In many breast cancers, full length cyclin E is post-translationally modified through elastase mediated proteolytic cleavage of 2 specific sites in the amino terminus, resulting in the generation of low molecular weight (LMW) isoforms that have increased activity in cell cycle and resistance to cyclin-dependent kinase inhibitors. The LMW forms of cyclin E are important because of their significant role as prognostic markers in breast cancer patients and their involvement in cell cycle pathways. Our previous studies have shown that the expression of the LMW forms of cyclin E is observed in 25-35% of patients affected with breast cancer and such expression correlates very strongly with poor clinical outcome. Additionally, we have reported that the LMW forms of cyclin E are functionally hyperactive and resistant to inhibition by p21 and p27. Recently we developed transgenic mice overexpressing the LMW forms of cyclin E in the mammary gland. These mice develop tumors with metastatic potential. The central hypothesis of the proposed research, is that the overexpression of the LMW forms of cyclin E, and not the full-length cyclin E, are directly related to breast cancer progression and metastasis, predisposing the mammary epithelium to oncogenesis. The investigations outlined in this proposal will provide details regarding the mechanism through which the LMW forms of cyclin E mediate their effects in mammary gland tumorigenesis. Specifically, we will: 1) Determine the oncogenic potential of full length cyclin E and the role of elastase cleavage in mediating LMW cyclin E-induced mammary tumors. 2) Identify the biochemical differences between the full length and LMW forms of cyclin E. 3) Investigate the role of CDK2 in breast tumor formation mediated by LMW cyclin E overexpression in the mammary gland, and lastly 4) Determine the requirement of cyclin E for tumor maintenance and recurrence. The proposed research is innovative because it investigates not only whether the LMW forms of cyclin E predispose mammary epithelium to oncogenesis, but also the mechanism by which cyclin E-associated downstream alterations lead to tumor formation in vivo. Collectively, the information gained through the proposed studies could have tremendous clinical relevance for women with early stage and advanced breast cancer. We already know that cyclin E overexpression correlates with poor patient outcome;if cyclin E overexpression also predisposes the mammary gland to genetic instability leading to tumorigenesis it would suggest a causative function for the expression of the LMW forms of cyclin E in breast cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
3R01CA087548-09S1
Application #
8061130
Study Section
Cancer Molecular Pathobiology Study Section (CAMP)
Program Officer
Spalholz, Barbara A
Project Start
2001-08-01
Project End
2010-12-16
Budget Start
2009-05-01
Budget End
2010-12-16
Support Year
9
Fiscal Year
2010
Total Cost
$36,150
Indirect Cost
Name
University of Texas MD Anderson Cancer Center
Department
Radiation-Diagnostic/Oncology
Type
Other Domestic Higher Education
DUNS #
800772139
City
Houston
State
TX
Country
United States
Zip Code
77030
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Carey, Jason P W; Karakas, Cansu; Bui, Tuyen et al. (2018) Synthetic Lethality of PARP Inhibitors in Combination with MYC Blockade Is Independent of BRCA Status in Triple-Negative Breast Cancer. Cancer Res 78:742-757
Chen, Xian; Low, Kwang-Huei; Alexander, Angela et al. (2018) Cyclin E Overexpression Sensitizes Triple-Negative Breast Cancer to Wee1 Kinase Inhibition. Clin Cancer Res 24:6594-6610
Doostan, Iman; Karakas, Cansu; Kohansal, Mehrnoosh et al. (2017) Cytoplasmic Cyclin E Mediates Resistance to Aromatase Inhibitors in Breast Cancer. Clin Cancer Res 23:7288-7300
Balaji, Kavitha; Vijayaraghavan, Smruthi; Diao, Lixia et al. (2017) AXL Inhibition Suppresses the DNA Damage Response and Sensitizes Cells to PARP Inhibition in Multiple Cancers. Mol Cancer Res 15:45-58
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Francis, Ashleigh M; Alexander, Angela; Liu, Yanna et al. (2017) CDK4/6 Inhibitors Sensitize Rb-positive Sarcoma Cells to Wee1 Kinase Inhibition through Reversible Cell-Cycle Arrest. Mol Cancer Ther 16:1751-1764
Hunt, Kelly K; Karakas, Cansu; Ha, Min Jin et al. (2017) Cytoplasmic Cyclin E Predicts Recurrence in Patients with Breast Cancer. Clin Cancer Res 23:2991-3002
Lucenay, Kimberly S; Doostan, Iman; Karakas, Cansu et al. (2016) Cyclin E Associates with the Lipogenic Enzyme ATP-Citrate Lyase to Enable Malignant Growth of Breast Cancer Cells. Cancer Res 76:2406-18
Nanos-Webb, A; Bui, T; Karakas, C et al. (2016) PKCiota promotes ovarian tumor progression through deregulation of cyclin E. Oncogene 35:2428-40

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