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1.  Nucleotide excision repair polymorphisms may modify ionizing radiation-related breast cancer risk in US radiologic technologists 
Exposure to ionizing radiation has been consistently associated with increased risk of female breast cancer. Although the majority of DNA damage caused by ionizing radiation is corrected by the base-excision repair pathway, certain types of multiple-base damage can only be repaired through the nucleotide excision repair pathway. In a nested case–control study of breast cancer in US radiologic technologists exposed to low levels of ionizing radiation (858 cases, 1,083 controls), we examined whether risk of breast cancer conferred by radiation was modified by nucleotide excision gene polymorphisms ERCC2 (XPD) rs13181, ERCC4 (XPF) rs1800067 and rs1800124, ERCC5 (XPG) rs1047769 and rs17655; and ERCC6 rs2228526. Of the 6 ERCC variants examined, only ERCC5 rs17655 showed a borderline main effect association with breast cancer risk (ORGC = 1.1, ORCC = 1.3; p-trend = 0.08), with some indication that individuals carrying the C allele variant were more susceptible to the effects of occupational radiation (EOR/GyGG = 1.0, 95% CI = <0, 6.0; EOR/GyGC/CC = 5.9, 95% CI = 0.9, 14.4; phet = 0.10). ERCC2 rs13181, although not associated with breast cancer risk overall, statistically significantly modified the effect of occupational radiation dose on risk of breast cancer (EOR/GyAA = 9.1, 95% CI = 2.1–21.3; EOR/GyAC/CC = 0.6, 95% CI = <0, 4.6; phet = 0.01). These results suggest that common variants in nucleotide excision repair genes may modify the association between occupational radiation exposure and breast cancer risk.
doi:10.1002/ijc.23779
PMCID: PMC3984912  PMID: 18767034
2.  Time since first sexual intercourse and the risk of cervical cancer 
Young age at first sexual intercourse is an important risk factor for cervical cancer, but no simple statistical model of its influence has been established. We investigated the relationship between risk of cervical carcinoma and time since first intercourse using data on monogamous women (5,074 cases and 16,137 controls) from the International Collaboration of Epidemiological Studies of Cervical Cancer. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated from pooled data on 20 studies using conditional logistic regression. The OR for invasive cervical carcinoma is approximately proportional to the square of time since first intercourse (exponent 1.95, 95% CI: 1.76–2.15) up to age 45. First cervical infection with human papillomavirus (HPV) often occurs soon after first sexual intercourse, so early age at first sexual intercourse is a reasonable proxy for early age at first exposure to HPV. In addition, age-specific incidence rates of cervical cancer in unscreened populations remain fairly constant above age 45. Cervical cancer thus resembles other cancers caused by strong early-stage carcinogens, with incidence rates proportional to a power of time since first exposure and also resembles cancers of the breast and other hormone-dependent epithelia where a similar flattening of age-specific incidence rates is seen at the time menopausal changes start. Taken together, these observations suggest that HPV vaccination may prevent the majority of cervical cancers by delaying HPV infection without necessarily providing lifetime protection against HPV.
doi:10.1002/ijc.26250
PMCID: PMC3982220  PMID: 21702036
cervical carcinoma; cervical intraepithelial neoplasia; age at first sexual intercourse; multi-stage carcinogenesis
3.  Tumor expressed PTHrP facilitates prostate cancer-induced osteoblastic lesions 
Expression of parathyroid hormone-related protein (PTHrP) correlates with prostate cancer skeletal progression; however, the impact of prostate cancer-derived PTHrP on the microenvironment and osteoblastic lesions in skeletal metastasis has not been completely elucidated. In this study, PTHrP overexpressing prostate cancer clones were stably established by transfection of full length rat PTHrP cDNA. Expression and secretion of PTHrP were verified by western blotting and IRMA assay. PTHrP overexpressing prostate cancer cells had higher growth rates in vitro, and generated larger tumors when inoculated subcutaneously into athymic mice. The impact of tumor-derived PTHrP on bone was investigated using a vossicle co-implant model. Histology revealed increased bone mass adjacent to PTHrP overexpressing tumor foci, with increased osteoblastogenesis, osteoclastogenesis and angiogenesis. In vitro analysis demonstrated pro-osteoclastic and pro-osteoblastic effects of PTHrP. PTHrP enhanced proliferation of bone marrow stromal cells and early osteoblast differentiation. PTHrP exerted a pro-angiogenic effect indirectly, as it increased angiogenesis but only in the presence of bone marrow stromal cells. These data suggest PTHrP plays a role in tumorigenesis in prostate cancer, and that PTHrP is a key mediator for communication and interactions between prostate cancer and the bone microenvironment. Prostate cancer-derived PTHrP is actively involved in osteoblastic skeletal progression.
doi:10.1002/ijc.23602
PMCID: PMC3979464  PMID: 18729185
parathyroid hormone-related protein; PTHrP; skeletal metastasis; prostate carcinoma; angiogenesis
4.  Extrarenal perivascular epithelioid cell tumors (PEComas) respond to mTOR inhibition: Clinical and molecular correlates 
Perivascular epithelioid cell tumors (PEComas) are a group of rare mesenchymal tumors that typically show both melanocytic and smooth muscle cell features. Some types of PEComa are seen at high frequency in tuberous sclerosis complex (TSC). The TSC1 and TSC2 genes are commonly mutated in both TSC-associated and sporadic PEComas, and mTOR signaling pathway activation is also common in these tumors. Preliminary reports have indicated that the mTOR inhibitors sirolimus and related drugs have activity in some patients with non-TSC-associated PEComa.
