Atm heterozygous deficiency enhances development of mammary carcinomas in p53heterozygous knockout mice

Umesako, Seiichi; Fujisawa, Kae; Iiga, Sayoko; Mori, Nobuko; Takahashi, Masahiro; Hong, Doo-Pyo; Song, Chuyi; Haga, Satomi; Imai, Syunsuke; Niwa, Osami; Okumoto, Masaaki

doi:10.1186/bcr968

Cited by 28 publications

(21 citation statements)

References 26 publications

(29 reference statements)

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“…We focused our chemoprevention studies on the antimalarial drug chloroquine, which can activate the tumor-suppressors ATM and p53, and which is well-tolerated in humans. The activation of the tumor-suppressors ATM and p53 by chloroquine is highly interesting because ATM and p53 deficiencies increase susceptibility to cancer (44)(45)(46)(47)(48). Our studies provide further proof-of-principle for developing prevention therapies based on the modulation of ATM-p53 pathways, whether based on chloroquine itself or targeting of other steps in the pathway.…”

Section: Discussionmentioning

confidence: 92%

Ataxia Telangiectasia-Mutated and p53 Are Potential Mediators of Chloroquine-Induced Resistance to Mammary Carcinogenesis

Loehberg

Thompson²,

Kastan³

et al. 2007

Cancer Research

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The use of agents to prevent the onset of and/or the progression to breast cancer has the potential to lower breast cancer risk. We have previously shown that the tumor-suppressor gene p53 is a potential mediator of hormone (estrogen/progesterone)-induced protection against chemical carcinogen-induced mammary carcinogenesis in animal models. Here, we show for the first time a breast cancer-protective effect of chloroquine in an animal model. Chloroquine significantly reduced the incidence of N-methyl-N-nitrosourea-induced mammary tumors in our animal model similar to estrogen/progesterone treatment. No protection was seen in our BALB/c p53-null mammary epithelium model, indicating a p53 dependency for the chloroquine effect. Using a human nontumorigenic mammary gland epithelial cell line, MCF10A, we confirm that in the absence of detectable DNA damage, chloroquine activates the tumor-suppressor p53 and the p53 downstream target gene p21, resulting in G 1 cell cycle arrest. p53 activation occurs at a posttranslational level via chloroquine-dependent phosphorylation of the checkpoint protein kinase, ataxia telangiectasia-mutated (ATM), leading to ATM-dependent phosphorylation of p53. In primary mammary gland epithelial cells isolated from p53-null mice, chloroquine does not induce G 1 cell cycle arrest compared with cells isolated from wildtype mice, also indicating a p53 dependency. Our results indicate that a short prior exposure to chloroquine may have a preventative application for mammary carcinogenesis.

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Section: Discussionmentioning

confidence: 92%

Ataxia Telangiectasia-Mutated and p53 Are Potential Mediators of Chloroquine-Induced Resistance to Mammary Carcinogenesis

Loehberg

Thompson²,

Kastan³

et al. 2007

Cancer Research

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“…The sequence of the Atm gene was analyzed by previously described genomic PCR method (12). Atm þ/þ : ATM-WT and Atm-deficient MEFs (Atm À/À : ATM-KO) were established from 12-to 14-day-old embryos produced by crossing Balb/cHeA/Atm þ/À mice.…”

Section: Establishment and Culture Of Mefsmentioning

confidence: 99%

Activation of Interferon-Stimulated Genes by γ-Ray Irradiation Independently of the Ataxia Telangiectasia Mutated–p53 Pathway

