Dissertation/Thesis Abstract

Targeting Breast Cancer Stem Cells generated through Epithelial-Mesenchymal Transition: The roles of AXL and ADM/RAMP3 Pathways
by Asiedu, Michael Kwabena, M.S., College of Medicine - Mayo Clinic, 2011, 119; 1533838
Abstract (Summary)

Breast cancer is the second most common cause of death from cancer among women in the United States. Treatment of breast cancer with radiation or chemotherapy often "cures" the cancer to the extent that there are no detectable tumor lesions, yet there is a relatively high risk of recurrence, suggesting that a subset of tumor cells with resistance to standard therapy evade treatment and are able to reconstitute a viable tumor. Currently, about 30% of all patients with early stage breast cancer who receive conventional treatment develop recurrence with locally invasive disease or distant metastasis. This pattern of disease relapse characterized by progressive tumor invasion and metastasis is the cause of most deaths from breast cancer. The existence of a sub-population of cancer cells termed cancer stem or progenitor-like cells that are resistant to standard chemotherapy and radiation therapy is thought to be responsible for disease relapse. Although neoplastic transformation of putative adult stem cells gives rise to cancer stem cells, recent studies have demonstrated that epithelial to mesenchymal transition (EMT), a biological process activated during development, could induce the generation of mesenchymal cancer cells with stem cell-like properties. EMT, which results in acquisition of invasive and migratory phenotype and cancer stemness, is an important step in tumor progression, metastasis, tumor maintenance, and relapse of cancer. The molecular mechanisms regulating breast cancer stem cells are not well understood, but they appear to be essential to the pathogenesis, relapse, and metastasis of the most aggressive types of breast cancer. Therefore the identification of factors that could be targeted to regulate EMT and breast cancer stem cell (BCSC) function could be critical for the development of effective breast cancer therapies. Furthermore, the link between EMT and CSCs function reinforces the significance of CSCs in breast cancer pathogenesis. In this study we demonstrated the generation of cancer stem cells via epithelial to mesenchymal transition and evaluated the respective roles of AXL and ADM/RAMP3 pathways in the regulation of both EMT induction and the function of breast cancer stem cells.

We demonstrate in this project that exposure to TGF-β and TNF-α induces a stable BCSC phenotype, characterized by self-renewal, greatly increased tumorigenicity, and increased resistance to chemotherapy. We further found that the TGF-β/TNF-α-derived cells showed downregulated expression of Claudins 3, 4 and 7 and the luminal marker KRT18, demonstrating a shift to the claudin low molecular subtype. Furthermore we found a novel function of AXL in acting upstream to induce EMT in normal and immortalized human mammary epithelial cells in an apparent positive feedback loop mechanism. Downregulation of AXL reversed EMT in mesenchymal breast cancer stem cells, attenuated self-renewing capacity, decreased tumorigenicity and restored the chemo-sensitivity of the BCSCs through activation of the NFκB pathway. Additionally, we show that ADM/RAMP3 pathway is important for maintaining the mesenchymal phenotype of BCSCs by regulating the expression of EMT markers E-Cadherin, Snail and Slug through activation of the PI3K/Akt/GSK3-β pathway, and that increased expression of RAMP3/CRLR is associated with increased tumor formation and enhanced self-renewal capacity of BCSCs. This study therefore reports of a novel model for studying BCSC biology and proposes that targeting the receptor tyrosine kinase AXL and the tumor microenvironment via regulation of ADM/RAMP3 pathway could be important therapeutic options to improve breast cancer treatment.

Indexing (document details)
Advisor: Roberts, Lewis R.
Commitee: Fernandez-Zapico, Martin E., Maherr, Lewis Jim, III, Radisky, Derek C.
School: College of Medicine - Mayo Clinic
Department: Immunology
School Location: United States -- Minnesota
Source: MAI 51/04M(E), Masters Abstracts International
Subjects: Cellular biology, Immunology, Oncology
Keywords: Adrenomedullin, Axl, Breast cancer, Cancer stem cells, Emt, Immune factors
Publication Number: 1533838
ISBN: 9781267921680
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