Here we report on the use of these medications in the treatment of five consecutive patients with extrarenal non-pulmonary PEComas seen at one institution. Three complete responses, one partial response and one case of progression were seen. Molecular studies identified TSC2 aberrations in four of these patients, and TFE3 translocation was excluded in the resistant case. A review of all published cases as well as those reported here indicates that partial or complete response was seen in 6 of 11 PEComas, with 5 of the 6 having a complete response. These findings highlight the consistent though incomplete activity of mTOR inhibitors in the treatment of PEComas.
doi:10.1002/ijc.27800
PMCID: PMC3558545  PMID: 22927055
perivascular epithelioid cell tumor; PEComa; mTOR; TSC2; sirolimus; everolimus
5.  Single cell molecular recognition of migrating and invading tumor cells using a targeted fluorescent probe to receptor PTPmu 
Detection of an extracellular cleaved fragment of a cell-cell adhesion molecule represents a new paradigm in molecular recognition and imaging of tumors. We previously demonstrated that probes that recognize the cleaved extracellular domain of PTPmu label human glioblastoma brain tumor sections and the main tumor mass of intracranial xenograft gliomas. In this manuscript, we examine whether one of these probes, SBK2, can label dispersed glioma cells that are no longer connected to the main tumor mass. Live mice with highly dispersive glioma tumors were injected intravenously with the fluorescent PTPmu probe to test the ability of the probe to label the dispersive glioma cells in vivo. Analysis was performed using a unique 3-D cryo-imaging technique to reveal highly migratory and invasive glioma cell dispersal within the brain and the extent of co-labeling by the PTPmu probe. The PTPmu probe labeled the main tumor site and dispersed cells up to 3.5 mm away. The cryo-images of tumors labeled with the PTPmu probe provide a novel, high-resolution view of molecular tumor recognition, with excellent 3-D detail regarding the pathways of tumor cell migration. Our data demonstrate that the PTPmu probe recognizes distant tumor cells even in parts of the brain where the blood-brain barrier is likely intact. The PTPmu probe has potential translational significance for recognizing tumor cells to facilitate molecular imaging, a more complete tumor resection and to serve as a molecular targeting agent to deliver chemotherapeutics to the main tumor mass and distant dispersive tumor cells.
doi:10.1002/ijc.27838
PMCID: PMC3558593  PMID: 22987116
receptor protein tyrosine phosphatase; proteolytic cleavage; glioma; molecular imaging; targeting agent; migration; invasion
6.  Prospective weight change and colon cancer risk in male US health professionals 
Epidemiological studies are remarkably consistent, especially among men, in showing that overweight and obesity [body mass index (BMI) >25] are associated with increased risk of colon cancer. However, no prospective studies address the influence of weight change in adulthood on subsequent colon cancer risk. In this study, we investigated whether weight change influences colon cancer risk utilizing prospectively collected weight data. We included 46,349 men aged 40–75 participating in the Health Professionals Follow-Up Study. Questionnaires including items on weight were completed every second year during follow-up from 1986 to 2004. Updated weight change between consecutive questionnaires during follow-up and recalled weight gain since age 21 was evaluated. All eligible men were cancer-free at baseline. Proportional hazard and restricted spline regression models were implemented. Over an 18-year period, we documented 765 cases of colon cancer. Cumulative mean BMI >22.5 was associated with significantly increased risk of colon cancer. The short-term weight change in the prior 2 to 4 years was positively and significantly associated with risk [HR = 1.14 (95% confidence interval, 1.00–1.29) for 4.54 kg (10 pounds) increment, p = 0.04 for overall trend]. Weight gain per 10 years since age 21 was associated with significantly increased risk [HR = 1.33 (1.12–1.58) for 4.54 kg increase per 10 years, p = 0.001]. We estimated that 29.5% of all colon cancer cases was attributable to BMI above 22.5. Our results add support that overweight and obesity are modifiable risk factors for colon cancer among men and suggest that weight has an important influence on colon cancer risk even in later life.
doi:10.1002/ijc.23612
PMCID: PMC3965300  PMID: 18546286
colonic neoplasms/epidemiology; weight gain; weight loss
7.  High load for most high risk human papillomavirus genotypes is associated with prevalent cervical cancer precursors but only HPV16 load predicts the development of incident disease 
Cervicovaginal human papillomavirus (HPV) viral load has been purported as a potential marker for the detection of high-grade cervical intraepithelial neoplasia or cancer (≥CIN2). To examine disease association with type-specific viral load for the full-range of anogenital HPV infections, we conducted cross-sectional and prospective analyses of ∼2,000 HPV-infected women from a 10,000-woman population-based study in Guanacaste, Costa Rica with 7 years of follow-up. Cervical specimens were tested for >40 HPV types using a MY09/MY11 L1 consensus primer PCR method with type-specific dot blot hybridization and PCR signal intensity as a measure of viral load. A positive association was observed between prevalent ≥CIN2 and high viral load compared to low viral load for women with baseline single HPV16 infections (OR = 19.2, 95% CI = 4.4–83.2) and single non-16 carcinogenic infections (OR = 9.2, 95% CI = 2.1–39.9). Inclusion of women with multiple HPV types did not substantially change these associations. In prospective follow-up, only women infected with HPV16 alone (OR = 27.2, 95% = 3.5-213.5) had a strong association between high viral load and incident ≥CIN2; non-16 carcinogenic high viral load was not associated with incident ≥CIN2 (OR = 0.7, 95% CI = 0.2–1.9). Single noncarcinogenic type viral load was not associated with increased risk of prevalent or incident ≥CIN2 (OR = 1.2 and 1.1, respectively). In conclusion, carcinogenic high viral load was associated with prevalent ≥CIN2; however HPV16 was uniquely associated with incident ≥CIN2. The extent to which these observations can be translated into clinical practice must be rigorously examined in the context of the method of viral load measurement and the type-specific differences observed for incident ≥CIN2.
