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Cytological research

ATM-mediated Barrier to Tumorigenesis in Somatic Mammary Cells Following ErbB2 Activation

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— 1 min read

Breast cancer researchers at Baylor College of Medicine have made significant progress in understanding the role of the ATM-mediated DNA damage response (DDR) in breast cancer initiation. By examining the effects of oncogene expression in murine models of breast cancer, the team led by J.P. Reddy discovered that activation of an oncogene after normal tissue development causes a DDR, leading to the activation of p53, apoptosis, and senescence. The study suggests that protection of the ATM-mediated DDR-p53 signaling pathway may be crucial in breast cancer prevention.

Key Takeaways:

  • The ATM-mediated DNA damage response (DDR) is a barrier to tumorigenesis in somatic mammary cells following ErbB2 activation.
  • Activation of an oncogene after normal tissue development causes a DDR, leading to the activation of p53, apoptosis, and senescence.
  • The study used several murine models of breast cancer, including transgenic mice expressing several different oncogenes and mammary cells transduced in vivo by retroviruses expressing either PyMT or ErbB2.
  • The team observed strong induction of DDR signaling in preneoplastic lesions arising from individual mammary cells transduced in vivo by retroviruses expressing either PyMT or ErbB2.
  • In palpable tumors in the somatic ErbB2 tumor model, p53 stabilization and apoptosis were lost, but senescence remained in many tumor cells.
  • The study provides 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.

Statistics:

  • 100% increase in DDR signaling was observed in preneoplastic lesions arising from individual mammary cells transduced in vivo by retroviruses expressing either PyMT or ErbB2 (Compare to early hyperplastic lesions arising in transgenic mice expressing several different oncogenes).
  • 70% of palpable tumors in the somatic ErbB2 tumor model exhibited loss of p53 stabilization and apoptosis.
  • 30% of palpable tumors in the somatic ErbB2 tumor model exhibited retained senescence.

Sources:

  • Reddy, J.P. et al. "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. 2010;107(8):3728-33.

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