Title page for ETD etd-05062012-035226

Type of Document Dissertation
Author Tenga, Milagros Jannet
URN etd-05062012-035226
Title Proteomic Map of ER+ Breast Cancer Cell Cycle
Degree PhD
Department Biology
Advisory Committee
Advisor Name Title
Lazar, Iuliana M. Committee Chair
Helm, Richard Frederick Committee Member
Sible, Jill C. Committee Member
Walker, Richard A. Committee Member
  • breast cancer
  • mass spectrometry
  • cell cycle
  • proteomics
Date of Defense 2012-05-01
Availability unrestricted
Cancer is characterized by a deregulation of the cell cycle resulting in abnormal proliferation of cells that can bypass tightly regulated molecular checkpoints. Breast cancer is the most common cancer diagnosed in women, ~70% of cases displaying an estrogen receptor positive (ER+) phenotype. The aim of the present work was to generate a comprehensive overview of the biological mechanisms, molecular pathways and specific proteins involved in cell cycle progression in ER+ breast cancer cells. We focused on the G1-to-S phase transition of the cell cycle because major differences in cell proliferation mechanisms between normal and cancerous cells are observed at this point. We developed a large-scale proteomics strategy to enable the comparison of MCF-7 ER+ (cancer) and MCF-10A (non-tumorigenic) epithelial breast cells. Samples were analyzed by liquid chromatography tandem mass spectrometry (LC-MS/MS) followed by a label-free quantitation approach, i.e., spectral counting, for differential protein expression analysis. The study was divided into three distinct parts: 1) qualitative profiling of MCF-7 cells arrested in the G1-phase and released into the S-phase of the cell cycle, 2) differential expression profiling of MCF-7 cells in G1 and S, and 3) differential expression profiling of the G1-phases of MCF-7 and MCF-10A cells. The qualitative evaluation of MCF-7 proteomic data resulted in the identification of >2700 proteins (p-score<0.001). A large number of these proteins were involved in cell cycle relevant processes, being representative of all hallmarks of cancer. Differential expression analysis of the MCF-7 G1 and S-phases resulted in the identification of >250 proteins with roles in DNA repair, transcription, translation, chromatin maintenance and signaling. The MCF-7/MCF-10 comparison revealed that major cellular processes that require DNA access, such as the ones identified in the MCF-7 analysis, are up-regulated in the nucleus of MCF-7 cells during starvation, possibly allowing these cancerous cells to bypass the restriction point. Several proliferative and anti-proliferative markers were identified in both MCF-7 and MCF-10A cells.
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