doi:10.1002/ijc.23012
PMCID: PMC3962984  PMID: 17722112
human papillomavirus; viral load; genotype; screening
8.  Modulation of Hyaluronan Production by CD44 Positive Glioma Cells 
SUMMARY
This study examines the functional relationship between glioma cell production of hyaluronan (HA), known to play a role in glioma invasion, expression of its CD44 receptor, and glioma cell viability. Production of HA by CD44 positive mouse G26 and human U373 glioma cell lines was evaluated and compared to that of a CD44 positive mouse fibroblast-like L929 cell line. We found that both G26 and U373 MG glioma cells, but not L929 fibroblast-like cells, synthesized HA. HA synthesis by glioma cells was found during the proliferative phase as well as post-confluency, as detected by fluorophore-assisted carbohydrate electrophoresis. Eighty to ninety percent of the HA synthesized was secreted into the medium and 10–20% remained associated with the cells. To examine a possible mechanistic link between the CD44-HA interaction and endogenous HA production, glioma cells were treated with either anti-CD44 antibodies (clones KM201 or IM7) or HA oligosaccharides (hexamer oligoHA-6 or decamer oligoHA-10). We found that oligoHA-10, which was previously shown to compete effectively with the CD44-HA interaction, enhanced glioma HA synthesis by approximately 1.5-fold, without affecting cell viability. IM7 treatment of human U373 glioma cells resulted in over 50% decrease of HA production, which was associated with changes in cell size and apoptosis. Taken together, these data show that CD44 specific ligands, such as the IM7 antibody or oligoHA-10 could down-regulate or up-regulate glioma HA production, respectively. Our results suggest that interference with CD44/HA may lead to the discovery and development of new treatment modalities for glioma.
doi:10.1002/ijc.25085
PMCID: PMC3962665  PMID: 19957333
Glioma; hyaluronan; CD44
9.  20(S)-Protopanaxadiol-aglycone Downregulation of the Full-length and Splice Variants of Androgen Receptor 
As a public health problem, prostate cancer engenders huge economic and life-quality burden. Developing effective chemopreventive regimens to alleviate the burden remains a major challenge. Androgen signaling is vital to the development and progression of prostate cancer. Targeting androgen signaling via blocking the production of the potent ligand dihydrotestosterone has been shown to decrease prostate cancer incidence. However, the potential of increasing the incidence of high-grade prostate cancers has been a concern. Mechanisms of disease progression after the intervention may include increased expression of androgen receptor (AR) in prostate tissue and expression of the constitutively-active AR splice variants (AR-Vs) lacking the ligand-binding domain. Thus, novel agents targeting the receptor, preferentially both the full-length and AR-Vs, are urgently needed. In the present study, we show that ginsenoside 20(S)-protopanaxadiol-aglycone (PPD) effectively downregulates the expression and activity of both the full-length AR and AR-Vs. The effects of PPD on AR and AR-Vs are manifested by an immediate drop in proteins followed by a reduction in transcripts, attributed to PPD induction of proteasome-mediated degradation and inhibition of the transcription of the AR gene. We further show that although PPD inhibits the growth as well as AR expression and activity in LNCaP xenograft tumors, the morphology and AR expression in normal prostates are not affected. This study is the first to show that PPD suppresses androgen signaling through downregulating both the full-length AR and AR-Vs, and provides strong rationale for further developing PPD as a promising agent for the prevention and/or treatment of prostate cancer.
doi:10.1002/ijc.27754
PMCID: PMC3509250  PMID: 22907191
20(S)-protopanaxadiol-aglycone; androgen receptor; prostate cancer
10.  Elevated methylation of HPV16 DNA is associated with the development of high grade cervical intraepithelial neoplasia 
We explored the association of HPV16 DNA methylation with age, viral load, viral persistence, and risk of incident and prevalent high grade CIN (CIN2+) in serially collected specimens from the Guanacaste, Costa Rica cohort. 273 exfoliated cervical cell specimens (diagnostic and pre-diagnostic) were selected: 1) 92 with HPV16 DNA clearance (controls), 2) 72 with HPV16 DNA persistence (without CIN2+), and 3) 109 with CIN2+. DNA was extracted, bisulfite converted and methylation was quantified using pyrosequencing assays at 66 CpGs across the HPV genome. The Kruskal-Wallis test was used to determine significant differences among groups, and receiver operating characteristic curve analyses were used to evaluate how well methylation identified women with CIN2+. In diagnostic specimens, 88% of CpG sites had significantly higher methylation levels in CIN2+ after correction for multiple tests compared with controls. The highest AUC was 0.82 for CpG site 6457 in L1, and a diagnostic sensitivity of 91% corresponded to a specificity of 60% for CIN2+. Prospectively, 17% of CpG sites had significantly higher methylation in pre-diagnostic CIN2+ specimens (median time of 3 years before diagnosis) vs. controls. The strongest pre-diagnostic CpG site was 6367 in L1 with an AUC of 0.76. Age-stratified analyses suggested that women older than the median age of 28 years have an increased risk of precancer associated with high methylation. Higher methylation in CIN2+ cases was not explained by higher viral load. We conclude that elevated levels of HPV16 DNA methylation may be useful to predict concurrently diagnosed as well as future CIN2+.
