PARP-1功能缺失与乳腺癌的相关性研究
摘要
乳腺癌是女性最常见的恶性肿瘤之一,其发病率逐年提高。尽管在乳腺癌的早期诊断和治疗等方面取得了进展,但是全球每年仍有约50万妇女死于乳腺癌,占女性恶性肿瘤死亡率第二位,因此,明确乳腺癌的发病机理从而防治乳腺癌是医学界乃至整个社会需迫切解决的问题。
目前,针对乳腺癌的遗传学和分子生物学研究发现,许多参与DNA损伤反应的基因—如BRCA1、BRCA2、ATM、CHK2以及p53等,它们的胚系突变与家族性乳腺癌的发生密切相关,表明DNA修复和细胞周期检验点的联合缺陷在乳腺癌的发生中具有重要作用但是,仍有约40%的家族性乳腺癌,其致病基因尚未明确。
自聚ADP-核糖聚合酶1(PARP-1)发现以来,大量的研究表明,其在DNA损伤的修复以及基因组稳定性的维持等方面具有重要作用,因此推测,PARP-1功能缺失可能与癌症的发生密切相关这方面的证据主要来自对PARP-1敲除小鼠模型的研究,PARP-1~(-/-)小鼠可出现自发肿瘤或致癌剂诱发肿瘤的发生率增高。
通过对PARP-1缺失小鼠模型的研究,Tong等发现,PARP-1的缺失改变了p53~(+/-)小鼠的肿瘤类型,使其出现大量的上皮来源的肿瘤,包括乳腺癌。进一步针对PARP-1~(-/-)小鼠乳腺癌的研究显示,PARP-1~(-/-)缺失导致19.5%的雌性小鼠出现晚发的乳腺癌,而p53的缺失可促进PARP-1~(-/-)小鼠乳腺癌的发生,提示在抑制乳腺癌发生过程中,PARP-1和p53之间可能存在协同作用。
一、研究内容:我们主要从两个方面进行研究1.从分子遗传学角度,筛查人类散发乳腺癌病例PARP-1基因突变;同时分析其SNP基因型与散发乳腺癌的相关性。2.从细胞和分子生物学角度,探讨PARP-1功能缺失对小鼠原代乳腺上皮细胞(PME)染色体稳定性的影响;以及PARP-1缺失对DNA损伤反应网络中相关因子—γH2AXBRCA1和p53功能的影响
二、研究结果:从本论文工作中我们得出如下结果:
1.通过对83例法国人群散发乳腺癌PARP-1的突变分析,并与100例同一人群正常人进行对比,共发现了20个杂合变异或突变。这些变异或突变分别位于启动子区(n=1)、5'非翻译区(n=1)、内含子(n=13)、编码外显子区(n=3)和3'非翻译区(n=2)。在编码区发现的3个变异中,2个为错义改变—Tyr383Ser和Arg940Lys,虽然它们已被列入SNP数据库中,但在本研究中仅出现于病例另一个为新发现的同义改变—Arg452Arg本研究提示,PARP-1基因的功能性突变在散发性乳腺癌中较为少见。
通过对正常人PARP-1基因多态性的分析,我们共检测到25个常见SNP(次等位基因频率≥10%),并根据基因型分布的一致性,将它们分为5组。我们发现A组SNP基因型的分布在病例—对照之间存在显著差异(P=0.035),提示PARP-1中某些SNP的基因型可能与乳腺癌的易感性相关。
进一步分析发现,A组SNP基因型也与乳腺癌细胞雌激素受体(ER)和孕激素受体(PR)的表达状况相关,例如,该组中的gtSNP—c.852T＞C,其基因型为TT者,与基因型为CC者相比,ER PR表达丧失的风险均明显增高(for ER,OR=38,95%CI 4.6-316;for PR,OR=5.17,95%CI 1.2-22.7)。由此我们推测,PARP-1的多态性可能会影响乳腺癌细胞ER和/或PR的表达。
2.本论文工作中,我们同时分析了PARP-1~(-/-)小鼠原代乳腺上皮细胞(PME)的早期细胞和分子生物学改变,发现:
(1) PARP-1的缺失可导致PME细胞染色体不稳定,出现非整倍体以及染色体结构异常等同时,PARP-1缺失也导致中心体的异常扩增而且,PARP-1与p53可协同维持PME细胞染色体的稳定性以及中心体的正常功能。
(2)在DNA损伤反应中,PARP-1的缺失影响p53功能的发挥。虽然PARP-1的缺失并不影响PME细胞p53~(ser15)的基础磷酸化水平;然而,经阿霉素诱导DNA产生双链断裂(DSB)后,与野生型相比,PARP-1~(-/-)PME细胞p53~(ser15)磷酸化水平的升高明显减弱,提示,PARP-1功能缺失导致p53在DNA损伤反应中的功能失调。这表明,PARP-1—p53相互作用对于DNA损伤反应中p53功能的发挥至关重要。
(3)经阿霉素(Adriamycin)诱导DNA产生双链断裂(DSB)损伤后,PARP-1的缺失并不影响PME细胞γH2AX聚集点(foci)的形成;但是与野生型相比,BRCA1聚集点的形成却显著减少,研究提示,在PME细胞中,PARP-1缺失影响BRCA1聚集点的形成免疫沉淀分析显示,BRCA1与PARP-1之间存在直接的相互作用。
