HER2 Oncogene-Induced DNA Damage Response as a Barrier that Must Be Overcome to Form Breast Tumors In Normal Mammary Epithelium

摘要

Activated ErbB2 stimulates mammary cell proliferation in culture and in mice; yet it is not sufficient by itself to cause mammary tumors when tested in mice. Oncogene-induced over-proliferation (but not high proliferation associated with normal development) has been reported to induce a DNA damage response (DDR), leading to apoptosis and senescence, but it is not known whether this response may be what prevents breast cancer initiation in cells that have activated ErbB2 or other common breast cancer genes. We discovered that 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, 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.