title: Epigenetic and genetic alterations of APC and CDH1 genes in lobular breast cancer: relationships with abnormal E-cadherin and catenin expression and microsatellite instability.
abstract: 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/beta-catenin pathway to permit oncogenic beta-catenin signaling. To test this hypothesis, we have analyzed the presence of genetic and epigenetic alterations affecting E-CD (CDH1), APC and beta-catenin (CTNNB1) genes and the immunohistochemical expression of E-CD, beta- and gamma-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/beta-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, beta- and gamma-catenin were severely reduced or absent in 90% of these tumors, implying that alterations in CDH1 and APC genes do not promote beta-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 beta-catenin accumulation in this tumor type.
authors.affiliation: Laboratory of Breast and Gynecological Cancer, Molecular Pathology Program, Centro Nacional de Investigaciones Oncológicas, Madrid, Spain.
authors.forename: David
authors.initials: D
authors.lastname: Sarrió
authors.forename: Gema
authors.initials: G
authors.lastname: Moreno-Bueno
authors.forename: David
authors.initials: D
authors.lastname: Hardisson
authors.forename: Carolina
authors.initials: C
authors.lastname: Sánchez-Estévez
authors.forename: Mingzhou
authors.initials: M
authors.lastname: Guo
authors.forename: James G
authors.initials: JG
authors.lastname: Herman
authors.forename: Carlos
authors.initials: C
authors.lastname: Gamallo
authors.forename: Manel
authors.initials: M
authors.lastname: Esteller
authors.forename: José
authors.initials: J
authors.lastname: Palacios
mesh_terms: D025601:Adenomatous Polyposis Coli Protein / Q000235:genetics*; D001943:Breast Neoplasms / Q000235:genetics*; D015820:Cadherins / Q000235:genetics*; D002278:Carcinoma in Situ / Q000235:genetics; D018270:Carcinoma, Ductal, Breast / Q000235:genetics; D018275:Carcinoma, Lobular / Q000235:genetics*; D003598:Cytoskeletal Proteins / Q000235:genetics*; D019175:DNA Methylation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006801:Humans; D007124:Immunoenzyme Techniques; D019656:Loss of Heterozygosity / Q000235:genetics; D018895:Microsatellite Repeats; D009154:Mutation; D009361:Neoplasm Invasiveness; D011401:Promoter Regions, Genetic / Q000235:genetics; D015534:Trans-Activators / Q000235:genetics*; D051176:beta Catenin
chemical_list: D025601:Adenomatous Polyposis Coli Protein; C495270:CTNNB1 protein, human; D015820:Cadherins; D003598:Cytoskeletal Proteins; D015534:Trans-Activators; D051176:beta Catenin