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Discerning the Role of LMO4 as a Global Modulator of G2/M Cell Cycle Progression and Centrosome Cycle in Breast Cancer Cells

Montanez-Wiscovich, Marjorie E.
http://rave.ohiolink.edu/etdc/view?acc_num=case1259899890

Abstract Details

2010, Doctor of Philosophy, Case Western Reserve University, Pharmacology.
A woman’s lifetime risk of developing breast cancer in the United States is 1 in 8 (12.3%). Of these women, 15% will die from this disease. In an effort to understand breast cancer pathology, previous studies have shown that breast cancer is not a single disease, but one composed of three major molecular subtypes: luminal-like, ErbB2-overexpressing and basal-like cancers. The molecular classification of breast cancers has provided a starting point for the development of tailored therapies that will provide better diagnostic tools and improved treatment strategies. They have additionally supplied potential targets for the study of breast oncogenesis. The LIM-only protein 4, LMO4, is one of these targets. Analysis of gene expression data revealed that LMO4 is overexpressed in a murine model of ErbB2-overexpressing cancers compared to wild-type tissue. LMO4 is also upregulated in human basal-like breast cancers compared to other subtypes, suggesting LMO4 is a common downstream effector of several oncogenic pathways. Thus, a major emphasis of this dissertation is to investigate the role of LMO4 in the different breast cancer subtypes. Loss of LMO4 in breast cancer cell lines representing the three major subtypes revealed that LMO4 is essential for progression through G2/M, indicating LMO4 acts as a global modulator of cell cycle progression. Additionally, LMO4 is necessary for sustained expression of several genes involved in cell division such as Cyclin D1, Cyclin E and Cullin-3. When LMO4 was evaluated in breast cancers, its expression was observed in all tumors examined, regardless of subtype with increased expression in ErbB2-overexpressing and basal-like cancers. The elevated levels of LMO4 in tumors known to have high mitotic indices further suggest that LMO4 correlates with the aggressiveness of tumors. Consistent with this notion, aberrant expression of LMO4 in breast cancer cells induces centrosome amplification and abnormal mitotic spindle formation, supporting a role for LMO4 in maintaining genomic stability. Together, the work presented herein provide insight into the signaling pathways that regulate expression of LMO4 in breast cancers as well as the mechanisms utilized by LMO4 to drive breast carcinogenesis.
Ruth Keri, Ph.D. (Advisor)
George Dubyak, Ph.D. (Committee Chair)
Yu-Chung Yang, Ph.D. (Committee Co-Chair)
Julian Kim, M.D. (Committee Member)
170 p.
Molecular Biology; Oncology; Pharmacology
LMO4; gene expression; ErbB2/HER2/Neu; centrosome

Recommended Citations

Citations

  • Montanez-Wiscovich, M. E. (2010). Discerning the Role of LMO4 as a Global Modulator of G2/M Cell Cycle Progression and Centrosome Cycle in Breast Cancer Cells [Doctoral dissertation, Case Western Reserve University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=case1259899890

    APA Style (7th edition)

  • Montanez-Wiscovich, Marjorie. Discerning the Role of LMO4 as a Global Modulator of G2/M Cell Cycle Progression and Centrosome Cycle in Breast Cancer Cells. 2010. Case Western Reserve University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=case1259899890.

    MLA Style (8th edition)

  • Montanez-Wiscovich, Marjorie. "Discerning the Role of LMO4 as a Global Modulator of G2/M Cell Cycle Progression and Centrosome Cycle in Breast Cancer Cells." Doctoral dissertation, Case Western Reserve University, 2010. http://rave.ohiolink.edu/etdc/view?acc_num=case1259899890

    Chicago Manual of Style (17th edition)

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This open access ETD is published by Case Western Reserve University School of Graduate Studies and OhioLINK.