综上所述,突变分析表明,PARP-1基因的功能性突变在散发性乳腺癌中较为少见;PARP-1的多态性可能与乳腺癌的易感性相关通过对小鼠PARP-1~(-/-)PME细胞的分析,我们认为PARP-1~(-/-)小鼠发生乳腺癌的部分机制是:PARP-1功能缺失导致PME细胞染色体不稳定,出现非整倍体以及染色体结构异常;而中心体异常扩增进一步导致PME细胞染色体不稳定当细胞DNA发生损伤时,由于PARP-1功能缺失,影响DNA修复因子BRCA1等的募集,同时造成p53-p21功能失调最终可能导致PME细胞在细胞周期调控DNA损伤修复以及细胞凋亡等方面出现异常,PME细胞出现增生和发育异常在此过程中,如果出现其它遗传学或表遗传学改变,例如p53的杂合性丢失等,PME细胞可能发生恶性转化,最终导致乳腺癌的发生。
本论文工作表明,(1) PARP-1基因的功能性突变在人类散发性乳腺癌中较为少见;PARP-1的多态性可能与乳腺癌的易感性相关。(2)PARP-1及聚ADP-核糖化(Poly(ADP-ribosyl)ation)修饰在DNA损伤反应中发挥重要作用,其功能缺失可导致小鼠乳腺上皮细胞基因组不稳定,从而促进了乳腺癌的发生。
PARP-1 functional deficiency with breast cancer carcinogenesis
Speciality:Biochemistry and Molecular Biology,School of Basic Medicine, Peking Union Medical College
PhD Candidate:Cao,Wen-Hui
Supervisor:Professor Shen,Yan
Breast cancer is one of the most common malignancies among females worldwide and its incidence is increasing with every year.Although there have been improvements in early diagnosis and therapy,this disease is still the second leading cause of cancer mortality in women.It is urgent to clarify its molecular mechanism.
It has been shown that germ line mutations in many genes,such as BRCA1、BRCA2、ATM、CHK2 and p53,which involve in DNA damage response,contribute to familial breast cancer,implying that combinational deficiency in both DNA repair and cell cycle checkpoint plays an important role in breast cancer carcinogenesis.For～40%familial breast cancer cases,their breast cancer-related genes are still not clear.
PARP-1 encodes a multifunctional protein,studies showed that loss of PARP-1 function lead to deficiencies in DNA-damage repair and chromosome instability,implying that PARP-1 deficiency may play a role in carcinogenisis.After more than ten years' studies on PARP-1 knockout mice,it is clear that loss of PARP-1 function would give rise to late-onset spontaneous tumors in mice,and carcinogenic agents could accelerate tumor formation in PARP-1~(-/-)mice.