doi:10.1002/ijc.27750
PMCID: PMC3493709  PMID: 22847263
HPV16; methylation; epidemiology; receiver operating curve; biomarker
11.  Nonsteroidal anti-inflammatory drugs and other analgesic use and bladder cancer in northern New England 
A few epidemiologic studies have found that use of nonsteroidal anti-inflammatory drugs (NSAIDs) is associated with reduced risk of bladder cancer. However, the effects of specific NSAID use and individual variability in risk have not been well studied. We examined the association between NSAIDs use and bladder cancer risk, and its modification by 39 candidate genes related to NSAID metabolism. A population-based case–control study was conducted in northern New England, enrolling 1,171 newly diagnosed cases and 1,418 controls. Regular use of nonaspirin, nonselective NSAIDs was associated with reduced bladder cancer risk, with a statistically significant inverse trend in risk with duration of use (ORs of 1.0, 0.8, 0.6 and 0.6 for <5, 5–9, 10–19 and 201 years, respectively; ptrend = 0.015). This association was driven mainly by ibuprofen; significant inverse trends in risk with increasing duration and dose of ibuprofen were observed (ptrend = 0.009 and 0.054, respectively). The reduced risk from ibuprofen use was limited to individuals carrying the T allele of a single nucleotide polymorphism (rs4646450) compared to those who did not use ibuprofen and did not carry the T allele in the CYP3A locus, providing new evidence that this association might be modified by polymorphisms in genes that metabolize ibuprofen. Significant positive trends in risk with increasing duration and cumulative dose of selective cyclooxygenase (COX-2) inhibitors were observed. Our results are consistent with those from previous studies linking use of NSAIDs, particularly ibuprofen, with reduced risk. We observed a previously unrecognized risk associated with use of COX-2 inhibitors, which merits further evaluation.
doi:10.1002/ijc.27590
PMCID: PMC3951299  PMID: 22505343
bladder cancer; nonsteroidal anti-inflammatory drugs; gene–drug interaction; CYP3A
12.  Secreted frizzled-related protein-5 (sFRP-5) is epigenetically downregulated and functions as a tumor suppressor in kidney cancer 
Secreted frizzled-related protein-5 (sFRP-5) has been identified as one of the secreted antagonists that bind Wnt protein. However, the functional significance of sFRP-5 in renal cell cancer (RCC) has not been reported. We hypothesized that sFRP-5 may be epigenetically downregulated through DNA methylation and histone modification and function as a tumor suppressor gene in RCC. Using tissue microarray and real-time RT-PCR, we found that sFRP-5 was significantly downregulated in kidney cancer tissues and cell lines, respectively. DNA bisulfite sequencing of the sFRP-5 promoter region in RCC cell lines showed it to be densely methylated whereas there was few promoter methylation in normal kidney. The sFRP-5 expression was restored and the acetylation of H3 and H4 histones associated with the sFRP-5 promoter region were significantly increased after treatment with demethylation agent (5-Aza-dc) and histone deacetylase inhibitor (TSA). When RCC cells were transfected with the sFRP-5 gene, significant inhibition of anchorage independent colony formation and cell invasion were observed compared to controls. The sFRP-5 transfection also significantly induced apoptosis in RCC cells. In conclusion, this is the first report documenting that the sFRP-5 is downregulated by promoter methylation and histone acetylation and functions as a tumor suppressor gene by inducing apoptosis in RCC cells.
doi:10.1002/ijc.25357
PMCID: PMC3940353  PMID: 20340127
RCC; sFRP-5; methylation; histone modification; tumor suppressor
13.  Double stranded-RNA-mediated activation of P21 gene induced apoptosis and cell cycle arrest in renal cell carcinoma 
Small double stranded RNAs (dsRNA) are a new class of molecules which regulate gene expression. Accumulating data suggest that some dsRNA can function as tumor suppressors. Here we report further evidence on the potential of dsRNA mediated p21 induction. Using the human renal cell carcinoma cell line A498, we found that dsRNA targeting the p21 promoter significantly induced the expression of p21 mRNA and protein levels. As a result, dsP21 transfected cells had a significant decrease in cell viability with a concomitant G1 arrest. We also observed a significant increase in apoptosis. These findings were associated with a significant decrease in survivin mRNA and protein levels. This is the first report that demonstrates dsRNA mediated gene activation in renal cell carcinoma and suggests that forced over-expression of p21 may lead to an increase in apoptosis through a survivin dependent mechanism.
