Mice heterozygous for mutation in Atm, the gene involved in ataxia-telangiectasia, have heightened susceptibility to cancer

Abstract

Ataxia-telangiectasia is characterized by radiosensitivity, genome instability and predisposition to cancer. Heterozygous carriers of ATM, the gene defective in ataxia-telangiectasia, have a higher than normal risk of developing breast and other cancers. We demonstrate here that Atm 'knock-in' (Atm-Delta SRI) heterozygous mice harboring an in-frame deletion corresponding to the human 7636del9 mutation show an increased susceptibility to developing tumors. In contrast, no tumors are observed in Atm knockout (Atm(+/-)) heterozygous mice. In parallel, we report the appearance of tumors in 6 humans from 12 families who are heterozygous for the 7636del9 mutation. Expression of ATM cDNA containing the 7636del9 mutation had a dominant-negative effect in control cells, inhibiting radiation-induced ATM kinase activity in vivo and in vitro. This reduces the survival of these cells after radiation exposure and enhances the level of radiation-induced chromosomal aberrations. These results show for the first time that mouse carriers of a mutated Atm that are capable of expressing Atm have a higher risk of cancer. This finding provides further support for cancer predisposition in human ataxia-telangiectasia carriers.

Combined antiestrogen, antiangiogenic and anti-invasion therapy inhibits primary and metastatic tumor growth in the MMTVneu model of breast cancer

“…35 Over the next few years, the contribution of other genes to breast cancer will be identified and the knock-out and knock-in technologies will probably give us new opportunities to create models for different subsets of breast cancer, as recently shown by the findings of breast tumors in Brca1 conditional knockouts 36 and in mice heterozygous for an in-frame three amino-acid deletion in the ATM gene. 37 In the present paper, we built on previous treatment protocols as well as on new experiments with singleagent treatments administered via various routes to select treatments showing the highest inhibition of tumor growth. We devised a combined therapy with three agents that affect tumor growth through different mechanisms.…”

Doxorubicin Activates ATM-dependent Phosphorylation of Multiple Downstream Targets in Part through the Generation of Reactive Oxygen Species

“…In addition, these carriers have an intermediate sensitivity to IR (54,55). Interestingly, many of the anti-tumor chemotherapeutics used in the treatment of breast cancer have the capacity to induce DSBs or generate ROS.…”

ATM and ATR: Sensing DNA damage

“…Mice homozygous for this mutation could produce small amounts of inactive ATM and usually showed the hallmarks of the Atm-knockout phenotype. Notably, mice heterozygous for this mutation were predisposed to various cancers, unlike the animals that carry a single knockout allele that does not produce any protein [81] . Therefore, ATM heterozygotes in human population might also be more radiosensitive, and have a higher risk for cancer [82] (Figure 3).…”