Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
Breast Cancer Research and Treatment
Published in: Breast Cancer Research and Treatment 2/2007

01-08-2007 | Review Paper

The role of ATM in breast cancer development

Authors: Jana Prokopcova, Zdenek Kleibl, Claire M. Banwell, Petr Pohlreich

Published in: Breast Cancer Research and Treatment | Issue 2/2007

Login to get access

Abstract

Complete or partial inability to sense and repair DNA damage increases the risk of developing cancer. The ataxia telangiectasia mutated (ATM) protein kinase has a crucial role in response to DNA double-strand breaks. Hereditary mutations in the ATM gene are the cause of a rare genomic instability syndrome ataxia telangiectasia (AT) characterized, among others, by elevated cancer risk. Although clear in homozygotes, numerous studies have failed to find a link between heterozygotes and cancer. However, there is increasing evidence that ATM heterozygotes have an increased risk of developing breast cancer. First, epidemiological studies conferred an increased risk of breast cancer among AT relatives. Second, in vitro studies of heterozygous cells provide strong evidence of hyperradiosensitivity. Third, some clinical studies found an increased frequency of ATM mutations among high-risk breast cancer families.
Literature
1.
Swift M, Morrell D, Cromartie E, Chamberlin AR, Skolnick MH, Bishop DT (1986) The incidence and gene frequency of ataxia-telangiectasia in the United States. Am J Hum Genet 39:573–583PubMed
2.
Savitsky K, Sfez S, Tagle DA, Ziv Y, Sartiel A, Collins FS, Shiloh Y, Rotman G (1995) The complete sequence of the coding region of the ATM gene reveals similarity to cell cycle regulators in different species. Hum Mol Genet 4:2025–2032PubMedCrossRef
3.
Concannon P, Gatti RA (1997) Diversity of ATM gene mutations detected in patients with ataxia-telangiectasia. Hum Mutat 10:100–107PubMedCrossRef
4.
Stankovic T, Kidd AM, Sutcliffe A, McGuire GM, Robinson P, Weber P, Bedenham T, Bradwell AR, Easton DF, Lennox GG, Haites N, Byrd PJ, Taylor AM (1998) ATM mutations and phenotypes in ataxia-telangiectasia families in the British Isles: expression of mutant ATM and the risk of leukemia, lymphoma, and breast cancer. Am J Hum Genet 62:334–345PubMedCrossRef
5.
Teraoka SN, Telatar M, Becker-Catania S, Liang T, Onengut S, Tolun A, Chessa L, Sanal O, Bernatowska E, Gatti RA, Concannon P (1999) Splicing defects in the ataxia-telangiectasia gene, ATM: underlying mutations and consequences. Am J Hum Genet 64:1617–1631PubMedCrossRef
6.
Sandoval N, Platzer M, Rosenthal A, Dork T, Bendix R, Skawran B, Stuhrmann M, Wegner RD, Sperling K, Banin S, Shiloh Y, Baumer A, Bernthaler U, Sennefelder H, Brohm M, Weber BH, Schindler D (1999) Characterization of ATM gene mutations in 66 ataxia telangiectasia families. Hum Mol Genet 8:69–79PubMedCrossRef
7.
Gatti RA, Tward A, Concannon P (1999) Cancer risk in ATM heterozygotes: a model of phenotypic and mechanistic differences between missense and truncating mutations. Mol Genet Metab 68:419–423PubMedCrossRef
8.
Gatti RA, Berkel I, Boder E, Braedt G, Charmley P, Concannon P, Ersoy F, Foroud T, Jaspers NG, Lange K (1988) Localization of an ataxia-telangiectasia gene to chromosome 11q22–23. Nature 336:577–580PubMedCrossRef
9.
Uziel T, Savitsky K, Platzer M, Ziv Y, Helbitz T, Nehls M, Boehm T, Rosenthal A, Shiloh Y, Rotman G (1996) Genomic organization of the ATM gene. Genomics 33:317–320PubMedCrossRef
10.
