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Signaling Networks as Possible Therapeutic Implications in Breast Cancer

Hicks, Mellissa
http://rave.ohiolink.edu/etdc/view?acc_num=osu1405945861

Abstract Details

2014, Doctor of Philosophy, Ohio State University, Comparative and Veterinary Medicine.
In 2014 there will be an estimated 235,030 new cases of invasive breast cancer in the United States. Even with the advances in breast cancer therapies, resistance remains a huge problem and the major limitation to overall survival. The research presented in this dissertation attempts to investigate breast cancer signaling pathways. The influence of MAPK signaling on RNA Polymerase II (Pol II) positioning and activation in association with the JUNB’s proximal promoter and JUNB expression in human breast cancer cell lines will be investigated. The results indicate that constitutive RAS/MAPK signaling enhances the association of activated Pol II with the JUNB proximal promoter and treatment with U0126 reduces Pol II association with the JUNB proximal promoter and reduces JUNB expression. As JUNB induction was found to be reliant on the MAPK control of Pol II, the influence of kinase inhibitors JUNB expression was investigated. The results demonstrate that JUNB is induced by lethal doses of kinase inhibitors in multiple breast cancer cell lines. Functional studies revealed that JUNB plays a pro-survival role in kinase inhibitor treatment. To understand how treatment combinations can affect breast cancer patients, a meta analysis was performed to investigate the role of neoadjuvant chemotherapy (NAC) in combination with dual anti-HER2 therapy compared to single anti-HER2 therapy on improving pathological complete response (pCR). Randomized clinical trials that evaluated safety and efficacy of dual anti-HER2 therapy plus NAC in patients with HER2+, operable breast cancer reveal mixed results. Dual anti-HER2 therapy with NAC improves pCR rates in patients with HER2+ breast cancer regardless of its definition and is not effected by hormone receptor status. To investigate how breast cancer cells develop resistance, trametinib resistant triple negative breast cancer (TNBC) cells were developed and characterized in chapter 5. This study is the first to investigate trametinib resistance in TNBC cell lines. PTEN status can accurately predict trametinib sensitivity as PTEN wild type cells are sensitive to trametinib and have an induction of pAKT. Trametinib resistant cells proliferate similar to the parental cell and can withstand a dramatic increase of trametinib. Using kinase antibody arrays, PRAS40, HSP60 and AKT seem to be highly activated in the resistant lines relative to the parental lines. In summary, the results uncovered in this dissertation provide clues into possible resistance mechanisms to targeted therapy in breast cancer cells for both FP (JUNB) and trametinib (PRAS40, HSP60, AKT, c-JUN), the pivotal role of MAPK signaling on Pol II activation on the JUNB proximal promoter and the clinical benefit of NAC in combination with lapatinib and trastuzumab for HER2+ breast cancers on pCR. Information gained from these studies can help design rationale drug combinations to prevent disease recurrence and cancer related deaths.
James DeWille (Advisor)
Erin Macrae (Committee Member)
Michael Ostrowski (Committee Member)
William Kisseberth (Committee Member)
Michael Oglesbee (Committee Member)
173 p.
Medicine; Molecular Biology
breast cancer; kinase inhibitors; trametinib; RNA Polymerase II; JUNB; HER2; triple negative breast cancer; pro-survival; MAPK; flavopiridol; U0126

Recommended Citations

Citations

  • Hicks, M. (2014). Signaling Networks as Possible Therapeutic Implications in Breast Cancer [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1405945861

    APA Style (7th edition)

  • Hicks, Mellissa. Signaling Networks as Possible Therapeutic Implications in Breast Cancer. 2014. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1405945861.

    MLA Style (8th edition)

  • Hicks, Mellissa. "Signaling Networks as Possible Therapeutic Implications in Breast Cancer." Doctoral dissertation, Ohio State University, 2014. http://rave.ohiolink.edu/etdc/view?acc_num=osu1405945861

    Chicago Manual of Style (17th edition)

osu1405945861
387
© 2014, some rights reserved.Creative Commons License Signaling Networks as Possible Therapeutic Implications in Breast Cancer by Mellissa Hicks is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported License. Based on a work at etd.ohiolink.edu.
This open access ETD is published by The Ohio State University and OhioLINK.