PMID- 30823486 OWN - NLM STAT- MEDLINE DCOM- 20191227 LR - 20221207 IS - 2073-4425 (Print) IS - 2073-4425 (Electronic) IS - 2073-4425 (Linking) VI - 10 IP - 3 DP - 2019 Feb 28 TI - Functional Analysis of Promoter Variants in Genes Involved in Sex Steroid Action, DNA Repair and Cell Cycle Control. LID - 10.3390/genes10030186 [doi] LID - 186 AB - Genetic variants affecting the regulation of gene expression are among the main causes of human diversity. The potential importance of regulatory polymorphisms is underscored by results from Genome Wide Association Studies, which have already implicated such polymorphisms in the susceptibility to complex diseases such as breast cancer. In this study, we re-sequenced the promoter regions of 24 genes involved in pathways related to breast cancer including sex steroid action, DNA repair, and cell cycle control in 60 unrelated Caucasian individuals. We constructed haplotypes and assessed the functional impact of promoter variants using gene reporter assays and electrophoretic mobility shift assays. We identified putative functional variants within the promoter regions of estrogen receptor 1 (ESR1), ESR2, forkhead box A1 (FOXA1), ubiquitin interaction motif containing 1 (UIMC1) and cell division cycle 7 (CDC7). The functional polymorphism on CDC7, rs13447455, influences CDC7 transcriptional activity in an allele-specific manner and alters DNA(-)protein complex formation in breast cancer cell lines. Moreover, results from the Breast Cancer Association Consortium show a marginal association between rs13447455 and breast cancer risk (p=9.3x10(-5)), thus warranting further investigation. Furthermore, our study has helped provide methodological solutions to some technical difficulties that were encountered with gene reporter assays, particularly regarding inter-clone variability and statistical consistency. FAU - Hamdi, Yosr AU - Hamdi Y AD - Department of Molecular Medicine, Faculty of Medicine, Universite Laval, Genomics Center, CHU de Quebec-Universite Laval Research Center, 2705 Laurier Boulevard, Quebec, G1V 4G2, Canada. Jacques.Simard@crchudequebec.ulaval.ca. FAU - Leclerc, Martin AU - Leclerc M AD - Department of Mathematics and Statistics, Faculty of Science and Engineering, Universite Laval, 1045, av. de la Medecine, Quebec, G1V 0A6, Canada. Jacques.Simard@crchudequebec.ulaval.ca. FAU - Dumont, Martine AU - Dumont M AD - Department of Molecular Medicine, Faculty of Medicine, Universite Laval, Genomics Center, CHU de Quebec-Universite Laval Research Center, 2705 Laurier Boulevard, Quebec, G1V 4G2, Canada. Jacques.Simard@crchudequebec.ulaval.ca. FAU - Dubois, Stephane AU - Dubois S AD - Department of Molecular Medicine, Faculty of Medicine, Universite Laval, Genomics Center, CHU de Quebec-Universite Laval Research Center, 2705 Laurier Boulevard, Quebec, G1V 4G2, Canada. Jacques.Simard@crchudequebec.ulaval.ca. FAU - Tranchant, Martine AU - Tranchant M AD - Department of Molecular Medicine, Faculty of Medicine, Universite Laval, Genomics Center, CHU de Quebec-Universite Laval Research Center, 2705 Laurier Boulevard, Quebec, G1V 4G2, Canada. Jacques.Simard@crchudequebec.ulaval.ca. FAU - Reimnitz, Guy AU - Reimnitz G AD - Department of Molecular Medicine, Faculty of Medicine, Universite Laval, Genomics Center, CHU de Quebec-Universite Laval Research Center, 2705 Laurier Boulevard, Quebec, G1V 4G2, Canada. Jacques.Simard@crchudequebec.ulaval.ca. FAU - Soucy, Penny AU - Soucy P AD - Department of Molecular Medicine, Faculty of Medicine, Universite Laval, Genomics Center, CHU de Quebec-Universite