Shafman T, Khanna KK, Kedar P, Spring K, Kozlov S, Yen T, Hobson K, Gatei M, Zhang N, Watters D, Egerton M, Shiloh Y, Kharbanda S, Kufe D, Lavin MF (1997) Interaction between ATM protein and c-Abl in response to DNA damage. Nature 387:520–523PubMedCrossRef
11.
Khanna KK (2000) Cancer risk and the ATM gene: a continuing debate. J Natl Cancer Inst 92:795–802PubMedCrossRef
12.
Lakin ND, Weber P, Stankovic T, Rottinghaus ST, Taylor AM, Jackson SP (1996) Analysis of the ATM protein in wild-type and ataxia telangiectasia cells. Oncogene 13:2707–2716PubMed
13.
Rotman G, Shiloh Y (1997) Ataxia-telangiectasia: is ATM a sensor of oxidative damage and stress? Bioessays 19:911–917PubMedCrossRef
14.
Lim DS, Kirsch DG, Canman CE, Ahn JH, Ziv Y, Newman LS, Darnell RB, Shiloh Y, Kastan MB (1998) ATM binds to beta-adaptin in cytoplasmic vesicles. Proc Natl Acad Sci USA 95:10146–10151PubMedCrossRef
15.
Bakkenist CJ, Kastan MB (2003) DNA damage activates ATM through intermolecular autophosphorylation and dimer dissociation. Nature 421:499–506PubMedCrossRef
16.
Burma S, Chen BP, Murphy M, Kurimasa A, Chen DJ (2001) ATM phosphorylates histone H2AX in response to DNA double-strand breaks. J Biol Chem 276:42462–42467PubMedCrossRef
17.
Banin S, Moyal L, Shieh S, Taya Y, Anderson CW, Chessa L, Smorodinsky NI, Prives C, Reiss Y, Shiloh Y, Ziv Y (1998) Enhanced phosphorylation of p53 by ATM in response to DNA damage. Science 281:1674–1677PubMedCrossRef
18.
Khosravi R, Maya R, Gottlieb T, Oren M, Shiloh Y, Shkedy D (1999) Rapid ATM-dependent phosphorylation of MDM2 precedes p53 accumulation in response to DNA damage. Proc Natl Acad Sci USA 96:14973–14977PubMedCrossRef
19.
Chen G, Yuan SS, Liu W, Xu Y, Trujillo K, Song B, Cong F, Goff SP, Wu Y, Arlinghaus R, Baltimore D, Gasser PJ, Park MS, Sung P, Lee EY (1999) Radiation-induced assembly of Rad51 and Rad52 recombination complex requires ATM and c-Abl. J Biol Chem 274:12748–12752PubMedCrossRef
20.
Wang H, Guan J, Wang H, Perrault AR, Wang Y, Iliakis G (2001) Replication protein A2 phosphorylation after DNA damage by the coordinated action of ataxia telangiectasia-mutated and DNA-dependent protein kinase. Cancer Res 61:8554–8563PubMed
21.
Foray N, Marot D, Gabriel A, Randrianarison V, Carr AM, Perricaudet M, Ashworth A, Jeggo P (2003) A subset of ATM- and ATR-dependent phosphorylation events requires the BRCA1 protein. EMBO J 22:2860–2871PubMedCrossRef
22.
Lee JH, Paull TT (2005) ATM activation by DNA double-strand breaks through the Mre11–Rad50–Nbs1 complex. Science 308:551–554PubMedCrossRef
23.
Lee JH, Paull TT (2004) Direct activation of the ATM protein kinase by the Mre11/Rad50/Nbs1 complex. Science 304:93–96PubMedCrossRef
24.
Carney JP, Maser RS, Olivares H, Davis EM, Le Beau M, Yates JR III, Hays L, Morgan WF, Petrini JH (1998) The hMre11/hRad50 protein complex and Nijmegen breakage syndrome: linkage of double-strand break repair to the cellular DNA damage response. Cell 93:477–486PubMedCrossRef
25.
Hopfner KP, Karcher A, Craig L, Woo TT, Carney JP, Tainer JA (2001) Structural biochemistry and interaction architecture of the DNA double-strand break repair Mre11 nuclease and Rad50-ATPase. Cell 105:473–485PubMedCrossRef
26.
Taylor AM, Groom A, Byrd PJ (2004) Ataxia-telangiectasia-like disorder (ATLD)—its clinical presentation and molecular basis. DNA Repair (Amst) 3:1219–1225CrossRef
27.
Cortez D, Wang Y, Qin J, Elledge SJ (1999) Requirement of ATM-dependent phosphorylation of brca1 in the DNA damage response to double-strand breaks. Science 286:1162–1166PubMedCrossRef
28.
