Altered expression of DNA double‐strand break detection and repair proteins in breast carcinomas

Angèle, Sandra; Treilleux, Isabelle; Brémond, A.; Tanière, Philippe; Hall, Janet

doi:10.1046/j.1365-2559.2003.01713.x

Cited by 50 publications

(54 citation statements)

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“…More recently, we determined that aberrant methylation of the ATM promoter occurs in a subset of head and neck tumors (Ai et al, 2004). Further, several reports showed that reduced ATM expression, as judged by immunohistochemical staining, occurs in a significant portion of breast tumors (Kairouz et al, 1999;Angele et al, 2000). Collectively, these findings led us to hypothesize that epigenetic events, rather than somatic mutation of the ATM gene itself, link reduced ATM function to sporadic breast cancer.…”

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confidence: 91%

The ATM gene is a target for epigenetic silencing in locally advanced breast cancer

Kim

Cvitanovic

et al. 2004

Oncogene

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Several epidemiological studies on ataxia-telangiectasia families indicate that obligate ATM heterozygotes display an elevated risk for developing breast cancer. However, a molecular basis for a potential link between diminished ATM function and sporadic breast malignancy remains elusive. Here, we show that 78% (18 out of a panel of 23) of surgically removed breast tumors (stage II or greater) displayed aberrant methylation of the ATM proximal promoter region as judged by methylation-specific PCR. Aberrant methylation of the ATM promoter was independently confirmed in several tumors by bisulfite sequencing. Moreover, bisulfite sequencing indicated that this region of the genome is subject to dense methylation. Further, we found a highly significant correlation (P ¼ 0.0006) between reduced ATM mRNA abundance, as measured by realtime RT-PCR, and aberrant methylation of the ATM gene promoter. These findings indicate that epigenetic silencing of ATM expression occurs in locally advanced breast tumors, and establish a link at the molecular level between reduced ATM function and sporadic breast malignancy. Oncogene (2004Oncogene ( ) 23, 9432-9437. doi:10.1038 Published online 1 November 2004Keywords: ATM; epigenetics; promoter hypermethylation; breast cancer Germline mutation of the ATM gene is the underlying cause of the cancer-prone disorder ataxia-telangiectasia (A-T) (Rotman and Shiloh, 1998). As outlined in the seminal work of Swift et al. (1987), and validated in subsequent studies (Easton, 1994;Athma et al., 1996), obligate ATM heterozygotes display an approximate fourfold elevated risk for developing breast cancer. Following the cloning of the ATM gene, several groups (FitzGerald et al., 1997;Bebb et al., 1999;Shafman et al., 2000) studied large cohorts of sporadic breast cancer patients and age-matched controls for nonsense or frame-shift mutations within the ATM gene. Neither group found evidence for a higher incidence of defective ATM alleles in the cancer patient cohort. Furthermore, the correlation between breast cancer and dominantnegative forms of ATM arising from defined missense or intronic mutations within the ATM gene remains controversial (Chenevix-Trench et al., 2002;Bernstein et al., 2003). Thus, a potential role for diminished ATM function in sporadic breast cancer remains unresolved.We have reported that, in cultured tumor cells, the ATM gene is subject to epigenetic silencing attributable to aberrant methylation of its proximal promoter region (Kim et al., 2002). More recently, we determined that aberrant methylation of the ATM promoter occurs in a subset of head and neck tumors (Ai et al., 2004). Further, several reports showed that reduced ATM expression, as judged by immunohistochemical staining, occurs in a significant portion of breast tumors (Kairouz et al., 1999;Angele et al., 2000). Collectively, these findings led us to hypothesize that epigenetic events, rather than somatic mutation of the ATM gene itself, link reduced ATM function to sporadic breast cancer.The putative proximal pro...