Laval Research Center, 2705 Laurier Boulevard, Quebec, G1V 4G2, Canada. Jacques.Simard@crchudequebec.ulaval.ca. FAU - Cassart, Pauline AU - Cassart P AD - Division of Hematology-Oncology, Research Center, Sainte-Justine University Health Center, 3175 Chemin de la Cote-Sainte-Catherine, University of Montreal, Montreal, H3T 1C5, Canada. Jacques.Simard@crchudequebec.ulaval.ca. FAU - Ouimet, Manon AU - Ouimet M AD - Division of Hematology-Oncology, Research Center, Sainte-Justine University Health Center, 3175 Chemin de la Cote-Sainte-Catherine, University of Montreal, Montreal, H3T 1C5, Canada. Jacques.Simard@crchudequebec.ulaval.ca. FAU - Sinnett, Daniel AU - Sinnett D AD - Division of Hematology-Oncology, Research Center, Sainte-Justine University Health Center, 3175 Chemin de la Cote-Sainte-Catherine, University of Montreal, Montreal, H3T 1C5, Canada. Jacques.Simard@crchudequebec.ulaval.ca. FAU - Chaieb, M'Hamed Lajmi Lakhal AU - Chaieb MLL AD - Department of Mathematics and Statistics, Faculty of Science and Engineering, Universite Laval, 1045, av. de la Medecine, Quebec, G1V 0A6, Canada. Jacques.Simard@crchudequebec.ulaval.ca. FAU - Simard, Jacques AU - Simard J AD - Department of Molecular Medicine, Faculty of Medicine, Universite Laval, Genomics Center, CHU de Quebec-Universite Laval Research Center, 2705 Laurier Boulevard, Quebec, G1V 4G2, Canada. Jacques.Simard@crchudequebec.ulaval.ca. LA - eng GR - 019511/CIHR/Canada PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20190228 PL - Switzerland TA - Genes (Basel) JT - Genes JID - 101551097 RN - 0 (Cell Cycle Proteins) RN - 0 (DNA-Binding Proteins) RN - 0 (ESR1 protein, human) RN - 0 (ESR2 protein, human) RN - 0 (Estrogen Receptor alpha) RN - 0 (Estrogen Receptor beta) RN - 0 (FOXA1 protein, human) RN - 0 (Hepatocyte Nuclear Factor 3-alpha) RN - 0 (Histone Chaperones) RN - 0 (Nuclear Proteins) RN - 0 (Receptors, Steroid) RN - 0 (UIMC1 protein, human) RN - EC 2.7.1.- (CDC7 protein, human) RN - EC 2.7.11.1 (Protein Serine-Threonine Kinases) SB - IM MH - Breast Neoplasms/*genetics MH - Cell Cycle Proteins/*genetics MH - DNA-Binding Proteins/*genetics MH - Estrogen Receptor alpha/genetics MH - Estrogen Receptor beta/genetics MH - Female MH - Gene Expression Regulation, Neoplastic MH - Genetic Predisposition to Disease MH - Genome-Wide Association Study MH - HeLa Cells MH - Hepatocyte Nuclear Factor 3-alpha/genetics MH - Histone Chaperones/*genetics MH - Humans MH - MCF-7 Cells MH - Nuclear Proteins/*genetics MH - *Polymorphism, Single Nucleotide MH - Promoter Regions, Genetic MH - Protein Serine-Threonine Kinases/*genetics MH - Receptors, Steroid/*genetics MH - White People/*genetics PMC - PMC6470759 OTO - NOTNLM OT - Breast cancer OT - candidate genes OT - cis-regulatory effects OT - functional analysis OT - promoter variants COIS- The authors declare that they have no conflict of interest and the funding sponsors had no role in the design of the study, in the collection, analyses, or interpretation of data; in the writing of the manuscript, and in the decision to publish the results. EDAT- 2019/03/03 06:00 MHDA- 2019/03/03 06:01 PMCR- 2019/03/01 CRDT- 2019/03/03 06:00 PHST- 2018/12/19 00:00 [received] PHST- 2019/02/09 00:00 [revised] PHST- 2019/02/21 00:00 [accepted] PHST- 2019/03/03 06:00 [entrez] PHST- 2019/03/03 06:00 [pubmed] PHST- 2019/03/03 06:01 [medline] PHST- 2019/03/01 00:00 [pmc-release] AID - genes10030186 [pii] AID - genes-10-00186 [pii] AID - 10.3390/genes10030186 [doi] PST - epublish SO - Genes (Basel). 2019 Feb 28;10(3):186. doi: 10.3390/genes10030186.