Li S, Ting NS, Zheng L, Chen PL, Ziv Y, Shiloh Y, Lee EY, Lee WH (2000) Functional link of BRCA1 and ataxia telangiectasia gene product in DNA damage response. Nature 406:210–215PubMedCrossRef
29.
Taniguchi T, Garcia-Higuera I, Xu B, Andreassen PR, Gregory RC, Kim ST, Lane WS, Kastan MB, D’Andrea AD (2002) Convergence of the fanconi anemia and ataxia telangiectasia signaling pathways. Cell 109:459–472PubMedCrossRef
30.
Bartek J, Lukas J (2003) Chk1 and Chk2 kinases in checkpoint control and cancer. Cancer Cell 3:421–429PubMedCrossRef
31.
Falck J, Mailand N, Syljuasen RG, Bartek J, Lukas J (2001) The ATM-Chk2-Cdc25A checkpoint pathway guards against radioresistant DNA synthesis. Nature 410:842–847PubMedCrossRef
32.
Gatei M, Sloper K, Sorensen C, Syljuasen R, Falck J, Hobson K, Savage K, Lukas J, Zhou BB, Bartek J, Khanna KK (2003) Ataxia-telangiectasia-mutated (ATM) and NBS1-dependent phosphorylation of Chk1 on Ser-317 in response to ionizing radiation. J Biol Chem 278:14806–14811PubMedCrossRef
33.
Pommier Y, Sordet O, Rao VA, Zhang H, Kohn KW (2005) Targeting chk2 kinase: molecular interaction maps and therapeutic rationale. Curr Pharm Des 11:2855–2872PubMedCrossRef
34.
Falck J, Petrini JH, Williams BR, Lukas J, Bartek J (2002) The DNA damage-dependent intra-S phase checkpoint is regulated by parallel pathways. Nat Genet 30:290–294PubMedCrossRef
35.
Formichi P, Battisti C, Tripodi SA, Tosi P, Federico A (2000) Apoptotic response and cell cycle transition in ataxia telangiectasia cells exposed to oxidative stress. Life Sci 66:1893–1903PubMedCrossRef
36.
Gladdy RA, Nutter LM, Kunath T, Danska JS, Guidos CJ (2006) p53-independent apoptosis disrupts early organogenesis in embryos lacking both ataxia-telangiectasia mutated and Prkdc. Mol Cancer Res 4:311–318PubMedCrossRef
37.
Piret B, Schoonbroodt S, Piette J (1999) The ATM protein is required for sustained activation of NF-kappaB following DNA damage. Oncogene 18:2261–2271PubMedCrossRef
38.
Karlseder J, Hoke K, Mirzoeva OK, Bakkenist C, Kastan MB, Petrini JH, de Lange T (2004) The telomeric protein TRF2 binds the ATM kinase and can inhibit the ATM-dependent DNA damage response. PLoS Biol 2:E240PubMedCrossRef
39.
Morrell D, Cromartie E, Swift M (1986) Mortality and cancer incidence in 263 patients with ataxia-telangiectasia. J Natl Cancer Inst 77:89–92PubMed
40.
Gumy-Pause F, Wacker P, Sappino AP (2004) ATM gene and lymphoid malignancies. Leukemia 18:238–242PubMedCrossRef
41.
Su Y, Swift M (2000) Mortality rates among carriers of ataxia-telangiectasia mutant alleles. Ann Intern Med 133:770–778PubMed
42.
Inskip HM, Kinlen LJ, Taylor AM, Woods CG, Arlett CF (1999) Risk of breast cancer and other cancers in heterozygotes for ataxia-telangiectasia. Br J Cancer 79:1304–1307PubMedCrossRef
43.
Lantelme E, Turinetto V, Mantovani S, Marchi A, Regazzoni S, Porcedda P, De Marchi M, Giachino C (2003) Analysis of secondary V(D)J rearrangements in mature, peripheral T cells of ataxia-telangiectasia heterozygotes. Lab Invest 83:1467–1475PubMedCrossRef
44.
Angele S, Hall J (2000) The ATM gene and breast cancer: is it really a risk factor? Mutat Res 462:167–178PubMedCrossRef
45.
Nathanson KL, Wooster R, Weber BL (2001) Breast cancer genetics: what we know and what we need. Nat Med 7:552–556PubMedCrossRef
46.
Swift M, Morrell D, Massey RB, Chase CL (1991) Incidence of cancer in 161 families affected by ataxia-telangiectasia. N Engl J Med 325:1831–1836PubMedCrossRef
47.
