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Dose-dependent oncogene-induced senescence in vivo and its evasion during mammary tumorigenesis

Nature Cell Biology volume 9, pages 493–505 (2007)Cite this article

Abstract

Activating Ras mutations can induce either proliferation or senescence depending on the cellular context. To determine whether Ras activation has context-dependent effects in the mammary gland, we generated doxycycline-inducible transgenic mice that permit Ras activation to be titrated. Low levels of Ras activation — similar to those found in non-transformed mouse tissues expressing endogenous oncogenic Kras2 — stimulate cellular proliferation and mammary epithelial hyperplasias. In contrast, high levels of Ras activation — similar to those found in tumours bearing endogenous Kras2 mutations — induce cellular senescence that is Ink4a–Arf- dependent and irreversible following Ras downregulation. Chronic low-level Ras induction results in tumour formation, but only after the spontaneous upregulation of activated Ras and evasion of senescence checkpoints. Thus, high-level, but not low-level, Ras activation activates tumour suppressor pathways and triggers an irreversible senescent growth arrest in vivo. We suggest a three-stage model for Ras-induced tumorigenesis consisting of an initial activating Ras mutation, overexpression of the activated Ras allele and, finally, evasion of p53–Ink4a–Arf-dependent senescence checkpoints.

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Figure 1: Induction and titration of activated Ras in MTB–TRAS mice.
Figure 2: Increasing ductal hyperplasia in response to increasing levels of Ras activation.
Figure 3: High-level, but not low-level, Ras activation results in inhibition of ductal elongation.
Figure 4: High-intensity Ras signalling induces a transient increase in proliferation with subsequent induction of cellular senescence.
Figure 5: The p53 and Ink4a–Arf pathways are required for the dose-specific senescence response to Ras.
Figure 6: Spontaneous upregulation of Ras, inactivation of p53 and escape from senescence accompany Ras-induced tumorigenesis.
Figure 7: Ras-induced inhibition of ductal elongation is reversible and accompanies alterations in oestrogen signaling.
Figure 8: Ras downregulation results in increased apoptosis and resumption of mammary epithelial proliferation, but not reversal of senescence.

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Acknowledgements

We thank K. Hahn and M. Coulton for assistance with animal studies, J. Zhou for her assistance with confocal microscopy, and the staff of the University of Pennsylvania John Morgan Animal services unit for housing and care of mice. We also thank D. Tuveson for the use of p48-Cre/LSL-Kras mice and C. Combs for the harvest of pancreata. This work was supported in part by grants CA92910, CA93719, CA98371, and CA105490 from the National Cancer Institute (NCI) as well as U.S. Army Breast Cancer Research Program grants W81XWH-05-1-0405 and DAMD17-00-1-0403 (C.J.S.), and a grant from the Susan G. Komen foundation.

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  1. Departments of Cancer Biology, Cell and Developmental Biology, and Medicine, and The Abramson Family Cancer Research Institute, University of Pennsylvania School of Medicine, Philadelphia, 19104-6160, PA, USA

    Christopher J. Sarkisian, Blaine A. Keister, Douglas B. Stairs, Robert B. Boxer, Susan E. Moody & Lewis A. Chodosh

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  1. Christopher J. Sarkisian
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Correspondence to Lewis A. Chodosh.

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Sarkisian, C., Keister, B., Stairs, D. et al. Dose-dependent oncogene-induced senescence in vivo and its evasion during mammary tumorigenesis. Nat Cell Biol 9, 493–505 (2007). https://doi.org/10.1038/ncb1567

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