This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. The Polo like kinase (PLK) family is comprised of 4 closely related proteins (PLK1-4) with multiple functions in cell cycle control, differentiation, and regulation of genotoxic and oxidative stress responses. Differential expression of PLK family members is observed in many breast cancer tissues and cell lines and following exposure to breast cancer treatments such as ionizing radiation. PLK1 and PLK3 in particular appear to have opposing roles in cancer;PLK1 overexpression contributes to malignant phenotypes by overriding cell cycle checkpoint controls, increasing cell proliferation, and contributing to metastasis while PLK3 has an apparent tumor suppressor function. Given that PLK1 overexpression can serve as a prognostic indicator of cancer and is involved in many cancer promoting cell functions, it has emerged as a strong target for small molecule inhibitors given alone or in conjunction with other breast cancer treatments. However, most of the identified PLK1 inhibitors effectively inhibit PLK3 as well and could have a negative impact on PLK3 positive breast tumors since PLK3 activation plays a role in p53 mediated apoptosis. Individual tumors will likely exhibit alterations in the abundance and/or function of PLK activators such as Aurora-A and interacting proteins such as p53 that mediate PLK dependent functions. Therefore, alternative strategies that target upstream kinases and/or downstream effectors of PLKs could be effective inhibitors of PLK signaling and treatments could be better tailored to reflect not only the PLK status of tumors but also the overall PLK signaling pathway. We hypothesize that there will be predominant protein complexes containing specific PTMs and binding partners present in normal vs cancer cells and before and after exposure to stimuli such as ionizing radiation and other types of cancer treatments. Identification of these context dependent biosignatures could serve as novel diagnostic markers, highlight the signaling pathways responsible for their generation, and aid in developing tailored cancer therapies.

National Institute of Health (NIH)
National Center for Research Resources (NCRR)
Biotechnology Resource Grants (P41)
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Special Emphasis Panel (ZRG1-BCMB-H (40))
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Battelle Pacific Northwest Laboratories
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