MEDI-573 safety profile, maximum tolerated dose (MTD), and optimal biologic dose (OBD). Secondary end points included MEDI-573 pharmacokinetics (PK), pharmacodynamics, immunogenicity, and antitumor activity. Results: In total, 43 patients (20 with urothelial cancer) received MEDI-573. No dose-limiting toxicities were identified, and only 1 patient experienced hyperglycemia related to treatment. Elevations in levels of insulin and/or growth hormone were not observed. Adverse events observed in >10% of patients included fatigue, anorexia, nausea, diarrhea, and anemia. PK evaluation demonstrated that levels of MEDI-573 increased with dose at all dose levels tested. At doses >5 mg/kg, circulating levels of insulin-like growth factor (IGF)-I and IGFII were fully suppressed. Of 39 patients evaluable for response, none experienced partial or complete response and 13 had stable disease as best response. Conclusions: The MTD of MEDI-573 was not reached. The OBD was 5 mg/kg weekly or 30 or 45 mg/kg every 3 weeks. MEDI-573 showed preliminary antitumor activity in a heavily pretreated population and had a favorable tolerability profile, with no notable perturbations in metabolic homeostasis. Clin Cancer Res; 20(18); 4747–57. ©2014 AACR.

Liver microenvironment is a critical determinant for development and progression of liver metastasis. Under transforming growth factor beta (TGF‐β) stimulation, hepatic stellate cells (HSCs), which are liver‐specific pericytes, transdifferentiate into tumor‐associated myofibroblasts that promote tumor implantation (TI) and growth in the liver. However, the regulation of this HSC activation process remains poorly understood. In this study, we tested whether vasodilator‐stimulated phosphoprotein (VASP) of HSCs regulated the TGF‐β‐mediated HSC activation process and tumor growth. In both an experimental liver metastasis mouse model and cancer patients, colorectal cancer cells reaching liver sinusoids induced up‐regulation of VASP and alpha‐smooth muscle actin (α‐SMA) in adjacent HSCs. VASP knockdown in HSCs inhibited TGF‐β‐mediated myofibroblastic activation of HSCs, TI, and growth in mice. Mechanistically, VASP formed protein complexes with TGF‐β receptor II (TβRII) and Rab11, a Ras‐like small GTPase and key regulator of recycling endosomes. VASP knockdown impaired Rab11 activity and Rab11‐dependent targeting of TβRII to the plasma membrane, thereby desensitizing HSCs to TGF‐β1 stimulation. Conclusions: Our study demonstrates a requirement of VASP for TGF‐β‐mediated HSC activation in the tumor microenvironment by regulating Rab11‐dependent recycling of TβRII to the plasma membrane. VASP and its effector, Rab11, in the tumor microenvironment thus present therapeutic targets for reducing TI and metastatic growth in the liver. (Hepatology 2015;61:361–374)

AbstractWe examined the specific cell types in normal human pituitaries that expressed PRL receptor (PRL-R) messenger ribonucleic acid (mRNA) by combined in situ hybridization and immunohistochemistry. The distribution of PRL-R mRNA in 28 pituitary adenomas was examined by in situ hybridization and reverse transcription-PCR in 12 cases of adenomas. In another set of experiments, 34 PRL adenomas from men, women, and bromocriptine-treated patients were analyzed for PRL-R by in situ hybridization.In the normal pituitary, PRL- and LH-producing cells had significantly more mean grain counts per cell and higher percentages of cells positive for PRL-R than GH and TSH cells. PRL-R mRNA was present in all groups of adenomas by in situ hybridization and reverse transcription-PCR. PRL adenomas had a significantly higher density of labeling compared to other adenoma types. Although there was no difference in the levels of PRL-R mRNA in PRL adenomas from men and premenopausal and postmenopausal women, patients treated with bromocriptine before pituitary surgery had significantly lower levels of PRL-R compared to all other groups. These results indicate that in the normal pituitary, PRL and LH cells have the highest level of PRL-R mRNA, whereas PRL adenomas have significantly higher levels of PRL-R mRNA than other types of adenomas, and bromocriptine treatment decreases the levels of PRL-R mRNA in PRL adenomas.

Abstract Integrative genomics has the potential to uncover relevant loci, as clinical outcome and response to chemotherapies are most likely not due to a single gene (or data type) but rather a complex relationship involving genetic variation, mRNA, DNA methylation, and copy number variation. In addition to this complexity, many complex phenotypes are thought to be controlled by the interplay of multiple genes within the same molecular pathway or gene set (GS). To address these two challenges, we propose an integrative gene set analysis approach and apply this strategy to a cisplatin (CDDP) pharmacogenomics study involving lymphoblastoid cell lines for which genome-wide SNP and mRNA expression data was collected. Application of the integrative GS analysis implicated the role of the RNA binding and cytoskeletal part GSs. The genes LMNB1 and CENPF, within the cytoskeletal part GS, were functionally validated with siRNA knockdown experiments, where the knockdown of LMNB1 and CENPF resulted in CDDP resistance in multiple cancer cell lines. This study demonstrates the utility of an integrative GS analysis strategy for detecting novel genes associated with response to cancer therapies, moving closer to tailored therapy decisions for cancer patients.