Triple negative breast cancer (TNBC) is a highly aggressive subset of invasive breast cancer, accounting for approximately 15% of all cases and defined by lack of estrogen receptor, progesterone receptor, and HER2. Improvements in the treatment of TNBC patients will likely come from identifying the oncogenes critical to the development and maintenance of TNBC. Most importantly, new therapies must treat not only the proliferative population of tumor cells, but also latent populations of disseminated tumor initiating cells, which are hypothesized to be responsible for recurrence and metastasis. Our past work has established important roles for cell cycle regulatory proteins in the initiation and proliferation of tumors in the mammary gland, with an emphasis on the low molecular weight forms of cyclin E (LMW-E). Recent work in our laboratory has demonstrated that LMW-E forms are overexpressed in 70% of TNBCs and correlates with poor prognosis in these patients. We identified novel ways in which LMW-E functions beyond tumor initiation and deregulated proliferation, demonstrating that LMW-E has a role tumor progression. Specifically, we have identified roles for LMW-E in the initiation of the epithelial-mesenchymal transition (EMT), generation of metastases in transgenic mice, and enrichment of a tumor initiating population of cells. The next challenge is to develop a mechanistic understanding of LMW-E in these processes and determine the feasibility of therapeutic attenuation of LMW-E activity in blocking tumor progression. However, we do not know if deregulation of pathways upstream of EL cyclin E is the initiating event. One of the key proteins that is upstream of cyclin E is elastase, which cleaves EL cyclin E to generate LMW-E. An unanswered question is if the deregulation of elastase in tumor cells is sufficient to generate LMW-E giving rise to the transformed phenotype. The central hypothesis of the proposed research is that proteolytic processing of EL cyclin E to LMW-E by elastase predisposes mammary epithelium to oncogenesis by altering cyclin E interacting partners and substrates and aberrantly activating signaling pathways that lead to induction of the EMT and cells with tumor initiating potentials. The following aims are designed to test each aspect of this hypothesis:
Aim 1 : Determine the requirement of LMW-E timing and expression for tumor maintenance and recurrence in an inducible transgenic mouse model and correlate with TNBC patients.
Aim 2 : Investigate the role of proteolytic processing of full length cyclin E to LMW-E by elastase in mammary tumorigenesis.
Aim 3 : Examine the mechanism of LMW-E mediated oncogenecity through identification and characterization of novel binding proteins and substrates for cytoplasmic LMW-E The successful completion of these studies will develop a mechanistic view of consequences of LMW-E expression in tumorigenesis and translate our findings to clinic. Additionally, our mouse model system will provide us with a unique system to examine the effectiveness of novel therapeutics targeted to TNBC in a preclinical in vivo setting.

Public Health Relevance

The information gained through the proposed studies could have tremendous clinical relevance for patients with triple negative breast cancer. We already know that LMW-E expression correlates with poor TNBC patient outcome;elucidating how the LMW-E expression can also alter the cytoplasmic signal transduction pathways which could then lead to EMT and tumorigenesis, will open novel avenues of cancer therapy that can take advantage of treatment strategies targeting LMW-E. As such, a targeted and personalized therapy can be justified for those patients who currently do not have such treatment strategies available to them.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA087548-13
Application #
8585030
Study Section
Molecular Oncogenesis Study Section (MONC)
Program Officer
Hildesheim, Jeffrey
Project Start
2000-07-01
Project End
2015-11-30
Budget Start
2014-01-07
Budget End
2014-11-30
Support Year
13
Fiscal Year
2014
Total Cost
$257,865
Indirect Cost
$94,659
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
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
Carey, Jason Pw; Karakas, Cansu; Bui, Tuyen et al. (2017) Synthetic lethality of PARP inhibitors in combination with MYC blockade is independent of BRCA status in triple negative breast cancer. Cancer Res :
Vijayaraghavan, Smruthi; Karakas, Cansu; Doostan, Iman et al. (2017) CDK4/6 and autophagy inhibitors synergistically induce senescence in Rb positive cytoplasmic cyclin E negative cancers. Nat Commun 8:15916
Nanos-Webb, A; Bui, T; Karakas, C et al. (2016) PKCiota promotes ovarian tumor progression through deregulation of cyclin E. Oncogene 35:2428-40
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
Caruso, J A; Akli, S; Pageon, L et al. (2015) The serine protease inhibitor elafin maintains normal growth control by opposing the mitogenic effects of neutrophil elastase. Oncogene 34:3556-67
Pickering, Curtis R; Bast Jr, Robert C; Keyomarsi, Khandan (2015) How will we recruit, train, and retain physicians and scientists to conduct translational cancer research? Cancer 121:806-16
Caruso, Joseph A; Karakas, Cansu; Zhang, Jing et al. (2014) Elafin is downregulated during breast and ovarian tumorigenesis but its residual expression predicts recurrence. Breast Cancer Res 16:3417
Caruso, Joseph A; Campana, Rody; Wei, Caimiao et al. (2014) Indole-3-carbinol and its N-alkoxy derivatives preferentially target ER?-positive breast cancer cells. Cell Cycle 13:2587-99

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