Sugihara

Murano

Nakamura

et al. 2011

Molecular Cancer Research

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The ataxia telangiectasia mutated (ATM)-p53 pathway is a well-known main signal transduction pathway for cellular responses, which is activated by g-ray irradiation. Microarray analysis showed changes in the expressions of IFN-stimulated genes (ISG) in g-ray-irradiated Balb/cA/Atm-deficient mouse embryonic fibroblasts (MEF) (ATM-KO), indicating that another pathway for cellular responses besides the ATM-p53 pathway was activated by g-ray irradiation. The basal expression levels of Irf7 and Stat1 in ATM-KO and p53-deficient MEFs (p53-KO) were higher than those in Atm-wild-type MEFs (ATM-WT) and p53-wild-type MEFs (p53-WT), respectively. Irradiation stimulated the expressions of Irf7 and Stat1 in ATM-KO, p53-KO, ATM-WT, and p53-WT, indicating that upregulation of Irf7 and Stat1 expressions by irradiation did not depend on the ATM-p53 pathway. When conditioned medium (CM) obtained from irradiated ATM-WT or ATM-KO was added to nonirradiated MEFs, the expressions of Irf7 and Stat1 increased. We predicted that gene activation in nonirradiated MEFs was caused by IFN-a/b. Unexpectedly, significant amount of IFN-a/b could not be detected in the CM from irradiated ATM-WT or ATM-KO. Meanwhile, increased expression of Ccl5 (RANTES) protein was detected in the CM from irradiated MEFs. These results indicate that ISGs were activated by g-ray irradiation independently of the ATM-p53 pathway and gene activation was caused by radiation-induced soluble factors. Mol Cancer Res; 9(4); 476-84. Ó2011 AACR.

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“…However, it is not known whether DDR signaling is activated in the mammary gland at any point after oncogene activation and is responsible for the induction of apoptosis or senescence in premalignant lesions. The only potential supporting evidence thus far has been the increased levels of γH2AX and phospho-Chk2 following ectopic expression of Wnt-1 in cultured mammary epithelial cells (19) and promotion of p53 heterozygous or DMBA-initiated mammary tumorigenesis by ATM heterozygosity (20,21).…”

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confidence: 99%

Defining the ATM-mediated barrier to tumorigenesis in somatic mammary cells following ErbB2 activation

Reddy

Peddibhotla

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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p53, apoptosis, and senescence are frequently activated in preneoplastic lesions and are barriers to progression to malignancy. These barriers have been suggested to result from an ATM-mediated DNA damage response (DDR), which may follow oncogene-induced hyperproliferation and ensuing DNA replication stress. To elucidate the currently untested role of DDR in breast cancer initiation, we examined the effect of oncogene expression in several murine models of breast cancer. We did not observe a detectable DDR in early hyperplastic lesions arising in transgenic mice expressing several different oncogenes. However, DDR signaling was strongly induced in preneoplastic lesions arising from individual mammary cells transduced in vivo by retroviruses expressing either PyMT or ErbB2. Thus, activation of an oncogene after normal tissue development causes a DDR. Furthermore, in this somatic ErbB2 tumor model, ATM, and thus DDR, is required for p53 stabilization, apoptosis, and senescence. In palpable tumors in this model, p53 stabilization and apoptosis are lost, but unexpectedly senescence remains in many tumor cells. Thus, this murine model fully recapitulates early DDR signaling; the eventual suppression of its endpoints in tumorigenesis provides compelling evidence that ErbB2-induced aberrant mammary cell proliferation leads to an ATM-mediated DDR that activates apoptosis and senescence, and at least the former must be overcome to progress to malignancy. This in vivo study also uncovers an unexpected effect of ErbB2 activation previously known for its prosurvival roles, and suggests that protection of the ATM-mediated DDR-p53 signaling pathway may be important in breast cancer prevention.oncogene | DNA damage response | p53 | apoptosis | senescence

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Atm heterozygous deficiency enhances development of mammary carcinomas in p53heterozygous knockout mice

Cited by 28 publications

References 26 publications

Ataxia Telangiectasia-Mutated and p53 Are Potential Mediators of Chloroquine-Induced Resistance to Mammary Carcinogenesis

Ataxia Telangiectasia-Mutated and p53 Are Potential Mediators of Chloroquine-Induced Resistance to Mammary Carcinogenesis

Activation of Interferon-Stimulated Genes by γ-Ray Irradiation Independently of the Ataxia Telangiectasia Mutated–p53 Pathway

Defining the ATM-mediated barrier to tumorigenesis in somatic mammary cells following ErbB2 activation

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