t-DARPP regulates phosphatidylinositol-3-kinase-dependent cell growth in breast cancer

<p>Abstract</p> <p>Background</p> <p>Recent reports have shown that t-DARPP (truncated isoform of DARPP-32) can mediate trastuzumab resistance in breast cancer cell models. In this study, we evaluated expression of t-DARPP in human primary breast tumors, and investigated the role of t-DARPP in regulating growth and proliferation in breast cancer cells.</p> <p>Results</p> <p>Quantitative real time RT-PCR analysis using primers specific for t-DARPP demonstrated overexpression of t-DARPP in 36% of breast cancers (13/36) as opposed to absent to very low t-DARPP expression in normal breast tissue (p < 0.05). The mRNA overexpression of t-DARPP was overwhelmingly observed in ductal carcinomas, including invasive ductal carcinomas and intraductal carcinomas, rather than other types of breast cancers. The immunohistochemistry analysis of DARPP-32/t-DARPP protein(s) expression in breast cancer tissue microarray that contained 59 tumors and matched normal tissues when available indicated overexpression in 35.5% of primary breast tumors that were more frequent in invasive ductal carcinomas (43.7%; 21/48). In vitro studies showed that stable overexpression of t-DARPP in MCF-7 cells positively regulated proliferation and anchorage-dependent and -independent growth. Furthermore, this effect was concomitant with induction of phosphorylation of AKT^ser473and its downstream target phospho^ser9GSK3β, and increased Cyclin D1 and C-Myc protein levels. The knockdown of endogenous t-DARPP in HCC1569 cells led to a marked decrease in phosphorylation of AKTs^ser473and GSK3β^ser9. The use of PI3K inhibitor LY294002 or Akt siRNA abrogated the t-DARPP-mediated phosphorylation of AKT^ser473and led to a significant reduction in cell growth.</p> <p>Conclusions</p> <p>Our findings underscore the potential role of t-DARPP in regulating cell growth and proliferation through PI3 kinase-dependent mechanism.</p

Neighbourhood deprivation and lung cancer risk: a nested case–control study in the USA

Objectives To examine the association between neighbourhood deprivation and lung cancer risk. Design Nested case–control study. Setting Southern Community Cohort Study of persons residing in 12 states in the southeastern USA. Participants 1334 cases of lung cancer and 5315 controls. Primary outcome measure Risk of lung cancer. Results After adjustment for smoking status and other confounders, and additional adjustment for individual-level measures of socioeconomic status (SES), there was no monotonic increase in risk with worsening deprivation score overall or within sex and race groups. There was an increase among current and shorter term former smokers (p=0.04) but not among never and longer term former smokers. There was evidence of statistically significant interaction by sex among whites, but not blacks, in which the effect of worsening deprivation on lung cancer existed in males but not in females. Conclusions Area-level measures of SES were associated with lung cancer risk in current and shorter term former smokers only in this population

Long intergenic non-coding RNA expression signature in human breast cancer

Breast cancer is a complex disease, characterized by gene deregulation. There is less systematic investigation of the capacity of long intergenic non-coding RNAs (lincRNAs) as biomarkers associated with breast cancer pathogenesis or several clinicopathological variables including receptor status and patient survival. We designed a two-stage study, including 1,000 breast tumor RNA-seq data from The Cancer Genome Atlas (TCGA) as the discovery stage, and RNA-seq data of matched tumor and adjacent normal tissue from 50 breast cancer patients as well as 23 normal breast tissue from healthy women as the replication stage. We identified 83 lincRNAs showing the significant expression changes in breast tumors with a false discovery rate (FDR) < 1% in the discovery dataset. Thirty-seven out of the 83 were validated in the replication dataset. Integrative genomic analyses suggested that the aberrant expression of these 37 lincRNAs was probably related with the expression alteration of several transcription factors (TFs). We observed a differential co-expression pattern between lincRNAs and their neighboring genes. We found that the expression levels of one lincRNA (RP5-1198O20 with Ensembl ID ENSG00000230615) were associated with breast cancer survival with P < 0.05. Our study identifies a set of aberrantly expressed lincRNAs in breast cancer

