Niu N.,Rochester College |
Liu T.,Rochester College |
Cairns J.,Rochester College |
Ly R.C.,Rochester College |
And 15 more authors.
Human Molecular Genetics | Year: 2016
Metformin is currently considered as a promising anticancer agent in addition to its anti-diabetic effect. To better individualize metformin therapy and explore novel molecular mechanisms in cancer treatment, we conducted a pharmacogenomic study using 266 lymphoblastoid cell lines (LCLs). Metformin cytotoxicity assay was performed using the MTS assay. Genomewide association (GWA) analyses were performed in LCLs using 1.3 million SNPs, 485k DNA methylation probes, 54k mRNA expression probe sets, and metformin cytotoxicity (IC50s). Top candidate genes were functionally validated using siRNA screening, followed by MTS assay in breast cancer cell lines. Further study of one top candidate, STUB1, was performed to elucidate the mechanisms by which STUB1 might contribute to metformin action. GWA analyses in LCLs identified 198 mRNA expression probe sets, 12 SNP loci, and 5 DNA methylation loci associated with metformin IC50 with P-values < 10-4 or < 10-5. Integrated SNP/methylation loci-expression-IC50 analyses found 3 SNP loci or 5 DNA methylation loci associated with metformin IC50 through trans-regulation of expression of 11 or 26 genes with P-value < 10-4 Functional validation of top 61 candidate genes in 4 IPA networks indicated down regulation of 14 genes significantly altered metformin sensitivity in two breast cancer cell lines. Mechanistic studies revealed that the E3 ubiquitin ligase, STUB1, could influence metformin response by facilitating proteasome-mediated degradation of cyclin A. GWAS using a genomic data-enriched LCL model system, together with functional and mechanistic studies using cancer cell lines, help us to identify novel genetic and epigenetic biomarkers involved in metformin anticancer response. © The Author 2016. Published by Oxford University Press.
Manne S.L.,UMDNJ The Cancer Institute of New Jersey |
Kashy D.A.,Michigan State University |
Weinberg D.S.,Fox Chase Cancer Center |
Boscarino J.A.,Center for Health Research |
And 2 more authors.
Psychology and Health | Year: 2013
The objective of this study was to evaluate the efficacy of a couple-tailored print (CTP) intervention on colorectal cancer screening (CRCS), CRCS intentions, and on knowledge and attitudes among couples in which neither partner is on schedule with regard to CRCS. A total of 168 married couples with both members non-adherent with CRCS were randomly assigned to receive either a CTP pamphlet accompanied by a generic print (GP) pamphlet or a GP pamphlet only. Couples completed measures of CRCS, intentions, relational perspective on CRCS, discussions about CRCS, spouse support for CRCS, spouse influence strategies, CRC knowledge, perceived CRC risk, and CRCS benefits and barriers. Results indicated there was no significant benefit of CTP vs. GP on CRCS, but there was a significant increase in CRCS intentions in CTP compared with GP. There was also a significant increase in relationship perspective on CRCS, a significant increase in husbands' support of their wives' CRCS, and a significant increase in CRCS benefits in CTP. In summary, CTP did not increase CRCS practices but increased intentions and perceived benefits of CRCS as well as improving couples' ability to view CRCS as having benefit for the marital relationship. © 2013 Taylor & Francis.