Previous work has shown that cyclin D1 expression is required for neu-and ras-induced, but not wnt-or c-myc-induced, breast tumorigenesis in mice. Although cyclin D1 binds and activates cyclin-dependent kinase 4 (Cdk4), thereby mediating activation of a program of E2F-dependent gene expression, it has been suggested that the oncogenic activities of cyclin D1 are independent of Cdk4. To determine whether Cdk4 expression is required for breast tumorigenesis in mice, we have generated compound mice ectopically expressing the neu or wnt oncogenes in the mammary glands of wild-type and Cdk4À/À mice. Our results show that Cdk4 expression is required for efficient neu-induced tumorigenesis but is dispensable for wnt-induced breast tumorigenesis. In contrast to results previously observed in the mammary glands of cyclin D1À/À virgin females, our results show defects in mammary gland development in Cdk4À/À virgin females, suggesting differences in compensatory mechanisms in the absence of either subunit of the cyclin D1/Cdk4 complex. These results suggest that drugs targeted to inhibit Cdk4 activities could be developed to specifically treat certain breast tumors as Cdk4 is not essential for viability. (Cancer Res 2005; 65(22): 10174-8)
Activating mutations in CDK4 and inactivation of its key kinase inhibitor, p16INK4A, have been implicated in the genesis and progression of human cancer. Previous work has demonstrated that CDK4 expression is required for Neu-induced, but not Wnt-induced breast tumorigenesis in mice. However, the role that CDK4 plays in ras-mediated breast tumor development is not well defined. To gain an understanding of the role of Cdk4 in ras-induced breast tumorigenesis, MMTV-v-Ha-ras transgenic mice were bread with Cdk4(+/neo) and Cdk4(R24C/R24C) mice to generate Cdk4(neo/neo):MMTV-v-Ha-ras, Cdk4(+/+):MMTV-v-Ha-ras and Cdk4(R24C/R24C):MMTV-v-Ha-ras mice. Our studies presented here demonstrate that Cdk4 expression is essential for Ras-mediated breast tumorigenesis. Surprisingly, our results also show that co-expression of mutant ras and Cdk4R24C genes in breast epithelial cells leads to an unexpected activation of senescent pathways that delay tumorigenesis. Analysis of the phosphorylated form of H2AX, a marker for DNA damage, indicated its increased presence in the tumors of Cdk4(R24C/R24C):MMTV-v-Ha-ras mice. These observations indicate that the increased apoptosis and senescence seen in breast tumors of these mice might be due to increased DNA damage response in cells expressing activated forms of ras and Cdk4(R24C).
Public reporting burden for this collection of information is estimated to average 1 hour per response, including the time for reviewing instructions, searching existing data sources, gathering and maintaining the data needed, and completing and reviewing this collection of information. Send comments regarding this burden estimate or any other aspect of this collection of information, including suggestions for reducing this burden to Department of Defense, Washington Headquarters Services, Directorate for Information Operations and Reports (0704-0188), 1215 Jefferson Davis Highway, Suite 1204, Arlington, VA 22202-4302. Respondents should be aware that notwithstanding any other provision of law, no person shall be subject to any penalty for failing to comply with a collection of information if it does not display a currently valid OMB control number. PLEASE DO NOT RETURN YOUR FORM TO THE ABOVE ADDRESS. (From -To) REPORT DATE (DD-MM-YYYY) April 2006 REPORT TYPE Annual Summary DATES COVERED SPONSOR/MONITOR'S REPORT NUMBER(S) DISTRIBUTION / AVAILABILITY STATEMENTApproved for Public Release; Distribution Unlimited SUPPLEMENTARY NOTES ABSTRACTCdk4 is an important regulator of G1/S cell cycle progression in mammalian cells. In about 15.8% (15 out of 95) of breast cancers, cdk4 gene was shown to be amplified and this amplification of cdk4 gene was correlated with high Cdk4 protein expression. Our studies with the breast tissues of cdk4 (neo/neo) mice revealed the presence of small fat pads and poor ductal branching when compared to that of wild type mice. In order to determine the importance of cdk4 in Wnt-and Neu-induced breast tumorigenesis, we generated cdk4 (neo/neo): MMTV-transgenic lines that express Wnt and Neu in breast specific manner. Our results from these studies indicated that there is impaired lobuloalveolar compartment development and poor ductal branching in case of cdk4 (neo/neo): MMTV-neu mice when compared to cdk4 (+/+): MMTV-neu mice. In contrast, the mammary gland development in case of both Wnt transgenic mice, cdk4 (+/+): MMTV-Wnt and cdk4 (neo/neo): MMTVWnt, is comparable. Further studies revealed that there is resistance to neu-induced breast tumorogenesis in case of cdk4 (neo/neo): MMTVneu mice when compared to cdk4 (+/+): MMTV-neu mice. In contrast, in case of Wnt transgenic mice, the tumorogenesis studies revealed that both cdk4 (+/+): MMTV-Wnt and cdk4 (neo/neo): MMTV-Wnt mice are equally susceptible to breast cancer induced by Wnt. This indicates that cdk4 is essential for neu-induced tumorigenesis and not for Wnt-induced tumorigenesis.
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