Genetic dissection of the BRCA2 promoter and transcriptional impact of DNA variants

Breast Cancer Research and Treatment
Eugenia Fraile-BethencourtEladio A Velasco

Abstract

Promoter mutations may affect transcription and can be associated with human diseases. However, the promoters of the breast cancer (BC) genes are not regularly screened. Our goal was to investigate the BRCA2 promoter in order to study a possible correlation between impaired transcription and disease. The proximal and core promoter of the BRCA2 gene was sequenced in 95 high-risk BC patients. A BRCA2-promoter insert [- 938 to + 312 from the transcription start site (TSS)] was generated and cloned into the firefly luciferase vector pGL4.10. Promoter variants and deletions were introduced by site-directed mutagenesis and quantified by Dual-Luciferase assays and semi-quantitative RT-PCR. Three different variants were detected in high-risk BC patients: rs3092989, rs206118, and rs563971900. Functional mapping of 13 overlapping deletions revealed four down-regulating segments (TSS positions): -59_-10del/µdel3 (16% of activity of the wild-type construct), -104_-55del/µdel4 (62%), -239_-190del/µdel7 (39%), -464_-415/µdel12 (78%), suggesting the presence therein of putative transcriptional activator motifs. Additionally, six microdeletions rendered luciferase overexpression: +32_+81del/µdel1 (356%), -14_+36del/µdel2 (180%), -194_-145del/µ...Continue Reading

References

Sep 28, 1999·Oncogene·I BiècheR Lidereau
Nov 11, 1999·Oncogene·P L DavisJ R Marks
Jul 26, 2002·Journal of Inherited Metabolic Disease·D N Cooper
Jun 26, 2003·Nucleic Acids Research·Domènec FarréXavier Messeguer
Dec 19, 2003·Nucleic Acids Research·Albin SandelinBoris Lenhard
Jun 24, 2006·Clinical Chemistry·Miguel de la HoyaTrinidad Caldes
Dec 29, 2007·Nature Genetics·Michael R Stratton, Nazneen Rahman
Nov 14, 2008·The New England Journal of Medicine·William D Foulkes
Feb 28, 2009·Clinical Chemistry·Karen M K de VooghtWouter W van Solinge
May 29, 2009·Proceedings of the National Academy of Sciences of the United States of America·Lucia A HindorffTeri A Manolio
Mar 11, 2010·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·David J SanzEladio A Velasco
May 12, 2010·Current Molecular Medicine·A Sarasin, P Dessen
Jun 24, 2010·BioTechniques·Anton V Bryksin, Ichiro Matsumura
Sep 3, 2010·PLoS Genetics·Matthew HalvorsenAlain Laederach
Sep 18, 2010·Breast Cancer Research and Treatment·Stéphanie LheureuxAgnès Hardouin
Feb 9, 2011·Breast Cancer Research and Treatment·Nicholas C Turner, Alan Ashworth
Dec 24, 2011·Nature Reviews. Cancer·Rohini RoySimon N Powell
Apr 20, 2012·Breast Cancer Research : BCR·Ana-Teresa MaiaBruce A J Ponder
May 29, 2012·Breast Cancer Research : BCR·Alberto AcedoEladio A Velasco
Sep 8, 2012·Nature·UNKNOWN ENCODE Project Consortium
May 30, 2013·Nature Genetics·UNKNOWN GTEx Consortium
Oct 15, 2014·Cancer Research·Mario CapassoJohn M Maris
Apr 8, 2015·Nucleic Acids Research·Weizhong LiRodrigo Lopez
Oct 28, 2015·Nature Reviews. Genetics·Andrew R HarperEric J Topol
Jan 19, 2016·Breast Cancer Research and Treatment·Francisco QuilesConxi Lázaro
Jan 20, 2016·Seminars in Cell & Developmental Biology·Vanja Haberle, Boris Lenhard
Aug 16, 2016·Nature Reviews. Cancer·Finn Cilius NielsenClaus Storgaard Sørensen
Oct 24, 2017·Nature·Kyriaki MichailidouDouglas F Easton

❮ Previous
Next ❯

Related Concepts

Related Feeds

Breast Cancer: BRCA1 & BRCA2

Mutations involving BRCA1, found on chromosome 17, and BRCA2, found on chromosome 13, increase the risk for specific cancers, such as breast cancer. Discover the last research on breast cancer BRCA1 and BRCA2 here.

Breast Cancer: Chemo-Resistance

Some cancers are difficult to treat and aggressive including the "triple-negative" breast cancer. This type of cancer is chemoresistant even before chemotherapy begins. Here are the latest discoveries chemo-resistance in breast cancer.