Department of Molecular & Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
Proc Natl Acad Sci U S A. 2010 Feb 23;107(8):3728-33. doi: 10.1073/pnas.0910665107. Epub 2010 Feb 3.
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.
p53、细胞凋亡和衰老通常在癌前病变中被激活，是阻止向恶性肿瘤进展的障碍。这些障碍被认为是 ATM 介导的 DNA 损伤反应 (DDR) 的结果，可能紧随致癌基因诱导的过度增殖和随后的 DNA 复制应激。为了阐明 DDR 在乳腺癌发生中的当前未经测试的作用，我们在几种乳腺癌的小鼠模型中检查了致癌基因表达的影响。我们在表达几种不同致癌基因的转基因小鼠中早期增生性病变中未观察到可检测的 DDR。然而，在体内通过逆转录病毒转导的单个乳腺细胞中诱导产生的癌前病变中，DDR 信号强烈诱导。因此，在正常组织发育后激活致癌基因会引起 DDR。此外，在这种体细胞 ErbB2 肿瘤模型中，ATM（因此 DDR）对于 p53 稳定、细胞凋亡和衰老都是必需的。在该模型中的可触及肿瘤中，p53 稳定和细胞凋亡丢失，但出乎意料的是，许多肿瘤细胞仍保持衰老。因此，这种小鼠模型完全再现了早期 DDR 信号；在肿瘤发生中最终抑制其终点提供了令人信服的证据，即 ErbB2 诱导的异常乳腺细胞增殖导致 ATM 介导的 DDR，激活细胞凋亡和衰老，至少前者必须克服才能进展为恶性肿瘤。这项体内研究还揭示了 ErbB2 激活的一个意外作用，先前已知其具有促进生存的作用，并表明保护 ATM 介导的 DDR-p53 信号通路可能在乳腺癌预防中很重要。