Genetic polymorphism in the manganese superoxide dismutase gene, antioxidant intake, and breast cancer risk: results from the Shanghai Breast Cancer Study

INTRODUCTION: It has been suggested that oxidative stress and mitochondrial DNA damage play important roles in breast cancer carcinogenesis. Manganese superoxide dismutase (MnSOD) is a major enzyme that is responsible for the detoxification of reactive oxygen species in the mitochondria. A T → C substitution in the MnSOD gene results in a Val → Ala change at the -9 position of the mitochondrial targeting sequence (Val-9Ala), which alters the protein secondary structure and thus affects transport of MnSOD into the mitochondria. METHODS: We evaluated this genetic polymorphism in association with breast cancer risk using data from the Shanghai Breast Cancer Study, a population-based case–control study conducted in urban Shanghai from 1996 to 1998. The MnSOD Val-9Ala polymorphism was examined in 1125 breast cancer cases and 1197 age-frequency-matched control individual. RESULTS: Breast cancer risk was slightly elevated in women with Ala/Ala genotype (odds ratio [OR] 1.3, 95% confidence interval [CI] 0.7–2.3), particularly among premenopausal women (OR 1.8, 95% CI 0.9–3.7), as compared with those with Val/Val genotype. The increased risk with the Ala/Ala genotype was stronger among premenopausal women with a higher body mass index (OR 2.5, 95% CI 0.9–7.0) and more years of menstruation (OR 2.6, 95% CI 0.8–8.0). The risk among premenopausal women was further increased twofold to threefold among those with a low intake of fruits, vegetables, vitamin supplements, selenium, or antioxidant vitamins, including carotenes and vitamins A, C, and E. However, the frequency of the Ala allele was low (14%) in the study population, and most of the ORs provided above were not statistically significant. CONCLUSION: The present study provides some evidence that genetic polymorphism in the MnSOD gene may be associated with increased risk of breast cancer among Chinese women with high levels of oxidative stress or low intake of antioxidants. Studies with a larger sample size are needed to confirm the findings

Joint Effect of Genetic and Lifestyle Risk Factors on Type 2 Diabetes Risk among Chinese Men and Women

More than 40 genetic susceptibility loci have been reported for type 2 diabetes (T2D). Recently, the combined effect of genetic variants has been investigated by calculating a genetic risk score. We evaluated 36 genome-wide association study (GWAS) identified SNPs in 2,679 T2D cases and 3322 controls in middle-age Han Chinese. Fourteen SNPs were significantly associated with T2D in analysis adjusted for age, sex and BMI. We calculated two genetic risk scores (GRS) (GRS1 with all the 36 SNPs and GRS2 with the 14 SNPs significantly associated with T2D). The odds ratio for T2D with each GRS point (per risk allele) was 1.08 (95% CI: 1.06–1.09) for GRS1 and 1.15 (95% CI: 1.13–1.18) for GRS2. The OR for quintiles were 1.00, 1.26, 1.69, 1.95 and 2.18 (P\u3c0.0001) for GRS1 and 1.00, 1.33, 1.60, 2.03 and 2.80 (P\u3c0.001) for GRS2. Participants in the higher tertile of GRS1 and the higher BMI category had a higher risk of T2D compared to those on the lower tertiles of the GRS1 and of BMI (OR = 11.08; 95% CI: 7.39–16.62). We found similar results when we investigated joint effects between GRS1 and WHR terciles and exercise participation. We finally investigated the joint effect between tertiles of GRSs and a composite high risk score (no exercise participation and high BMI and WHR) on T2D risk. We found that compared to participants with low GRS1 and no high risk factors for T2D, those with high GRS1 and three high risk factors had a higher risk of T2D (OR = 13.06; 95% CI: 8.65–19.72) but the interaction factor was of marginal significance. The association was accentuated when we repeated analysis with the GRS2. In conclusion we found an association between GRS and lifestyle factors, alone and in combination, contributed to the risk of and T2D among middle age Chinese

Comparison of Biomarker Expression between Proximal and Distal Colorectal Adenomas: The Tennessee-Indiana Adenoma Recurrence Study