Broeks A, Urbanus JH, Floore AN, Dahler EC, Klijn JG, Rutgers EJ, Devilee P, Russell NS, van Leeuwen FE, van’t Veer LJ (2000) ATM-heterozygous germline mutations contribute to breast cancer-susceptibility. Am J Hum Genet 66:494–500PubMedCrossRef
48.
Thompson D, Duedal S, Kirner J, McGuffog L, Last J, Reiman A, Byrd P, Taylor M, Easton DF (2005) Cancer risks and mortality in heterozygous ATM mutation carriers. J Natl Cancer Inst 97:813–822PubMedCrossRef
49.
Thorstenson YR, Roxas A, Kroiss R, Jenkins MA, Yu KM, Bachrich T, Muhr D, Wayne TL, Chu G, Davis RW, Wagner TM, Oefner PJ (2003) Contributions of ATM mutations to familial breast and ovarian cancer. Cancer Res 63:3325–3333PubMed
50.
Renwick A, Thompson D, Seal S, Kelly P, Chagtai T, Ahmed M, North B, Jayatilake H, Barfoot R, Spanova K, McGuffog L, Evans DG, Eccles D, Easton DF, Stratton MR, Rahman N (2006) ATM mutations that cause ataxia-telangiectasia are breast cancer susceptibility alleles. Nat Genet 38(8):873–875PubMedCrossRef
51.
Teraoka SN, Malone KE, Doody DR, Suter NM, Ostrander EA, Daling JR, Concannon P (2001) Increased frequency of ATM mutations in breast carcinoma patients with early onset disease and positive family history. Cancer 92:479–487PubMedCrossRef
52.
Sommer SS, Jiang Z, Feng J, Buzin CH, Zheng J, Longmate J, Jung M, Moulds J, Dritschilo A (2003) ATM missense mutations are frequent in patients with breast cancer. Cancer Genet Cytogenet 145:115–120PubMedCrossRef
53.
FitzGerald MG, Bean JM, Hegde SR, Unsal H, MacDonald DJ, Harkin DP, Finkelstein DM, Isselbacher KJ, Haber DA (1997) Heterozygous ATM mutations do not contribute to early onset of breast cancer. Nat Genet 15:307–310PubMedCrossRef
54.
Ramsay J, Birrell G, Lavin M (1998) Testing for mutations of the ataxia telangiectasia gene in radiosensitive breast cancer patients. Radiother Oncol 47:125–128PubMedCrossRef
55.
Dork T, Bendix R, Bremer M, Rades D, Klopper K, Nicke M, Skawran B, Hector A, Yamini P, Steinmann D, Weise S, Stuhrmann M, Karstens JH (2001) Spectrum of ATM gene mutations in a hospital-based series of unselected breast cancer patients. Cancer Res 61:7608–7615PubMed
56.
Broeks A, Urbanus JH, de Knijff P, Devilee P, Nicke M, Klopper K, Dork T, Floore AN, van’t Veer LJ (2003) IVS10-6T > G, an ancient ATM germline mutation linked with breast cancer. Hum Mutat 21:521–528PubMedCrossRef
57.
Thompson D, Antoniou AC, Jenkins M, Marsh A, Chen X, Wayne T, Tesoriero A, Milne R, Spurdle A, Thorstenson Y, Southey M, Giles GG, Khanna KK, Sambrook J, Oefner P, Goldgar D, Hopper JL, Easton D, Chenevix-Trench G (2005) Two ATM variants and breast cancer risk. Hum Mutat 25:594–595PubMedCrossRef
58.
Szabo CI, Schutte M, Broeks A, Houwing-Duistermaat JJ, Thorstenson YR, Durocher F, Oldenburg RA, Wasielewski M, Odefrey F, Thompson D, Floore AN, Kraan J, Klijn JG, van den Ouweland AM, Wagner TM, Devilee P, Simard J, van’t Veer LJ, Goldgar DE, Meijers-Heijboer H (2004) Are ATM mutations 7271T→G and IVS10-6T→G really high-risk breast cancer-susceptibility alleles? Cancer Res 64:840–843PubMedCrossRef
59.
Clarke RA, Fang ZH, Marr PJ, Lee CS, Kearsley JH, Papadatos G (2002) ATM induction insufficiency in a radiosensitive breast-cancer patient. Australas Radiol 46:329–335PubMedCrossRef
60.
Weil MM, Kittrell FS, Yu Y, McCarthy M, Zabriskie RC, Ullrich RL (2001) Radiation induces genomic instability and mammary ductal dysplasia in Atm heterozygous mice. Oncogene 20:4409–4411PubMedCrossRef
61.
Hampton GM, Mannermaa A, Winqvist R, Alavaikko M, Blanco G, Taskinen PJ, Kiviniemi H, Newsham I, Cavenee WK, Evans GA (1994) Loss of heterozygosity in sporadic human breast carcinoma: a common region between 11q22 and 11q23.3. Cancer Res 54:4586–4589PubMed
