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Role of Cyclin E in the Presence or Absence of CDK2 in Breast Tumorigenesis
Cyclin E overexpression occurs in 25% of breast cancer tumors and is linked to poor prognosis. Recently, we have found that overexpression of the low molecular weight (LMW) forms of cyclin E, but not the full-length form results in their hyperactivity due to resistance to inhibition by the CDK inhibitors p21 and p27. LMW forms of cyclin E are resistant to anti-estrogens treatment, and they induce chromosomal instability. In addition, recent experimental evidence point to a CDK2-independent role of cyclin E. We will test the hypothesis that CDK2 removal in the breast tissue of cyclin E overexpressing transgenic mice can prevent tumor formation or alternatively if cyclin E can bypass CDK2 requirement for breast tumor formation. We will also test the hypothesis that cyclin-dependent kinase (CDK) inhibition by flavopiridol or downregulation of cyclin E by siRNA will lead to tumor regression and increase survival in our transgenic model. In this proposal, we aim (1) To investigate if CDK2 deletion can protect mice against breast tumor formation induced by mammary gland-specific full length and LMW cyclin E overexpression, (2) To investigate if targeting CDKs using flavopiridol can suppress mammary tumorigenesis in MMTV-cyclin E transgenic mice, and (3) To investigate if inhibition of cyclin E by siRNA lead to tumor regression and increased survival. We have developed a mouse model of cyclin E associated breast cancer in which 15% of the mice developed breast tumors with a mean latency of 16 months. When crossed with p53 heterozygote mice, the incidence increases to 100% with a latency of 11 months. We will cross the cyclin E/p53 +/- mice with CDK2 knockout mice to generate cyclin E; p53+/- ;CDK2-/- mice which will be followed for tumor formation. In parallel, we will determine if inhibition of CDK activity by the CDK inhibitor, flavopiridol or inhibition of cyclin E overexpression by lentiviral delivery of siRNAs targeting the human cyclin E can lead to inhibition of tumor proliferation and/or metastasis. The proposed experimental strategy will determine if (a) CDK2 is necessary for cyclin E mediated tumorigenesis, (b) CDK2 can be targeted for therapy of cyclin E overexpressing tumors, or (c) cyclin E mediated tumorigenesis is independent of CDK2 during the tumor formation. Collectively these studies will allow us to develop a treatment strategy to offer to women whose breast cancers have a poor prognosis due to overexpression of cyclin E.
Cyclin E is the regulatory subunit of the cyclin dependent kinase CDK2. Cyclin E associates with CDK2 in late G1 and activates its kinase activity believed to be necessary for the initiation of DNA replication. Cyclin E overexpression occurs in 25% of breast cancer tumors and is linked to poor prognosis. We have recently shown that tumor-specific processing of full length cyclin E generate hyperactive low-molecular-form (LMW) of cyclin E. These forms are resistant to CDK inhibitors and induce genomic instability providing a molecular mechanism for the poor clinical outcome observed in breast cancer patients with tumors expressing high levels of the LMW forms of cyclin E. However, some new experimental evidence point to a CDK2-independent role of cyclin E. This project will determine the role of this CDK2-independent activity of full length and LMW forms cyclin E in breast tumorigenesis using a transgenic model system. We will test whether cyclin E or cyclin dependent kinase inhibition can block the growth of breast tumors in mice overexpressing cyclin E and deleted of one allele of p53. Since 56% of human breast tumors with high cyclin E protein levels also have p53 mutations and are among the most aggressive breast tumors, this transgenic model is highly relevant to the human disease. We have developed a mouse model of cyclin E-associated breast cancer in which 15% of the mice developed breast tumors with a mean latency of 16 months. When crossed with p53 heterozygote mice, the incidence increases to 100% with a latency of 11 months. These mice will be crossed with CDK2 knockout mice to generate CDK2-/-; cyclin E; p53+/- mice and these mice will be followed for tumor formation. The goal of this project is to explore the feasibility of CDK2 inhibition as an effective therapeutic strategy to inhibit breast tumor formation in the context of cyclin E overexpression and p53 mutation. The first specific aim will examine if CDK2 deletion can protect mice against breast tumor formation induced by p53 mutation and cyclin E overexpression. The second aim is to test if CDK inhibition by flavopiridol suppress mammary tumorigenesis. The third aim will test if sequence specific inhibition of cyclin E will lead to tumor regression and increase survival of the transgenic mice. Collectively these studies will allow us to develop a treatment strategy to offer to women whose breast cancers have a poor prognosis due to overexpression of cyclin E.