Tong's studies indicate that PARP-1 deficiency changed tumor types in p53~(+/-) mice,and gave rise to many cancers,including breast cancer.Further studies showed that PARP-1 deficiency caused late onset breast cancer in 19.5%female mice,and p53 deficiency could promote the incidence of breast cancer,indicating that PARP-1 and p53 have synergistic functions in suppressing breast cancer carcinogenesis.
1.Our studies in this work
Based on the above evidences,our work mainly focused on two sides.First,we study the molecular and cellular changes existed in primary epithelial cells,which were separated from the PARP-1~(-/-) mice model.Second,we also analyzed PARP-1 mutations and single nucleotide polymorphisms(SNP) in sporadic French breast cancer cases to evaluate the correlation between PARP-1 mutation/polymorphism and human sporadic breast cancer.
2.Results
1) In this study,twenty rare heterozygous variants were found in nine(10.8%) breast cancer cases,including novel variants in promoter g.2772371T＞C(n=1),at 5'UTR c.-62C＞T(n=1),at introns(n=9),and at exon c.2819A＞G(Arg452Arg,n=1).Although two exon variants c.1148C＞A(Tyr383Ser) and c.2819A＞G(Arg940Lys),two 3'UTR variants c.3140G＞A and c.3415T＞C,and 4 intron variants of PARP-1 are registered in SNPs database,none of these rare variants was detected in the 100 controls.Mutational analysis indicated that functional mutation are rare in sporadic breast cancer.
In this study,we detected a total of Twenty-five common SNPs(minor allele frequency＞10%) in 100 controls.We next divided them into 5 groups according to their genotype distribution.The genotype distribution for group A was significantly different between cases and controls(P=0.035),suggesting that their genotypes may be associated with susceptibility for breast cancer.We further performed association analysis between expression of ER,PR and PARP-1 SNPs.Interestingly,gtSNP of PARP-1 c.852T＞C CC-carriers had a significantly increased frequency of loss of ER expression compared with homozygote TT carriers(OR=38,95%CI 4.6-316).In addition,CC-carriers also showed a strong association of loss of PR expression compared with homozygote TT carriers(OR=5.17,95%CI 1.2-22.7).
In summary,the results imply that functional PARP-lmutations are rare in sporadic breast cancer cases,but PARP-1 polymorphisms may confer susceptibility to breast cancer. 2) In this work,we mainly analyzed the early molecular and cellular changes in PARP-1~(-/-) PME cell,which may lead to carcinogenesis,and found that
(1) PARP-1 deficiency causes aneupoidy,chromosome aberration and centrosome amplification in PME cells;PARP-1 and p53 play a synergistic role in the maintenance of centrosome function and chromosomal stability in PME cells.
(2) PARP-1 deficiency compromises p53 function upon DNA damage response(DDR). Although Western blotting analysis revealed a similar basal level of p53 phosphorylation at serl5 in PARP-1-proficient and-deficient PME cells,upon DNA damage induced by adriamycin,phosphorylation of p53 in wild-type PME cells was significantly increased at 4 hrs.Although phosphorylation of p53 at ser15 could occur in response to DNA damage,PARP-1 deficiency reduced level of p53 activation.In addition,PARP-1 deficiency compromised activation of p21.
(3) Upon DNA DSB damage induced by adriamycin treatment,PARP-1 deficiency didn't affectγH2AX foci formation.But compared to wild-type cells,BRCA1 foci were dramatically reduced in PARP-1~(-/-) PME cells,suggesting that PARP-1 deficiency compromises BRCA1 foci formation after DSB induction.Immunoprecipitation analysis showed that PARP-1 and BRCA1 has direct interaction.
