Metastasis and recurrent tumors caused by drug resistance are the main reasons for breast-cancer associated deaths. The mechanisms are still not fully understood. In this study, we address novel mechanisms underlying which localized cancer metastasis turns wildly aggressive to multiple organs during anticancer treatment. We show that Krüppel-like factor 8 (KLF8) expression can be over-induced by chemotherapeutic drugs. Data from large-cohorts of patients shows that after chemotherapy there is a close correlation between the aberrant high levels of KLF8 and C-X-C chemokine receptor type 4 (CXCR4) with drug resistance, metastasis, and poor prognosis. To mimic the drug-induced upregulation, KLF8 or CXCR4 was overexpressed in the lung-specific metastatic cell line LM2. We unexpectedly found that KLF8 or CXCR4 overexpressing cells metastasized extensively to multiple organs, particularly the C-X-C motif chemokine ligand 12 (CXCL12)-rich organs. We found that KLF8 or CXCR4 overexpression enhanced angiogenesis involving increased expression and secretion of vascular endothelial growth factor (VEGF) protein. We also found that KLF8 or CXCR4 overexpression strongly enhanced the formation of filopodia-like protrusions (FLPs) and proliferation. In addition, we opened a new avenue for developing an effective anticancer therapy against Herceptin-resistance, which is a major problem during the treatment of human epidermal growth factor receptor 2 (HER2) positive breast cancer patients. Hypoxia-inducible factor 1 subunit alpha (HIF-1α) plays a critical role in drug-resistance. However, no active drug that can selectively target HIF-1α is available. Cerium oxide nanoparticles (CNPs) have recently emerged as anticancer agents with minimal side effects on normal tissues. We proved that CNPs showed a strong ability to sensitize Herceptin-resistant breast cancer cells to the cytotoxicity of Herceptin. Herceptin combined with CNPs was shown to effectively eliminate Herceptin-resistant breast cancer cells via HIF-1α and VEGF signaling suppression. We suggest great potential for their combination to overcome drug resistance, metastasis, and tumor relapse.
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Doctor of Philosophy (Ph.D.)
College of Medicine
Burnett School of Biomedical Sciences
Length of Campus-only Access
Doctoral Dissertation (Campus-only Access)
College of Medicine
Hao, Jie, "Novel Mechanisms Underlying Drug-resistant Metastasis and Relapse in Breast Cancer" (2021). Electronic Theses and Dissertations, 2020-. 691.