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

Proceedings of the National Academy of Sciences of the United States of America
Jay P ReddyYi Li

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...Continue Reading

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Citations

Jun 18, 2011·Journal of Mammary Gland Biology and Neoplasia·Jay P Reddy, Yi Li
Jul 22, 2010·Molecular Cancer Research : MCR·Marina ZemskovaAndrew S Kraft
Apr 1, 2014·International Journal of Molecular Sciences·Venturina StagniDaniela Barilà
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