In summary,this study indicates that,(1) PARP-1 functional mutations are rare in sporadic breast cancer cases;polymorphisms existed in PARP-1 gene may contribute to breast cancer susceptibility.(2) PARP-1 and Poly(ADP-ribosyl)ation play an important role in DNA damage response;PARP-1 functional deficiency could result in genomic instability in PME cell,promoting breast cancer carcinogenesis.
目前,针对乳腺癌的遗传学和分子生物学研究发现,许多参与DNA损伤反应的基因—如BRCA1、BRCA2、ATM、CHK2以及p53等,它们的胚系突变与家族性乳腺癌的发生密切相关,表明DNA修复和细胞周期检验点的联合缺陷在乳腺癌的发生中具有重要作用但是,仍有约40%的家族性乳腺癌,其致病基因尚未明确。
自聚ADP-核糖聚合酶1(PARP-1)发现以来,大量的研究表明,其在DNA损伤的修复以及基因组稳定性的维持等方面具有重要作用,因此推测,PARP-1功能缺失可能与癌症的发生密切相关这方面的证据主要来自对PARP-1敲除小鼠模型的研究,PARP-1~(-/-)小鼠可出现自发肿瘤或致癌剂诱发肿瘤的发生率增高。
通过对PARP-1缺失小鼠模型的研究,Tong等发现,PARP-1的缺失改变了p53~(+/-)小鼠的肿瘤类型,使其出现大量的上皮来源的肿瘤,包括乳腺癌。进一步针对PARP-1~(-/-)小鼠乳腺癌的研究显示,PARP-1~(-/-)缺失导致19.5%的雌性小鼠出现晚发的乳腺癌,而p53的缺失可促进PARP-1~(-/-)小鼠乳腺癌的发生,提示在抑制乳腺癌发生过程中,PARP-1和p53之间可能存在协同作用。
一、研究内容:我们主要从两个方面进行研究1.从分子遗传学角度,筛查人类散发乳腺癌病例PARP-1基因突变;同时分析其SNP基因型与散发乳腺癌的相关性。2.从细胞和分子生物学角度,探讨PARP-1功能缺失对小鼠原代乳腺上皮细胞(PME)染色体稳定性的影响;以及PARP-1缺失对DNA损伤反应网络中相关因子—γH2AXBRCA1和p53功能的影响
二、研究结果:从本论文工作中我们得出如下结果:
1.通过对83例法国人群散发乳腺癌PARP-1的突变分析,并与100例同一人群正常人进行对比,共发现了20个杂合变异或突变。这些变异或突变分别位于启动子区(n=1)、5'非翻译区(n=1)、内含子(n=13)、编码外显子区(n=3)和3'非翻译区(n=2)。在编码区发现的3个变异中,2个为错义改变—Tyr383Ser和Arg940Lys,虽然它们已被列入SNP数据库中,但在本研究中仅出现于病例另一个为新发现的同义改变—Arg452Arg本研究提示,PARP-1基因的功能性突变在散发性乳腺癌中较为少见。
通过对正常人PARP-1基因多态性的分析,我们共检测到25个常见SNP(次等位基因频率≥10%),并根据基因型分布的一致性,将它们分为5组。我们发现A组SNP基因型的分布在病例—对照之间存在显著差异(P=0.035),提示PARP-1中某些SNP的基因型可能与乳腺癌的易感性相关。
进一步分析发现,A组SNP基因型也与乳腺癌细胞雌激素受体(ER)和孕激素受体(PR)的表达状况相关,例如,该组中的gtSNP—c.852T＞C,其基因型为TT者,与基因型为CC者相比,ER PR表达丧失的风险均明显增高(for ER,OR=38,95%CI 4.6-316;for PR,OR=5.17,95%CI 1.2-22.7)。由此我们推测,PARP-1的多态性可能会影响乳腺癌细胞ER和/或PR的表达。
2.本论文工作中,我们同时分析了PARP-1~(-/-)小鼠原代乳腺上皮细胞(PME)的早期细胞和分子生物学改变,发现:
(1) PARP-1的缺失可导致PME细胞染色体不稳定,出现非整倍体以及染色体结构异常等同时,PARP-1缺失也导致中心体的异常扩增而且,PARP-1与p53可协同维持PME细胞染色体的稳定性以及中心体的正常功能。
(2)在DNA损伤反应中,PARP-1的缺失影响p53功能的发挥。虽然PARP-1的缺失并不影响PME细胞p53~(ser15)的基础磷酸化水平;然而,经阿霉素诱导DNA产生双链断裂(DSB)后,与野生型相比,PARP-1~(-/-)PME细胞p53~(ser15)磷酸化水平的升高明显减弱,提示,PARP-1功能缺失导致p53在DNA损伤反应中的功能失调。这表明,PARP-1—p53相互作用对于DNA损伤反应中p53功能的发挥至关重要。
