Ras mutations are extremely common in human cancers yet; paradoxically oncogenic forms of Ras are unable to transform primary cells. Instead, high levels of Ras signaling induce a permanent and presumed irreversible growth arrest with features of replicative senescence. Oncogene-induced senescence has been hypothesized to constitute a general defense mechanism by which cells at risk for tumorigenesis are induced to undergo irreversible growth arrest. Consistent with this, mutations that disable this arrest program cooperate with Ras in transformation. Given the high frequency with which the Ras, p53, and RB pathways are altered in human cancers, it is likely that the senescence program triggered by oncogene activation is an important tumor suppressor mechanism. Most information regarding the mechanism of oncogene-induced senescence is based on in vitro studies in fibroblasts. In contrast, much less is known about the response of epithelial cells to Ras activation - a critical issue given that most adult human cancers are epithelial. Similarly, even less is known about oncogene-induced senescence in vivo. As such, there are clearly major gaps in our understanding of senescence programs as they occur in intact tissues. Unfortunately, constitutive transgenic models are not well suited for studying oncogene-induced senescence due to the inability to examine early events following oncogene activation or to modulate levels of Ras activity. Indeed, given the lack of animal models in which senescence can be induced in vivo and shown to protect against tumorigenesis, whether senescence is in fact sufficient to prevent cancer in vivo is unknown. This proposal is aimed at understanding the earliest cellular and molecular events that occur in intact tissues in response to defined levels of Ras activation, as well as at understanding the impact that these events have on cancer susceptibility. Specifically, we hypothesize that high levels of Ras activation induce mammary epithelial cells to undergo an irreversible proliferation arrest in vivo, and that the resulting state of cellular senescence is sufficient to suppress tumorigenesis. To test this hypothesis, we have developed a novel doxycycline-dependent transgenic mouse model that permits the inducible, homogeneous expression of oncogenic Ras in the mammary epithelium. The experiments proposed in this application will use this transgenic system to test the hypothesis that high levels of Ras activation induce cellular senescence in the mammary gland in vivo, and that oncogene-induced senescence protects against tumorigenesis. This system will also be used to assess the reversibility of Ras-induced senescence in the mammary glands of transgenic animals following transgene de-induction. Finally, additional in vivo studies will examine the dependence of Ras-induced effects on genetic pathways implicated in oncogene-induced senescence, including the ability of Ras to suppress tumorigenesis induced by other oncogenic pathways as well as the ability of these other oncogenic pathways to suppress Ras-induced senescence. We believe that the animal model system we have developed provides a valuable new opportunity for studying the molecular events that contribute to oncogene-induced senescence in the intact mammary gland, and anticipate that defining the response of the normal mammary gland to oncogenic Ras signaling will contribute to our understanding of the molecular pathways that promote - and prevent - mammary carcinogenesis.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA098371-04
Application #
7023080
Study Section
Special Emphasis Panel (ZRG1-CAMP (01))
Program Officer
Blair, Donald G
Project Start
2003-04-18
Project End
2008-02-28
Budget Start
2006-03-01
Budget End
2007-02-28
Support Year
4
Fiscal Year
2006
Total Cost
$344,375
Indirect Cost
Name
University of Pennsylvania
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Feng, Yi; Pan, Tien-Chi; Pant, Dhruv K et al. (2014) SPSB1 promotes breast cancer recurrence by potentiating c-MET signaling. Cancer Discov 4:790-803
Alvarez, James V; Belka, George K; Pan, Tien-Chi et al. (2014) Oncogene pathway activation in mammary tumors dictates FDG-PET uptake. Cancer Res 74:7583-98
Payne, Ania W; Pant, Dhruv K; Pan, Tien-Chi et al. (2014) Ceramide kinase promotes tumor cell survival and mammary tumor recurrence. Cancer Res 74:6352-63
Bean, Gregory R; Ganesan, Yogesh Tengarai; Dong, Yiyu et al. (2013) PUMA and BIM are required for oncogene inactivation-induced apoptosis. Sci Signal 6:ra20
Magnitsky, S; Belka, G K; Sterner, C et al. (2013) Lactate detection in inducible and orthotopic Her2/neu mammary gland tumours in mouse models. NMR Biomed 26:35-42
Alvarez, James V; Pan, Tien-Chi; Ruth, Jason et al. (2013) Par-4 downregulation promotes breast cancer recurrence by preventing multinucleation following targeted therapy. Cancer Cell 24:30-44
Chen, Chien-Chung; Stairs, Douglas B; Boxer, Robert B et al. (2012) Autocrine prolactin induced by the Pten-Akt pathway is required for lactation initiation and provides a direct link between the Akt and Stat5 pathways. Genes Dev 26:2154-68
Yeh, Elizabeth S; Yang, Thomas W; Jung, Jason J et al. (2011) Hunk is required for HER2/neu-induced mammary tumorigenesis. J Clin Invest 121:866-79
Zeng, X; Shaikh, F Y; Harrison, M K et al. (2010) The Ras oncogene signals centrosome amplification in mammary epithelial cells through cyclin D1/Cdk4 and Nek2. Oncogene 29:5103-12
Liu, Zhandong; Wang, Min; Alvarez, James V et al. (2008) Singular value decomposition-based regression identifies activation of endogenous signaling pathways in vivo. Genome Biol 9:R180

Showing the most recent 10 out of 17 publications