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confidence: 91%

The ATM gene is a target for epigenetic silencing in locally advanced breast cancer

Kim

Cvitanovic

et al. 2004

Oncogene

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“…To compare the relative frequencies of aberrant reduction of the ATM protein among breast carcinomas with germline BRCA1/2 mutations (n ¼ 76) versus non-BRCA1/2 tumours (n ¼ 1106), we employed an established immunohistochemical protocol (Lukas et al, 2001;Vahteristo et al, 2002) using the monoclonal antibody ATML2p recognizing an epitope between amino acids 2581 and 2599 of ATM (a kind gift from Yossi Shiloh), previously validated for immunostaining on archival specimens of formalin-fixed and paraffin-embedded human tissues (Angele et al, 2003;Bartkova et al, 2005a, b). Representative examples of the ATM-staining patterns in normal human breast and invasive carcinomas with either preserved or aberrantly reduced ATM expression are shown in Figure 1.…”

Section: Resultsmentioning

confidence: 99%

The DNA damage signalling kinase ATM is aberrantly reduced or lost in BRCA1/BRCA2-deficient and ER/PR/ERBB2-triple-negative breast cancer

et al. 2007

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The ataxia-telangiectasia-mutated (ATM) kinase is a key transducer of DNA damage signals within the genome maintenance machinery and a tumour suppressor whose germline mutations predispose to familial breast cancer. ATM signalling is constitutively activated in early stages of diverse types of human malignancies and cell culture models in response to oncogene-induced DNA damage providing a barrier against tumour progression. As BRCA1 and BRCA2 are also components of the genome maintenance network and their mutations predispose to breast cancer, we have examined the ATM expression in human breast carcinomas of BRCA1/2 mutation carriers, sporadic cases and familial non-BRCA1/2 patients. Our results show that ATM protein expression is aberrantly reduced more frequently among BRCA1 (33%; P ¼ 0.0003) and BRCA2 (30%; P ¼ 0.0009) tumours than in non-BRCA1/2 tumours (10.7%). Furthermore, the non-BRCA1/2 tumours with reduced ATM expression were more often estrogen receptor (ER) negative (P ¼ 0.0002), progesterone receptor (PR) negative (P ¼ 0.004) and were of higher grade (P ¼ 0.0004). In our series of 1013 non-BRCA1/2 cases, ATM was more commonly deficient (20%; P ¼ 0.0006) and p53 was overabundant (47%; Po0.0000000001) among the difficult-to-treat ER/PR/ ERBB2-triple-negative subset of tumours compared with cases that expressed at least one of these receptors (10 and 16% of aberrant ATM and p53, respectively). We propose a model of 'conditional haploinsufficiency' for BRCA1/2 under conditions of enhanced DNA damage in precancerous lesions resulting in more robust activation and hence increased selection for inactivation or loss of ATM in tumours of BRCA1/2 mutation carriers, with implications for genomic instability and curability of diverse subsets of human breast cancer.

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“…ATM is frequently altered in hematological cancers, where T-cell prolymphocytic leukemia, B-cell chronic lymphocytic leukemia, and mantle cell lymphoma are all characterized by high rates of inactivating mutations, and/or deletion of ATM. 38 Reduced ATM protein levels have also been reported in breast cancer, 39 glioblastoma, 40 gastric cancer, 41 and colorectal cancer, 42 yet the cellular mechanisms that lead to deregulation of ATM expression are poorly understood. In sporadic breast cancer, although loss of heterozygosity (LOH) in the region of ATM on chromosome 11q22.3 has been reported in up to 40% cases, somatic mutations of ATM are infrequent.…”

Section: Discussionmentioning

confidence: 99%

“…45 However, these mechanisms could only occur in a small proportion of breast cancers, whereas downregulation of ATM is observed in up to 75% cases. 39 Interestingly, increased TPD52 expression has been identified in many different types of cancer, including breast cancer, [46][47][48] colorectal cancer, 49 leukemia, and lymphoma, [50][51][52] which overlap with the spectrum of ATM-deficient malignancies. It is of particular interest that increased TPD52 expression has been associated with radiosensitivity in independent studies using lymphocytes or lymphoblastoid cell lines, 23,24 indicating that variations in TPD52 levels could alter radiosensitivity in normal cells.…”

Section: Discussionmentioning

confidence: 99%

Tumor protein D52 represents a negative regulator of ATM protein levels

et al. 2013

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Altered expression of DNA double‐strand break detection and repair proteins in breast carcinomas

Abstract: The pattern of protein changes observed supports our hypothesis that alterations in DNA double-strand break repair capacity are involved in mammary carcinogenesis.

Cited by 50 publications

References 20 publications

The ATM gene is a target for epigenetic silencing in locally advanced breast cancer

The ATM gene is a target for epigenetic silencing in locally advanced breast cancer

The DNA damage signalling kinase ATM is aberrantly reduced or lost in BRCA1/BRCA2-deficient and ER/PR/ERBB2-triple-negative breast cancer

Tumor protein D52 represents a negative regulator of ATM protein levels

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