(3)经阿霉素(Adriamycin)诱导DNA产生双链断裂(DSB)损伤后,PARP-1的缺失并不影响PME细胞γH2AX聚集点(foci)的形成;但是与野生型相比,BRCA1聚集点的形成却显著减少,研究提示,在PME细胞中,PARP-1缺失影响BRCA1聚集点的形成免疫沉淀分析显示,BRCA1与PARP-1之间存在直接的相互作用。
综上所述,突变分析表明,PARP-1基因的功能性突变在散发性乳腺癌中较为少见;PARP-1的多态性可能与乳腺癌的易感性相关通过对小鼠PARP-1~(-/-)PME细胞的分析,我们认为PARP-1~(-/-)小鼠发生乳腺癌的部分机制是:PARP-1功能缺失导致PME细胞染色体不稳定,出现非整倍体以及染色体结构异常;而中心体异常扩增进一步导致PME细胞染色体不稳定当细胞DNA发生损伤时,由于PARP-1功能缺失,影响DNA修复因子BRCA1等的募集,同时造成p53-p21功能失调最终可能导致PME细胞在细胞周期调控DNA损伤修复以及细胞凋亡等方面出现异常,PME细胞出现增生和发育异常在此过程中,如果出现其它遗传学或表遗传学改变,例如p53的杂合性丢失等,PME细胞可能发生恶性转化,最终导致乳腺癌的发生。
本论文工作表明,(1) PARP-1基因的功能性突变在人类散发性乳腺癌中较为少见;PARP-1的多态性可能与乳腺癌的易感性相关。(2)PARP-1及聚ADP-核糖化(Poly(ADP-ribosyl)ation)修饰在DNA损伤反应中发挥重要作用,其功能缺失可导致小鼠乳腺上皮细胞基因组不稳定,从而促进了乳腺癌的发生。
PARP-1 functional deficiency with breast cancer carcinogenesis
Speciality:Biochemistry and Molecular Biology,School of Basic Medicine, Peking Union Medical College
PhD Candidate:Cao,Wen-Hui
Supervisor:Professor Shen,Yan
Breast cancer is one of the most common malignancies among females worldwide and its incidence is increasing with every year.Although there have been improvements in early diagnosis and therapy,this disease is still the second leading cause of cancer mortality in women.It is urgent to clarify its molecular mechanism.
It has been shown that germ line mutations in many genes,such as BRCA1、BRCA2、ATM、CHK2 and p53,which involve in DNA damage response,contribute to familial breast cancer,implying that combinational deficiency in both DNA repair and cell cycle checkpoint plays an important role in breast cancer carcinogenesis.For～40%familial breast cancer cases,their breast cancer-related genes are still not clear.
PARP-1 encodes a multifunctional protein,studies showed that loss of PARP-1 function lead to deficiencies in DNA-damage repair and chromosome instability,implying that PARP-1 deficiency may play a role in carcinogenisis.After more than ten years' studies on PARP-1 knockout mice,it is clear that loss of PARP-1 function would give rise to late-onset spontaneous tumors in mice,and carcinogenic agents could accelerate tumor formation in PARP-1~(-/-)mice.
