Author Description

This dissertation, "The Role of FOXO3a in the Development of Chemoresistance in Breast Cancer" by Jie, Chen,, was obtained from The University of Hong Kong (Pokfulam, Hong Kong) and is being sold pursuant to Creative Commons: Attribution 3.0 Hong Kong License. The content of this dissertation has not been altered in any way. We have altered the formatting in order to facilitate the ease of printing and reading of the dissertation. All rights not granted by the above license are retained by the author. Abstract: Breast cancer is the most common malignancy in women and represents one of the major causes of death worldwide. The PI3K-Akt-FOXO3a signalling pathway has been shown to play a crucial role in tumorigenesis and the development of drug resistance in many cancer types. However, previous studies on FOXO3a using breast cancer tissues were controversial. So this study aims at better understanding of the role of FOXO3a in the development of drug resistance, especially endocrine resistance and anthracycline resistance in breast cancer. Examination of FOXO3a and phosphorylated-Akt (P-Akt) expressions in breast cancer tissue microarrays revealed nuclear FOXO3a was significantly associated with poor prognosis (p=0.014) and lymph node positivity (p=0.052) in invasive ductal carcinoma. Using the tamoxifen and anthracycline-sensitive and -resistant breast cancer cell lines as models, we found that the nuclear accumulation of FOXO3a was associated with enhanced anthracycline-resistance but not tamoxifen-resistance. This was consistent with the finding that sustained nuclear FOXO3a was associated with poor prognosis, as cytotoxic chemotherapy resistance is linked to limited therapeutic options and poor prognosis. We demonstrated a possible feedback mechanism in which induction of FOXO3a activity in the anthracycline-sensitive MCF-7 cells induced Akt phosphorylation and promoted cell proliferation arrest. Using MDA-MB-231-FOXO3a(A3): ER cells in which FOXO3a