doi:10.1002/ijc.24370
PMCID: PMC3940355  PMID: 19384944
renal cell carcinoma; RNAa; saRNA; p21WAF1/CIP1; apoptosis; survivin/Birc5
14.  Human Vγ2Vδ2 T cells limit breast cancer growth by modulating cell survival-, apoptosis-related molecules and microenvironment in tumors 
Innate immune system has been known to play an important role in inhibiting the malignant transformation, tumor progression and invasion. However, the mechanistic basis remains ambiguous. Despite polyclonality of human γδ T cells, Vγ2Vδ2 T cell subset was shown to recognize and limit the growth of various tumors at various degrees. The differential recognition of the tumor cells by Vγ2Vδ2 T cells are yet to be defined. Our study reveals that γδ T cells limit in vitro growth of most breast tumor cells, such as SkBr7 (HER2+), MCF7 (ER+) and MDA-MB-231 (ER−) by inhibiting their survival and inducing apoptosis, except BrCa-MZ01 (PR+) cells. To investigate detail mechanisms of antineoplastic effects, we found that cell death was associated with the surface expression levels of MICA/B and ICAM1. Molecular signaling analysis demonstrated that inhibition of cell growth by γδ T cells was associated with the lower expression levels of cell survival-related molecules such as AKT, ERK and concomitant upregulation of apoptosis-related molecules, such as PARP, cleaved caspase 3 and tumor suppressor genes PTEN and P53. However, opposite molecular signaling was observed in the resistant cell line after coculture with γδ T cells. In vivo, antineoplastic effects of γδ T cells were also documented, where tumor growth was inhibited due to the downregulation of survival signals, strong induction of apoptotic molecules, disruption of microvasculature and increased infiltration of tumor associated macrophages. These findings reveal that a complex molecular signaling is involved in γδ T cell-mediated antineoplastic effects.
doi:10.1002/ijc.28217
PMCID: PMC3939063  PMID: 23595559
Vγ2Vδ2 T cell; breast cancer; cell survival; apoptosis; angiogenesis; xenotransplant; NOD/SCID mice
15.  Dairy foods and nutrients in relation to risk of ovarian cancer and major histological subtypes 
Inconsistent results for the role of dairy food intake in relation to ovarian cancer risk may reflect the potential adverse effects of lactose, which has been hypothesized to increase gonadotropin levels, and the beneficial anti-proliferative effects of calcium and vitamin D. Using data from the New England case-control study (1909 cases; 1989 controls) we examined dairy foods and nutrients in relation to risk of ovarian cancer overall, histological subtypes, and rapidly fatal versus less aggressive disease. We used logistic regression and polytomous logistic regression to estimate odds ratios and 95% confidence intervals. In models that were simultaneously adjusted for total (dietary plus supplements) calcium, total vitamin D and lactose, we observed a decreased overall risk of ovarian cancer with high intake of total calcium (Quartile 4 (Q4, >1319 mg/day) vs. Quartile 1 (Q1, <655 mg/day), odds ratio (OR)=0.62, 95% Confidence Interval (CI)=0.49 – 0.79); the inverse association was strongest for serous borderline and mucinous tumors. High intake of total vitamin D was not associated overall with ovarian cancer risk, but was inversely associated with risk of serous borderline (Q4, >559 IU/day vs. Q1, <164 IU/day, OR=0.51, 95% CI=0.34–0.76) and endometrioid tumors (Q4 vs. Q1, OR=0.55, 95% CI=0.39-0.80). We found no evidence that lactose intake influenced ovarian cancer risk, or that risk varied by tumor aggressiveness in the analyses of intake of dairy foods and nutrients. The overall inverse association with high intake of calcium, and the inverse associations of calcium and vitamin D with specific histological subtypes warrant further investigation.
doi:10.1002/ijc.27701
PMCID: PMC3495088  PMID: 22740148
dairy foods; calcium; vitamin D; lactose; ovarian cancer
16.  Plumbagin inhibits tumorigenesis and angiogenesis of ovarian cancer cells in vivo 
Angiogenesis is a hallmark of tumor development and metastatic progression, and antiangiogenic drugs targeting the VEGF pathway have shown to decrease the disease progression in cancer patients. In this study, we have analyzed the anti-proliferative and anti-angiogenic property of plumbagin in cisplatin sensitive, BRCA2 deficient, PEO-1 and cisplatin resistant, BRCA2 proficient PEO-4 ovarian cancer cells. Both PEO-1 and PEO-4 ovarian cancer cells are sensitive to plumbagin irrespective of BRCA2 status in both normoxia and hypoxia. Importantly, plumbagin treatment effectively inhibits VEGF-A and Glut-1 in PEO-1 and PEO-4 ovarian cancer cells. We have also analyzed the p53 mutant, cisplatin resistant, and BRCA2 proficient OVCAR-5 cells. Plumbagin challenge also restricts the VEGF induced pro-angiogenenic signaling in HUVECs and subsequently endothelial cell proliferation. In addition, we observe a significant effect on tumor regression among OVCAR-5 tumor-bearing mice treated with plumbagin, which is associated with significant inhibition of Ki67 and vWF expressions. Plumbagin also significantly reduces CD31 expression in an ear angiogenesis assay. Collectively, our studies indicate that plumbagin, as an anti-cancer agent disrupts growth of ovarian cancer cells through the inhibition of proliferation as well as angiogenesis.
