Aberrations of theAPC gene in primary breast carcinoma

Kashiwaba, Masahiro; Tamura, Gen; Ishida, Motoo

doi:10.1007/bf01194271

Cited by 44 publications

(27 citation statements)

References 25 publications

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“…Mutated APC has also been reported in a range of sporadic tumours, including pancreatic and gastric tumours and the majority of adenomas and carcinomas of the colorectum Horii et al, 1992;Nakatsuru et al, 1992). Furthermore, loss of heterozygosity at 5q21 has been observed in sporadic tumours of the breast and oesophagus (Boynton et al, 1992;Thompson et al, 1993;Kashiwaba et al, 1994).…”

Section: Introductionmentioning

confidence: 99%

Dysregulated expression of β-catenin marks early neoplastic change in Apc mutant mice, but not all lesions arising in Msh2 deficient mice

Kongkanuntn¹,

Bubb²,

Sansom³

et al. 1999

Oncogene

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We have analysed the pattern of b-catenin expression by immunohistochemistry in mice singly or multiply mutant for Apc, p53 and Msh2. We observed increased expression of b-catenin in all intestinal lesions arising on an Apc Min +/7 background. In all categories of lesion studied mosaic patterns of b-catenin expression were observed, with the proportion of cells showing enhanced expression decreasing with increasing lesion size. p53 status did not alter these patterns. We also show that bcatenin dysregulation marks pancreatic abnormalities occurring in Apc Min +/7 and (Apc Min +/7, p537/7) mice. In these mice both adenomas and adenocarcinomas of the pancreas arose and were characterized by increased expression of b-catenin. We have extended these analyses to intestinal lesions arising in mice mutant for the mismatch repair gene Msh2. In these mice, increased expression of b-catenin was again observed. However, in contrast with Apc Min +/7 mice, a subset of lesions retained normal expression. Taken together, these ®ndings show that increased expression of b-catenin is an e cient marker of early neoplastic change in both murine intestine and pancreas in Apc mutant mice. However, we also show that dysregulation of b-catenin is not an obligate step in the development of intestinal lesions, and therefore that genetic events other than the loss of Apc function may initiate the transition from normal to neoplastic epithelium.

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Section: Introductionmentioning

confidence: 99%

Dysregulated expression of β-catenin marks early neoplastic change in Apc mutant mice, but not all lesions arising in Msh2 deficient mice

Kongkanuntn¹,

Bubb²,

Sansom³

et al. 1999

Oncogene

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“…PCR-SSCP analyses for codons 998-1141 and 1260-1547 of the APC gene, and exon 3 of the β-catenin gene were performed using published primer sequences and conditions (Kashiwaba et al, 1994;Park et al, 1999).…”

Section: Mutations Analysismentioning

confidence: 99%

“…In addition, APC promoter CpG island hypermethylation has been reported in colorectal (Hiltunen et al, 1997;Esteller et al, 2000b) and gastric cancers (Tsuchiya et al, 2000). Somatic mutations in APC have been reported only in 6% of primary breast cancers (Kashiwaba et al, 1994), despite frequent loss of heterozygosity (LOH) at the APC locus (Thompson et al, 1993;Medeiros et al, 1994;Kashiwaba et al, 1994) as well as frequent loss of APC protein expression (Ho et al, 1999). Therefore, we hypothesized that APC might be inactivated through promoter hypermethylation in primary breast cancers.…”

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confidence: 99%

Adenomatous polyposis coli (APC) gene promoter hypermethylation in primary breast cancers

et al. 2001

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Summary Similar to findings in colorectal cancers, it has been suggested that disruption of the adenomatous polyposis coli (APC)/β-catenin pathway may be involved in breast carcinogenesis. However, somatic mutations of APC and β-catenin are infrequently reported in breast cancers, in contrast to findings in colorectal cancers. To further explore the role of the APC/β-catenin pathway in breast carcinogenesis, we investigated the status of APC gene promoter methylation in primary breast cancers and in their non-cancerous breast tissue counterparts, as well as mutations of the APC and β-catenin genes. Hypermethylation of the APC promoter CpG island was detected in 18 of 50 (36%) primary breast cancers and in none of 21 non-cancerous breast tissue samples, although no mutations of the APC and β-catenin were found. No significant associations between APC promoter hypermethylation and patient age, lymph node metastasis, oestrogen and progesterone receptor status, size, stage or histological type of tumour were observed. These results indicate that APC promoter CpG island hypermethylation is a cancer-specific change and may be a more common mechanism of inactivation of this tumour suppressor gene in primary breast cancers than previously suspected.

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“…First, loss of heterozygosity at 5q21 (the chromosomal location of human Apc) has been observed in sporadic tumours of the breast (Kashiwaba et al, 1994;Thompson et al, 1993). Second, lost or reduced Apc protein expression has been demonstrated in human breast cancers (Ho et al, 1999;Schlosshauer et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

Inactivation of Apc perturbs mammary development, but only directly results in acanthoma in the context of Tcf-1 deficiency

et al. 2002

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Apc (adenomatous polyposis coli) encodes a tumour suppressor gene that is mutated in the majority of colorectal cancers. Recent evidence has also implicated Apc mutations in the aetiology of breast tumours. Apc is a component of the canonical Wnt signal transduction pathway, of which one target is Tcf-1. In the mouse, mutations of both Apc and Tcf-1 have been implicated in mammary tumorigenesis. We have conditionally inactivated Apc in both the presence and absence of Tcf-1 to examine the function of these genes in both normal and neoplastic development. Mice harbouring mammaryspecific mutations in Apc show markedly delayed development of the mammary ductal network. During lactation, the mice develop multiple metaplastic growths which, surprisingly, do not spontaneously progress to neoplasia up to a year following their induction. However, additional deficiency of Tcf-1 completely blocks normal mammary development and results in acanthoma.

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Aberrations of theAPC gene in primary breast carcinoma

Cited by 44 publications

References 25 publications

Dysregulated expression of β-catenin marks early neoplastic change in Apc mutant mice, but not all lesions arising in Msh2 deficient mice

Dysregulated expression of β-catenin marks early neoplastic change in Apc mutant mice, but not all lesions arising in Msh2 deficient mice

Adenomatous polyposis coli (APC) gene promoter hypermethylation in primary breast cancers

Inactivation of Apc perturbs mammary development, but only directly results in acanthoma in the context of Tcf-1 deficiency

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