Veterinary and Biomedical Sciences, Department of


Defining the ATM-Mediated Barrier to Tumorigenesis in Somatic Mammary Cells Following ErbB2 Activation

Jay Reddy, University of Nebraska - Lincoln
Sirisha Peddibhotla, Baylor College of Medicine
Wen Bu, Baylor College of Medicine
Jing Zhao, Baylor College of Medicine
Svasti Haricharan, Baylor College of Medicine
Yi-Chieh Nancy Du, Memorial Sloan-Kettering Cancer Center
Katrina Podsypanina, Memorial Sloan-Kettering Cancer Center
Jeffrey M. Rosen, Baylor College of Medicine
Larry A. Donehower, Baylor College of Medicine
Yi Li, Baylor College of Medicine
Michael B. Kastan, St. Jude Children’s Research Hospital

Copyright 2010, PNAS. Used by permission. Edited by Michael B. Kastan.


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),whichmay followoncogene-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 tumormodel, 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 compellingevidencethat ErbB2-inducedaberrantmammary cell proliferation leads to anATM-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.