doi:10.1002/ijc.27724
PMCID: PMC3496826  PMID: 22806981
Plumbagin; Ovarian cancer; Cytotoxicity; Angiogenesis
17.  ROLE OF GRB2-ASSOCIATED BINDER 1 (GAB1) IN EPIDERMAL GROWTH FACTOR RECEPTOR (EGFR)-INDUCED SIGNALING IN HEAD AND NECK SQUAMOUS CELL CARCINOMA 
The Epidermal Growth Factor Receptor (EGFR) plays an important role in the pathogenesis of head and neck squamous cell carcinoma (HNSCC). Despite the high expression of EGFR in HNSCC, EGFR inhibitors have only limited success as monotherapy. The Grb2-associated binder (GAB) family of adaptor proteins acts as docking/scaffolding molecules downstream of tyrosine kinase receptors. We hypothesized that GAB1 may amplify EGFR-induced signaling in HNSCCs and therefore could play a role in the reduced sensitivity of HNSCC to EGFR inhibitors. We used representative human HNSCC cell lines overexpressing wild type EGFR, and expressing GAB1 but not GAB2. We demonstrated that baseline Akt and MAPK signaling were reduced in HNSCC cells in which GAB1 expression was reduced. Furthermore, the maximal EGF-induced activation of the Akt and MAPK pathway was reduced and delayed, and the duration of the EGF-induced activation of these pathways was reduced in cells with GAB1 knock-down. In agreement with this, HNSCC cells in which GAB1 levels were reduced showed an increased sensitivity to the EGFR inhibitor gefitinib. Our work demonstrates that GAB1 plays an important role as part of the mechanism of by which EGFR induces induced activation of the MAPK and AKT pathway. Our results identify GAB1 as an amplifier of the EGFR-initiated signaling, which may also interfere with EGFR degradation. These findings support the emerging notion that reducing GAB1 function may sensitize HNSCC to EGFR inhibitors, hence representing a new therapeutic target HNSCC treatment in combination with EGFR targeting agents.
doi:10.1002/ijc.27763
PMCID: PMC3498529  PMID: 22865653
18.  Epigenetic inactivation of endothelin-2 (ET-2) and ET-3 in colon cancer 
Endothelin-1 (ET-1) and its receptors are overexpressed in human cancers, but much less is known about the roles of ET-2 and ET-3 in cancer etiology. We sought to examine human and rat colon tumors for dysregulation of ET-2 and ET3 expression, and determine the underlying mechanisms. Human primary colon cancers and carcinogen-induced rat colon tumors were subjected to real-time RT-PCR, immunoblotting, and immunohistochemistry; EDN2 and EDN3 genes were examined by methylation-specific PCR, bisulfite sequencing, and pyrosequencing; and forced expression of ET-2 and ET-3 was conducted in human colon cancer cells followed by real-time cell migration and invasion assays. Rat and human colon tumors had markedly reduced expression of ET-2 and ET-3 mRNA and protein compared with matched controls. Mechanistic studies revealed hypermethylation of EDN2 and EDN3 genes in human primary colon cancers, and in a panel of human colon cancer cell lines. Forced expression of ET-2 and ET-3 attenuated significantly the migration and invasion of human colon cancer cells. We conclude that epigenetic inactivation of ET-2 and ET-3 occurs frequently in both rat and human colon cancers. Current therapeutic strategies target overexpressed members of the ET axis via small molecule inhibitors and receptor antagonists, but this work supports a complementary approach based on the re-expression of ET-2 and ET-3 as natural antagonists of ET-1 in colon cancer.
doi:10.1002/ijc.27762
PMCID: PMC3500448  PMID: 22865632
Colorectal Cancer; DNA methylation; Endothelin Axis; Epigenetics
19.  Early Childhood Infection of Kaposi’s Sarcoma-associated Herpesvirus in Zambian Households: a Molecular Analysis 
Sub-Saharan Africa is endemic for Kaposi’s sarcoma-associated herpesvirus (KSHV) and there is a high rate of early childhood infection; however, the transmission sources are not well characterized. We examined household members as potential KSHV transmission sources to young children in the KSHV-endemic country of Zambia. To this end, we enrolled and followed Zambian households with at least one KSHV-seropositive child and collected longitudinal buccal swab samples. KSHV burden was evaluated and K1 sequences from the children were determined and analyzed for differences to K1 sequences from household members. The K1 sequences were also analyzed for evolution over time. We generated K1 sequences from 31 individuals across 16 households. Nine households contained multiple KSHV-positive members, including at least one child. In 6 of 9 households, the child had 100% sequence identity to all household members. However, in two households the child and mother had distinct K1 sequences. In the remaining household, the children were the only KSHV-infected individuals. Furthermore, we report that 1 of 18 individuals had K1 sequence variation within the timespan analyzed. In the present study, we provide evidence that (1) early childhood KSHV transmission occurs from both within and outside the household, (2) intra-household transmission can occur via non-maternal sources, (3) viral shedding in the buccal cavity is highly variable, and (4) the dominant K1 sequence within an individual did not rapidly evolve over time. These results are important for developing KSHV intervention strategies.
doi:10.1002/ijc.27729
PMCID: PMC3535687  PMID: 22815207
Kaposi’s sarcoma-associated herpesvirus; children; households; Zambia; K1; transmission
20.  Associations of insulin-like growth factor and insulin-like growth factor binding protein-3 with mortality in women with breast cancer 
Elevated circulating insulin-like growth factor-1 (IGF-1), a breast epithelial cell mitogen, is associated with breast cancer development. However, its association with breast cancer survival is not established. Circulating concentrations of IGF-1 are controlled via binding proteins, including IGF Binding Protein-3 (IGFBP-3), that may modulate the association of IGF1 with breast-cancer outcomes.
