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Dissertation
Mechanisms regulating breast cancer invasion in response to ionizing radiation
Doctor of Philosophy (Ph.D.), Drexel University
Aug 2012
DOI:
https://doi.org/10.17918/00010080
Abstract
Breast cancer is the second most common malignancy among women in the U.S. Approximately 20-25% of U.S. diagnoses are of the premalignant condition, ductal carcinoma in situ (DCIS). Though DCIS is considered a direct stepping stone between normal and malignant tissue, the course of untreated disease is poorly understood. ErbB2 is frequently expressed in DCIS; however, little is known about how it contributes to carcinogenesis. Here we show that clinically relevant doses of ionizing radiation (IR) activate ErbB2 and induce invasion of ErbB2-expressing breast cancer cells as well as MCF10A cells overexpressing ErbB2. ErbB2-negative breast cancer cells do not invade following treatment with IR, nor do MCF10A cells overexpressing EGFR. ErbB2 becomes phosphorylated at Y877 in a dose- and time- dependent manner following exposure to X-rays, and activates downstream signaling cascades including PI3K/Akt. Inhibition of these pathways, as well as inhibition of reactive oxygen species (ROS) with antioxidants, prevents IR-induced invasion. Activation of ErbB2 and Akt results in upregulation of the forkhead family transcription factor, FoxM1, and its transcriptional targets, including MMP2. Inhibition of FoxM1 by RNAi prevented induction of invasion by IR, and overexpression of FoxM1 in MCF10A cells was sufficient to promote IR-induced invasion. Moreover, we found that 14-3-3[zeta] is also upregulated by IR in cancer cells in a ROS-dependent manner, is required for IR-induced invasion in ErbB2- and FoxM1-positive breast cancer cells and together with FoxM1 is sufficient for invasion in ErbB2-negative breast cancer cells. Thus, our data show that IR-mediated activation of ErbB2 and induction of 14-3-3[zeta] collaborate to regulate FoxM1 and promote invasion of breast cancer cells. This work has identified ErbB2, and more specifically FoxM1 and 14-3-3[zeta] as potential biomarkers for differentiating pre-invasive DCIS from less aggressive lesions. Furthermore, novel antagonists targeting these molecules may yield innovative neoadjuvant therapies for radiosensitization and/or overcoming drug resistance in ErbB2-positive tumors.
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Details
- Title
- Mechanisms regulating breast cancer invasion in response to ionizing radiation
- Creators
- Diane Marie Kambach
- Contributors
- Jane Clifford (Advisor) - Drexel University, Drexel University (1970-)Mauricio Reginato (Advisor) - Drexel University, Drexel University (1970-)
- Awarding Institution
- Drexel University
- Degree Awarded
- Doctor of Philosophy (Ph.D.)
- Publisher
- Drexel University; Philadelphia, Pennsylvania
- Resource Type
- Dissertation
- Language
- English
- Academic Unit
- College of Medicine; Drexel University
- Other Identifier
- 991021888858704721