Tong's studies indicate that PARP-1 deficiency changed tumor types in p53~(+/-) mice,and gave rise to many cancers,including breast cancer.Further studies showed that PARP-1 deficiency caused late onset breast cancer in 19.5%female mice,and p53 deficiency could promote the incidence of breast cancer,indicating that PARP-1 and p53 have synergistic functions in suppressing breast cancer carcinogenesis.
1.Our studies in this work
Based on the above evidences,our work mainly focused on two sides.First,we study the molecular and cellular changes existed in primary epithelial cells,which were separated from the PARP-1~(-/-) mice model.Second,we also analyzed PARP-1 mutations and single nucleotide polymorphisms(SNP) in sporadic French breast cancer cases to evaluate the correlation between PARP-1 mutation/polymorphism and human sporadic breast cancer.
2.Results
1) In this study,twenty rare heterozygous variants were found in nine(10.8%) breast cancer cases,including novel variants in promoter g.2772371T＞C(n=1),at 5'UTR c.-62C＞T(n=1),at introns(n=9),and at exon c.2819A＞G(Arg452Arg,n=1).Although two exon variants c.1148C＞A(Tyr383Ser) and c.2819A＞G(Arg940Lys),two 3'UTR variants c.3140G＞A and c.3415T＞C,and 4 intron variants of PARP-1 are registered in SNPs database,none of these rare variants was detected in the 100 controls.Mutational analysis indicated that functional mutation are rare in sporadic breast cancer.
In this study,we detected a total of Twenty-five common SNPs(minor allele frequency＞10%) in 100 controls.We next divided them into 5 groups according to their genotype distribution.The genotype distribution for group A was significantly different between cases and controls(P=0.035),suggesting that their genotypes may be associated with susceptibility for breast cancer.We further performed association analysis between expression of ER,PR and PARP-1 SNPs.Interestingly,gtSNP of PARP-1 c.852T＞C CC-carriers had a significantly increased frequency of loss of ER expression compared with homozygote TT carriers(OR=38,95%CI 4.6-316).In addition,CC-carriers also showed a strong association of loss of PR expression compared with homozygote TT carriers(OR=5.17,95%CI 1.2-22.7).
In summary,the results imply that functional PARP-lmutations are rare in sporadic breast cancer cases,but PARP-1 polymorphisms may confer susceptibility to breast cancer. 2) In this work,we mainly analyzed the early molecular and cellular changes in PARP-1~(-/-) PME cell,which may lead to carcinogenesis,and found that
(1) PARP-1 deficiency causes aneupoidy,chromosome aberration and centrosome amplification in PME cells;PARP-1 and p53 play a synergistic role in the maintenance of centrosome function and chromosomal stability in PME cells.
(2) PARP-1 deficiency compromises p53 function upon DNA damage response(DDR). Although Western blotting analysis revealed a similar basal level of p53 phosphorylation at serl5 in PARP-1-proficient and-deficient PME cells,upon DNA damage induced by adriamycin,phosphorylation of p53 in wild-type PME cells was significantly increased at 4 hrs.Although phosphorylation of p53 at ser15 could occur in response to DNA damage,PARP-1 deficiency reduced level of p53 activation.In addition,PARP-1 deficiency compromised activation of p21.
(3) Upon DNA DSB damage induced by adriamycin treatment,PARP-1 deficiency didn't affectγH2AX foci formation.But compared to wild-type cells,BRCA1 foci were dramatically reduced in PARP-1~(-/-) PME cells,suggesting that PARP-1 deficiency compromises BRCA1 foci formation after DSB induction.Immunoprecipitation analysis showed that PARP-1 and BRCA1 has direct interaction.
In summary,this study indicates that,(1) PARP-1 functional mutations are rare in sporadic breast cancer cases;polymorphisms existed in PARP-1 gene may contribute to breast cancer susceptibility.(2) PARP-1 and Poly(ADP-ribosyl)ation play an important role in DNA damage response;PARP-1 functional deficiency could result in genomic instability in PME cell,promoting breast cancer carcinogenesis.
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