title: Cooperation of DLC1 and CDK6 affects breast cancer clinical outcome.
abstract: Low DLC1 expression is found to frequently co-occur with aberrant expression of cell cycle genes including CDK6 in human lung and colon cancer. Here, we explore the influence of the synergistic effect of DLC1 and CDK6 on human breast cancer survival at the genetic, transcriptional, and translational levels. We found that high DLC1 and low CDK6 expression are associated with good prognosis. The DLC1 intronic SNP rs561681 is found to fit a recessive model, complying with the tumor suppressive role of DLC1. The heterozygote of the DLC1 SNP is found to increase the hazard when the CDK6 intronic SNP rs3731343 is rare homozygous, and it becomes protective when rs3731343 is common homozygous. We propose that DLC1 expression is the lowest in patients harboring the rare homozygote of rs561681 and functional DLC1 is the lowest when rs561681 is heterozygous and rs3731343 is rare homozygous. We are the first to report such synergistic effects of DLC1 and CDK6 on breast cancer survival at the transcriptional level, the overdominant model fitted by the SNP pair, and the dominant negative effect at the translational level. These findings link the germline genetic polymorphisms and synergistic effect of DLC1 and CDK6 with breast cancer progression, which provide the basis for experimentally elucidating the mechanisms driving differential tumor progression and avail in tailoring the clinical treatments for such patients based on their genetic susceptibility.
authors.affiliation: National Engineering Laboratory for Cereal Fermentation Technology, Jiangnan University, Wuxi 214122, China School of Biotechnology, Jiangnan University, Wuxi 214122, China Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland.
authors.forename: Xiaofeng
authors.initials: X
authors.lastname: Dai
authors.affiliation: National Engineering Laboratory for Cereal Fermentation Technology, Jiangnan University, Wuxi 214122, China School of Biotechnology, Jiangnan University, Wuxi 214122, China.
authors.forename: Lu
authors.initials: L
authors.lastname: Li
authors.affiliation: National Engineering Laboratory for Cereal Fermentation Technology, Jiangnan University, Wuxi 214122, China School of Biotechnology, Jiangnan University, Wuxi 214122, China.
authors.forename: Xiuxia
authors.initials: X
authors.lastname: Liu
authors.affiliation: National Engineering Laboratory for Cereal Fermentation Technology, Jiangnan University, Wuxi 214122, China School of Biotechnology, Jiangnan University, Wuxi 214122, China.
authors.forename: Weiguo
authors.initials: W
authors.lastname: Hu
authors.affiliation: National Engineering Laboratory for Cereal Fermentation Technology, Jiangnan University, Wuxi 214122, China School of Biotechnology, Jiangnan University, Wuxi 214122, China yangyankun@jiangnan.edu.cn baizhonghu@jiangnan.edu.cn.
authors.forename: Yankun
authors.initials: Y
authors.lastname: Yang
authors.affiliation: National Engineering Laboratory for Cereal Fermentation Technology, Jiangnan University, Wuxi 214122, China School of Biotechnology, Jiangnan University, Wuxi 214122, China yangyankun@jiangnan.edu.cn baizhonghu@jiangnan.edu.cn.
authors.forename: Zhonghu
authors.initials: Z
authors.lastname: Bai
mesh_terms: D000328:Adult; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism*; D051361:Cyclin-Dependent Kinase 6 / Q000235:genetics* / Q000378:metabolism*; D005260:Female; D020690:GTPase-Activating Proteins / Q000235:genetics* / Q000378:metabolism*; D018628:Gene Dosage; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D015810:Linkage Disequilibrium; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism*
chemical_list: C112352:DLC1 protein, human; D020690:GTPase-Activating Proteins; D025521:Tumor Suppressor Proteins; C495911:CDK6 protein, human; D051361:Cyclin-Dependent Kinase 6
keywords: CDK6; DLC1; breast cancer; cooperation; survival