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Genes (Basel). 2019 Feb 28;10(3). pii: E186. doi: 10.3390/genes10030186.

Functional Analysis of Promoter Variants in Genes Involved in Sex Steroid Action, DNA Repair and Cell Cycle Control.

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Department of Molecular Medicine, Faculty of Medicine, Université Laval, Genomics Center, CHU de Quebec-Université Laval Research Center, 2705 Laurier Boulevard, Quebec, G1V 4G2, Canada.
Department of Mathematics and Statistics, Faculty of Science and Engineering, Université Laval, 1045, av. de la Médecine, Québec, G1V 0A6, Canada.
Division of Hematology-Oncology, Research Center, Sainte-Justine University Health Center, 3175 Chemin de la Côte-Sainte-Catherine, University of Montreal, Montreal, H3T 1C5, Canada.


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.


Breast cancer; candidate genes; cis-regulatory effects; functional analysis; promoter variants

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Conflict of interest statement

 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.

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