Polymorphism of Emphasis Type="Italic"UBC9/Emph

Authors: Katarzyna Wozniak Renata Krupa Ewelina Synowiec Zbigniew Morawiec

Publish Date: 2013/07/20

Volume: 20, Issue: 1, Pages: 67-72

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Abstract

UBC9 protein E2conjugating enzyme plays a key role in posttranslation modification named sumoylation Proteins which are sumoylated take part in many cellular processes including cell growth maintaining the genome integrity and stability and cancer development The aim of this study was to investigate an association between three polymorphisms of the UBC9 gene c73GA rs11553473 c430TG rs75020906 and g1289209TC rs7187167 and a risk of ductal breast cancer occurrence We performed a casecontrol study in 181 breast cancer cases and 277 controls using PCRRLFP and ASOPCR In the case of the 430TG polymorphism of the UBC9 gene lack of variability suggests that there is not a polymorphic site in polish population We observed that a risk of breast cancer occurrence is elevated in patients with the G/A genotype OR 503 95  Cl 305–828 the A/A genotype OR 113 95  Cl 424–303 and the A allele OR 686 95  Cl 443–106 of the c73GA polymorphism In the case of the g1289209TC polymorphism we found a correlation between estrogen receptor ER expression and the T/T genotype OR 022 95  Cl 007–064 and the T allele OR 053 95  Cl 032–088 We also found a correlation between the T/T genotype OR 413 95  Cl 121–141 and the T allele OR 209 95  Cl 107–408 of the g1289209TC polymorphism with triple negative breast cancer Our results suggest that the variability of the UBC9 gene can play a role in breast cancer occurrenceSmall ubiquitinrelated modifier SUMO1 2 and 3 conjugation is a type of posttranslational modification of proteins named sumoylation Sumoylation is the process that requires few steps of enzymatic reactions like maturation activation conjugation and ligation Mature SUMO protein is activated by the heterodimeric SUMO E1 enzyme SAE1/SAE2 Next SUMO protein is displaced from the E1 complex to the E2 conjugating enzyme named UBC9 The enzyme catalyzes the formation of izopeptide bond between the Cterminal Gly residue of SUMO protein and ɛamino group of Lys residue in the target protein In the last step SUMO protein is attached to its substrate This step can occur on two ways directly by E2 or by the E3 enzyme 1 Sumoylation is similar to ubiquitination but the biological functions of these two processes can be quite distinct Unlike ubiquitination that normally targets proteins for degradation through proteasome pathway sumoylation regulates divers cellular processes including DNA replication and repair chromosome packing and dynamics genome integrity nuclear transport signal transduction and cell proliferation 2UBC9 is the only known E2 conjugating enzyme that exists for sumoylation It exerts a central function for the sumoylation pathway interacting with almost all the partners required for sumoylation In addition recent evidences indicate that UBC9 is a multifunctional protein that can exert its functions independent of sumoylation 3 4 It is overexpressed in several cancers like colon prostate breast lung ovarian melanomas head and neck 5 6 7 Wu et al 8 reported that in breast cancer the UBC9 level was 5fold higher than the matched normal tissues UBC9 has also been shown to bind to HMG1 proteins and integrate both positive and negative signals for proliferation and transformation 9 Recently UBC9 was found to promote cell invasion and metastasis of breast cancer cells 4 implicating a role in tumorigenesisSUMO modification can influence a plethora of transcription factors and cofactors Sumoylation of transcription factors can lead to transcriptional activation but has been mostly associated with transcriptional repression Attenuation or repression of their transcriptional activity has been observed for the majority of nuclear receptors like ER estrogen receptor PR progesterone receptor and AR androgen receptor 10 11 12The SUMO modification pathway was also shown to be involved in response to DNA damage 13 14 Number of studies suggests a link between repair of DNA especially DNA double strand breaks DSBs and genetics predisposition to hereditary as well as sporadic breast cancer 15 16 17 18 Known breast cancer susceptibility genes like BRCA1 BRCA2 ATM CHK2 TP53 are involved in the repair of DSBs and related processes such as cell cycle control indicating that disturbances of DNA DSBs repair might result in breast cancer developmentUBC9 protein the key enzyme of sumoylation may take part in breast cancer development resulting in a change of localization activity and stability of modified proteins For this reason UBC9 may also serve as a potential biomarker for diagnosis or prognosis as well as a therapeutic target for breast cancer therapy Genetic variability may affect expression and activity of UBC9 gene or/and protein and may have an impact on breast cancer occurrence and progressionIn the present study we investigated a correlation between three polymorphic variants SNPs of the UBC9 gene c73GA rs11553473 c430TG rs75020906 g1289209TC rs7187167 and breast cancer risk We also studied an association between the above polymorphisms of the UBC9 gene and clinical characteristics of breast cancer patients such as tumor grade tumor stage and ER and PR estrogen and progesterone receptors respectively and HER2 expression human epidermal growth factor 2Blood samples were collected from 181 women mean age 60 ± 11 years diagnosed with ductal breast cancer treated at the Department of Surgical Oncology N Copernicus Hospital Lodz Poland Blood was collected before surgical treatment and chemotherapy The control group consisting of 277 women is agematched women who were not diagnosed with cancer and recruited from Commune Health Clinic in Rzgow and Institute Polish Mother’s Health Center Lodz Poland The Local Ethic Committee approved the study and each patient gave a written consent

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