It is unclear if proximal and distal traditional adenomas present with differences in molecular events which contribute to cancer heterogeneity by tumor anatomical subsite. Participants from a colonoscopy-based study (n=380) were divided into subgroups based on the location of their most advanced adenoma: proximal, distal, or “equivalent both sides”. Eight biomarkers in the most advanced adenomas were evaluated by immunohistochemistry (Ki-67, COX-2, TGFβRII, EGFR, β-catenin, cyclin D1, c-Myc) or TUNEL (apoptosis). After an adjustment for pathological features, there were no significant differences between proximal and distal adenomas for any biomarker. Conversely, expression levels did vary by other features, such as their size, villous component, and synchronousness. Large adenomas had higher expression levels of Ki-67(P<0.001), TGFβRII (P<0.0001), c-Myc (P<0.001), and cyclin D1 (P<0.001) in comparison to small adenomas, and tubulovillous/villous adenomas also were more likely to have similar higher expression levels in comparison to tubular adenomas. Adenoma location is not a major determinant of the expression of these biomarkers outside of other pathological features. This study suggests similarly important roles of Wnt/β-catenin and TGF-β pathways in carcinogenesis in both the proximal and distal colorectum

Longer telomere length in peripheral white blood cells is associated with risk of lung cancer and the rs2736100 (CLPTM1L-TERT) polymorphism in a prospective cohort study among women in China.

A recent genome-wide association study of lung cancer among never-smoking females in Asia demonstrated that the rs2736100 polymorphism in the TERT-CLPTM1L locus on chromosome 5p15.33 was strongly and significantly associated with risk of adenocarcinoma of the lung. The telomerase gene TERT is a reverse transcriptase that is critical for telomere replication and stabilization by controlling telomere length. We previously found that longer telomere length measured in peripheral white blood cell DNA was associated with increased risk of lung cancer in a prospective cohort study of smoking males in Finland. To follow up on this finding, we carried out a nested case-control study of 215 female lung cancer cases and 215 female controls, 94% of whom were never-smokers, in the prospective Shanghai Women's Health Study cohort. There was a dose-response relationship between tertiles of telomere length and risk of lung cancer (odds ratio (OR), 95% confidence interval [CI]: 1.0, 1.4 [0.8-2.5], and 2.2 [1.2-4.0], respectively; P trend = 0.003). Further, the association was unchanged by the length of time from blood collection to case diagnosis. In addition, the rs2736100 G allele, which we previously have shown to be associated with risk of lung cancer in this cohort, was significantly associated with longer telomere length in these same study subjects (P trend = 0.030). Our findings suggest that individuals with longer telomere length in peripheral white blood cells may have an increased risk of lung cancer, but require replication in additional prospective cohorts and populations

Serum Adiponectin in Relation to Body Mass Index and Other Correlates in Black and White Women

Adiponectin is a promising biomarker linking obesity and disease risk; however, limited data are available regarding adiponectin in black women among whom obesity is highly prevalent

Genetic polymorphisms in the matrix metalloproteinase 12 gene (MMP12) and breast cancer risk and survival: the Shanghai Breast Cancer Study

INTRODUCTION: Matrix metalloproteinase 12 (MMP12) is a proteolytic enzyme responsible for cleavage of plasminogen to angiotensin, which has an angiostatic effect. Using data from a population-based case–control study conducted among Chinese women in Shanghai, we evaluated the association of breast cancer risk and survival with two common polymorphisms in the MMP12 gene: A-82G in the promoter region and A1082G in exon, resulting in an amino acid change of asparagine to serine. METHODS: Included in the study were 1,129 cases and 1,229 age-frequency-matched population controls. Breast cancer patients were followed up to determine the intervals of overall survival and disease-free survival. RESULTS: The frequencies of the G allele in the A-82G and A1082G polymorphism among controls were 0.029 and 0.107, respectively. There were no associations between MMP12 polymorphisms and breast cancer risk. Patients with the AG or GG genotype of the A1082G polymorphism showed poorer overall survival (though the difference was not statistically significant) than patients with the AA genotype (hazard ratio 1.36, 95% CI 0.92 to 2.00). CONCLUSION: This result suggests that MMP12 A1082G polymorphism may be related to prognosis in breast cancer patients. Additional studies with larger sample sizes are warranted