We measured IGF-1 and IGFBP-3 concentrations in serum from 600 women enrolled in the Health, Eating, Activity, and Lifestyle (HEAL) Study, a multiethnic, prospective cohort study of women diagnosed with stage I-IIIA breast cancer. We evaluated the association between IGF-1 and IGFBP-3, and as a ratio, modeled using quintile cut-points, with risk of breast cancer-specific (n=42 deaths) and all-cause mortality (n=87 deaths) using Cox proportional hazards models. In models adjusted for body mass index, ethnicity, tamoxifen use at time of blood draw, treatment received at diagnosis, and IGFBP-3, women in the highest quintile of IGF-1 level had an increased risk of all-cause mortality (Hazard Ratio (HR)=3.10 95% CI 1.21-7.93, p=0.02), although no dose-response association was evident. The IGF-1/IGFBP-3 ratio, an indicator of free IGF-I levels, was significantly associated with increasing risk of all-cause mortality (HR=2.83 95% CI 1.25-6.36 Ptrend=0.01, upper vs. lower quintile) in a fully adjusted model.
In conclusion, high serum levels of IGF-1 and the IGF-1/IGFBP-3 ratio were associated with increased risk of all-cause mortality in women with breast cancer. These results need to be confirmed in larger breast cancer survivor cohorts.
doi:10.1002/ijc.27753
PMCID: PMC3764990  PMID: 22847383
IGF-1; IGFBP-3; breast cancer survival; mortality
21.  Analgesic use and the risk of kidney cancer: a meta-analysis of epidemiologic studies 
Analgesics are the most commonly used over-the-counter drugs worldwide with certain analgesics having cancer prevention effect. The evidence for an increased risk of developing kidney cancer with analgesic use is mixed. Using a meta-analysis design of available observational epidemiologic studies, we investigated the association between analgesic use and kidney cancer risk. We searched the MEDLINE and EMBASE databases to identify eligible case-control or cohort studies published in English until June 2012 for 3 categories of analgesics: acetaminophen, aspirin or other Non-Steroidal Anti-Inflammatory Drugs (NSAIDs). Study-specific effect estimates were pooled to compute an overall relative risk (RR) and its 95% confidence interval (CI) using a random effects model for each category of the analgesics. We identified 20 studies (14 with acetaminophen, 13 with aspirin, and 5 with other NSAIDs) that were performed in 6 countries, including 8,420 cases of kidney cancer. Use of acetaminophen and non-aspirin NSAIDs were associated with an increased risk of kidney cancer (pooled RR, 1.28; 95% CI, 1.15 to 1.44 and 1.25; 95% CI, 1.06 to 1.46, respectively). For aspirin use, we found no overall increased risk (pooled RR, 1.10; 95% CI, 0.95 to 1.28), except for non-US studies (5 studies, pooled RR=1.17, 95% CI, 1.04 to 1.33). Similar increases in risks were seen with higher analgesic intake. In this largest meta-analysis to date, we found that acetaminophen and non-aspirin NSAIDs are associated with a significant risk of developing kidney cancer. Further work is needed to elucidate biologic mechanisms behind these findings.
doi:10.1002/ijc.28093
PMCID: PMC3815746  PMID: 23400756
analgesics; aspirin; non-aspirin non-steroidal anti-inflammatory drugs (NSAIDs); acetaminophen; kidney cancer
22.  Non-Hodgkin lymphoma and Obesity: a pooled analysis from the InterLymph consortium 
Nutritional status is known to alter immune function, a suspected risk factor for non-Hodgkin lymphoma (NHL). To investigate whether long-term over, or under, nutrition is associated with NHL self-reported anthropometric data on weight and height from over 10000 cases of NHL and 16000 controls were pooled across 18 case-control studies identified through the International Lymphoma Epidemiology Consortium. Study-specific odds ratios (OR) were estimated using logistic regression and combined using a random-effects model. Severe obesity, defined as BMI of 40 kg m−2 or more, was not associated with NHL overall (pooled OR=1.00, 95% confidence interval (CI) 0.70–1.41) or the majority of NHL subtypes. An excess was however observed for diffuse large B-cell lymphoma (pooled OR=1.80, 95% CI 1.24–2.62), although not all study-specific ORs were raised. Among the overweight (BMI 25–29.9 kg m−2) and obese (BMI 30–39.9 kg m−2), associations were elevated in some studies and decreased in others, while no association was observed among the underweight (BMI<18.5 kg m−2). There was little suggestion of increasing ORs for NHL or its subtypes with every 5 kg m−2 rise in BMI above 18.5 kg m−2. BMI components height and weight were also examined, and the tallest men, but not women, were at marginally increased risk (pooled OR=1.19, 95% CI 1.06–1.34). In summary, whilst we conclude that there is no evidence to support the hypothesis that obesity is a determinant of all types of NHL combined, the association between severe obesity and diffuse large B-cell lymphoma may warrant further investigation.
