TY - JOUR
T1 - Epigenetic and genetic alterations of APC and CDH1 genes in lobular breast cancer
T2 - Relationships with abnormal E-cadherin and catenin expression and microsatellite instability
AU - Sarrió, David
AU - Moreno-Bueno, Gema
AU - Hardisson, David
AU - Sánchez-Estévez, Carolina
AU - Guo, Mingzhou
AU - Herman, James G.
AU - Gamallo, Carlos
AU - Esteller, Manel
AU - Palacios, José
PY - 2003/8/20
Y1 - 2003/8/20
N2 - The causes and functional consequences of E-cadherin (E-CD) loss in breast cancer are poorly understood. E-CD loss might act in concert with alterations in the APC/β-catenin pathway to permit oncogenic β-catenin signaling. To test this hypothesis, we have analyzed the presence of genetic and epigenetic alterations affecting E-CD (CDH1), APC and β-catenin (CTNNB1) genes and the immunohistochemical expression of E-CD, β- and γ-catenin in a series of 46 infiltrating lobular breast carcinomas (ILCs). Since 80% of ILCs featured complete loss of E-CD expression, we analyzed the molecular alterations responsible for E-CD inactivation in these tumors. We found that 10 of 46 (22%) cases harbored mutations in CDH1, including 1 case with 2 different mutations (1 of which was germline). CDH1 was also inactivated by loss of heterozygosity (LOH; 30/41, 73%) and promoter hypermethylation (19/46, 41%). Interestingly, LOH and mutations were also detected in the corresponding in situ lesions of the ILCs, implying that these alterations are early events in lobular cancer tumorogenesis. Additionally, the presence of a polymorphism in the CDH1 promoter was found to be inversely correlated with CDH1 mutations, but not with E-CD levels. We next examined whether alterations in the APC/β-catenin pathway also occurred in the same series of ILCs. Although no CTNNB1 or APC mutations were detected, promoter methylation (25/46, 52%) and LOH (7/30, 23%) of APC were found. Moreover, methylation of APC and CDH1 occurred concordantly. However, β- and γ-catenin were severely reduced or absent in 90% of these tumors, implying that alterations in CDH1 and APC genes do not promote β-catenin accumulation in ILC. These molecular alterations were not associated with microsatellite instability. In summary, several different mechanisms (mutations, LOH, methylation) are involved in the frequent CDH1 inactivation in invasive and in situ lobular breast cancer. The same tumors also show genetic and epigenetic alterations of APC gene. However, altered CDH1 and APC genes do not promote β-catenin accumulation in this tumor type.
AB - The causes and functional consequences of E-cadherin (E-CD) loss in breast cancer are poorly understood. E-CD loss might act in concert with alterations in the APC/β-catenin pathway to permit oncogenic β-catenin signaling. To test this hypothesis, we have analyzed the presence of genetic and epigenetic alterations affecting E-CD (CDH1), APC and β-catenin (CTNNB1) genes and the immunohistochemical expression of E-CD, β- and γ-catenin in a series of 46 infiltrating lobular breast carcinomas (ILCs). Since 80% of ILCs featured complete loss of E-CD expression, we analyzed the molecular alterations responsible for E-CD inactivation in these tumors. We found that 10 of 46 (22%) cases harbored mutations in CDH1, including 1 case with 2 different mutations (1 of which was germline). CDH1 was also inactivated by loss of heterozygosity (LOH; 30/41, 73%) and promoter hypermethylation (19/46, 41%). Interestingly, LOH and mutations were also detected in the corresponding in situ lesions of the ILCs, implying that these alterations are early events in lobular cancer tumorogenesis. Additionally, the presence of a polymorphism in the CDH1 promoter was found to be inversely correlated with CDH1 mutations, but not with E-CD levels. We next examined whether alterations in the APC/β-catenin pathway also occurred in the same series of ILCs. Although no CTNNB1 or APC mutations were detected, promoter methylation (25/46, 52%) and LOH (7/30, 23%) of APC were found. Moreover, methylation of APC and CDH1 occurred concordantly. However, β- and γ-catenin were severely reduced or absent in 90% of these tumors, implying that alterations in CDH1 and APC genes do not promote β-catenin accumulation in ILC. These molecular alterations were not associated with microsatellite instability. In summary, several different mechanisms (mutations, LOH, methylation) are involved in the frequent CDH1 inactivation in invasive and in situ lobular breast cancer. The same tumors also show genetic and epigenetic alterations of APC gene. However, altered CDH1 and APC genes do not promote β-catenin accumulation in this tumor type.
KW - β-catenin
KW - APC
KW - E-cadherin
KW - Lobular breast cancer
KW - Loss of heterozygosity
KW - Methytation
KW - Microsatellite instability
KW - Mutation
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U2 - 10.1002/ijc.11197
DO - 10.1002/ijc.11197
M3 - Article
C2 - 12800196
AN - SCOPUS:0037479867
SN - 0020-7136
VL - 106
SP - 208
EP - 215
JO - International Journal of Cancer
JF - International Journal of Cancer
IS - 2
ER -