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

Abstract

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

Constitutive HER2 Signaling Promotes Breast Cancer Metastasis through Cellular Senescence

“…However, in line with our conclusions with nude mice, it has been shown that senescent cells expressing an oncogenic form of HER2 are long lived in vivo, also in immunocompetent mice (28). Therefore, these reports also support that clearance of senescent cells in vivo depends on the oncogene that induced senescence, presumably because of the differences in senescence secretomes.…”

Imaging DNA Damage Allows Detection of Preneoplasia in the BALB-neuT Model of Breast Cancer

“…In contrast to this robust activation of the DDR in BALBneuT-associated preneoplastic lesions, Reddy et al found that the DDR was either weak or absent in hyperplastic lesions arising in some other transgenic mouse models of breast cancer. For example, only modest induction of gH2AX was observed in mammary lesions from MMTV-ErbB2 transgenic animals (18). One possible explanation for this difference is that NeuT is more potently oncogenic than ErbB2 (11) and so is more likely to cause DDR activation.…”

ATM kinase sustains HER2 tumorigenicity in breast cancer

“…As a consequence, HER2 promotes cell transformation 25,26 and elicits the constitutive activation of a panel of downstream signalling molecules including PI3K, SRC, AKT and MAPKs (reviewed in refs 23,24). Interestingly, it has been recently shown that ATM is phosphorylated on Ser1981 in a somatic mouse model of breast cancer dependent on the expression of HER2 (ERBB2/NeuN) receptor tyrosine kinase 27 . Although the functional significance of ATM phosphorylation (ATM-p) on Ser1981 in this context has not been fully elucidated 27 , the authors, given the identification of ATM phosphorylation on Ser1981 as a marker of ATM kinase activation in response to several stimuli 28 , propose that, in this context ATM is activated as part of the DDR to counteract tumour progression 27 as previously reported (reviewed in ref.…”