doi:10.1002/ijc.23344
PMCID: PMC3928289  PMID: 18167059
non-Hodgkin lymphoma; lymphoma; body mass index; weight; height; epidemiology
23.  Sleep duration, spot urinary 6-sulfatoxymelatonin levels and risk of breast cancer among Chinese women in Singapore 
We previously reported an inverse association between sleep duration and breast cancer risk in the prospective, population-based Singapore Chinese Health Study (SCHS) cohort (Wu et al., Carcinogenesis 2008;29:1244–8). Sleep duration was significantly positively associated with 6-sulfatoxymelatonin (aMT6s) levels determined in a spot urine, but aMT6s levels in breast cancer cases were lacking (Wu et al., Carcinogenesis 2008;29:1244–8). We updated the sleep duration–breast cancer association with 14 years of follow-up of 34,028 women in the SCHS. In a nested case–control study conducted within the SCHS, randomly timed, prediagnostic urinary aMT6s concentrations were compared between 248 incident breast cancer and 743 individually matched cohort controls. Three female controls were individually matched to each case on age at baseline interview (within 3 years), dialect group, menopausal status, date of baseline interview (within 2 years), date of urine sample collection (within 6 months) and timing of urine collection during the day (within 1 hr). Cox proportional hazards and conditional regression models with appropriate adjustment for confounders were used to examine the sleep– and aMT6s–breast cancer relationships. Breast cancer risk was not significantly associated with sleep duration; adjusted odds ratio (OR) for 9+ vs. ≤6 hr is 0.89 [95% confidence interval (95% CI) 5 0.64–1.22]. Prediagnostic aMT6s levels did not differ between breast cancer cases and matched controls; adjusted OR for highest versus lowest quartiles is 1.00 (95% CI 5 0.64-1.54). We conclude that sleep duration is not significantly associated with breast cancer risk reduction. Melatonin levels derived from randomly timed spot urine are unrelated to breast cancer. Randomly timed, spot urine-derived melatonin levels are noninformative as surrogates of nocturnal melatonin production.
doi:10.1002/ijc.27653
PMCID: PMC3477268  PMID: 22644618
sleep duration; spot urinary melatonin; breast cancer; prospective; Singaporean Chinese
24.  Thyroid cancer risk and dietary nitrate and nitrite intake in the Shanghai Women’s Health Study 
Nitrate and nitrite are precursors in the endogenous formation of N-nitroso compounds and nitrate can disrupt thyroid homeostasis by inhibiting iodide uptake. We evaluated nitrate and nitrite intake and risk of thyroid cancer in the Shanghai Women’s Health Study that included 73,317 women, aged 40–70 years enrolled in 1996–2000. Dietary intake was assessed at baseline using a food frequency questionnaire. During approximately 11 years of follow-up, 164 incident thyroid cancer cases with complete dietary information were identified. We used Cox proportional hazards regression to estimate relatives risks (RRs). We determined the nitrate and nitrite contents of foods using values from the published literature and focusing on regional values for Chinese foods. Nitrate intake was not associated with thyroid cancer risk (RRQ4 = 0.93; 95%CI: 0.42–2.07; p for trend = 0.40). Compared with the lowest quartile, women with the highest dietary nitrite intake had about a two-fold risk of thyroid cancer (RRQ4 = 2.05; 95%CI: 1.20–3.51;) but there was not a monotonic trend with increasing intake (p for trend= 0.36). The trend with increasing nitrite intake from animal sources was significant (p for trend = 0.02) and was stronger for nitrite from processed meats (RRQ4 = 1.96; 95%CI: 1.28–2.99; p for trend <0.01). Although we did not observe an association for nitrate as hypothesized, our results suggest that women consuming higher levels of nitrite from animal sources, particularly from processed meat, may have an increased risk of thyroid cancer.
doi:10.1002/ijc.27659
PMCID: PMC3443521  PMID: 22674227
25.  Interleukin genes and associations with colon and rectal cancer risk and overall survival 
Interleukins are a group of cytokines that contribute to growth and differentiation, cell migration, and inflammatory and anti-inflammatory responses by the immune system. In this study we examined genetic variation in genes from various anti-inflammatory and pro-inflammatory interleukins to determine association with colon and rectal cancer risk and overall survival. Data from two population-based incident studies of colon cancer (1555 cases and 1956 controls) and rectal cancer (754 cases and 954 controls) were utilized. After controlling for multiple comparisons, single nucleotide polymorphisms (SNPs) from four genes, IL3, IL6R, IL8, IL15, were associated with increased colon cancer risk and CXCR1, and CXCR2 were significantly associated with increased rectal cancer risk. Only SNPs from genes within the IL-8 pathway (IL8, CXCR1, and CXCR2) showed a significant association with both colon and rectal cancer risk. Several SNPs interacted significantly with IL8 and IFNG SNPs and with aspirin/NSAID, cigarette smoking, estrogen use and BMI. For both colon and rectal cancer, increasing numbers of risk alleles were associated with increased hazard of death from cancer; the estimated hazard of death for colon cancer for the highest category of risk alleles was 1.74 (95% CI 1.18–2.56) and 1.96 (95% CI 1.28–2.99) for rectal cancer. These data suggest interleukin genes play a role in risk and overall survival for colon and rectal cancer.
doi:10.1002/ijc.27660
PMCID: PMC3470814  PMID: 22674296
Interleukins; colon cancer; rectal cancer; single nucleotide polymorphisms; inflammatory

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