62.
Rio PG, Pernin D, Bay JO, Albuisson E, Kwiatkowski F, De Latour M, Bernard-Gallon DJ, Bignon YJ (1998) Loss of heterozygosity of BRCA1, BRCA2 and ATM genes in sporadic invasive ductal breast carcinoma. Int J Oncol 13:849–853PubMed
63.
Koike M, Takeuchi S, Park S, Hatta Y, Yokota J, Tsuruoka N, Koeffler HP (1999) Ovarian cancer: loss of heterozygosity frequently occurs in the ATM gene, but structural alterations do not occur in this gene. Oncology 56:160–163PubMedCrossRef
64.
Bay JO, Uhrhammer N, Pernin D, Presneau N, Tchirkov A, Vuillaume M, Laplace V, Grancho M, Verrelle P, Hall J, Bignon YJ (1999) High incidence of cancer in a family segregating a mutation of the ATM gene: possible role of ATM heterozygosity in cancer. Hum Mutat 14:485–492PubMedCrossRef
65.
Feng J, Yan J, Chen J, Schlake G, Jiang Z, Buzin CH, Sommer SS, Dritschilo A (2003) Absence of somatic ATM missense mutations in 58 mammary carcinomas. Cancer Genet Cytogenet 145:179–182PubMedCrossRef
66.
Janatova M, Zikan M, Dundr P, Matous B, Pohlreich P (2005) Novel somatic mutations in the BRCA1 gene in sporadic breast tumors. Hum Mutat 25:319PubMedCrossRef
67.
Futreal PA, Liu Q, Shattuck-Eidens D, Cochran C, Harshman K, Tavtigian S, Bennett LM, Haugen-Strano A, Swensen J, Miki Y (1994) BRCA1 mutations in primary breast and ovarian carcinomas. Science 266:120–122PubMedCrossRef
68.
Boultwood J (2001) Ataxia telangiectasia gene mutations in leukaemia and lymphoma. J Clin Pathol 54:512–516PubMedCrossRef
69.
Jones PA, Baylin SB (2002) The fundamental role of epigenetic events in cancer. Nat Rev Genet 3:415–428PubMedCrossRef
70.
Gao G, Bracken AP, Burkard K, Pasini D, Classon M, Attwooll C, Sagara M, Imai T, Helin K, Zhao J (2003) NPAT expression is regulated by E2F and is essential for cell cycle progression. Mol Cell Biol 23:2821–2833PubMedCrossRef
71.
Kim WJ, Vo QN, Shrivastav M, Lataxes TA, Brown KD (2002) Aberrant methylation of the ATM promoter correlates with increased radiosensitivity in a human colorectal tumor cell line. Oncogene 21:3864–3871PubMedCrossRef
72.
Vo QN, Kim WJ, Cvitanovic L, Boudreau DA, Ginzinger DG, Brown KD (2004) The ATM gene is a target for epigenetic silencing in locally advanced breast cancer. Oncogene 23:9432–9437PubMedCrossRef
Metadata
Title
The role of ATM in breast cancer development
Authors
Jana Prokopcova
Zdenek Kleibl
Claire M. Banwell
Petr Pohlreich
Publication date
01-08-2007
Published in
Breast Cancer Research and Treatment / Issue 2/2007
Print ISSN: 0167-6806
Electronic ISSN: 1573-7217
DOI
https://doi.org/10.1007/s10549-006-9406-6

Other articles of this Issue 2/2007

Breast Cancer Research and Treatment 2/2007 Go to the issue

Original Paper

Inhibition of steroid sulfatase activity and cell proliferation in ZR-75-1 and BT-474 human breast cancer cells by KW-2581 in vitro and in vivo

Abstract

Revised Abstracts San Antonio Breast Cancer Symposium 2006

Original Paper

Proteomic analysis of nipple aspirate fluid throughout the menstrual cycle in healthy pre-menopausal women

Epidemiology

MDM2 SNP309 accelerates familial breast carcinogenesis independently of estrogen signaling

Clinical Trial

A cognitive behavioral therapy intervention to promote weight loss improves body composition and blood lipid profiles among overweight breast cancer survivors

Review Paper

Identifying menopause in breast cancer patients: considerations and implications
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits