The Src/Stat3 axis in Met signaling in human invasive breast cancer: a potential predictive marker

• Main Author: Carefoot, Esther
• Other Authors: Queen's University (Kingston, Ont.). Theses (Queen's University (Kingston, Ont.))
• Language: en; en
• Published: 2014
• Subjects: Breast Cancer; xenografts; Therapeutics; Metastasis
• Online Access: http://hdl.handle.net/1974/8582

Met has been found to be over-expressed in human breast cancer, correlating with disease progression and poor prognosis. Src and Stat3 have also been found to be over-expressed in many human cancers, including breast. Met, Src and Stat3 have all been proposed as potential therapeutic targets for basal-like breast cancer (BLBC), an aggressive subtype of breast cancer defined by expression of Cytokeratin 5/6 and epidermal growth factor receptor (EGFR). In addition, Src and Stat3 have been shown to act co-operatively to promote the transcription of HGF, while Stat3 can also increase the expression of Met mRNA. The goal of this study was to determine if Src and Stat3 affect the activity and expression of Met in human breast cancer. The study has also assessed the functional effect of Src, Stat3 and Met blockade on cultured breast cancer cells and a breast tumour xenograft model. Finally, a preliminary assessment was performed of Src, Stat3 and Met as biomarkers for distinct clinico-pathological parameters in a breast cancer cohort, and of the prognostic value of these markers in an online, publically available, breast cancer database. The results demonstrate a density- and Src-dependent increase in Met protein levels in cultured cells, through Stat3 (Src/Stat3-Met). Furthermore Src, Stat3 or Met blockade in tumour xenograft models were found to inhibit primary tumour growth. However treatment with Dasatinib (Src inhibitor) or Met knockdown had no effect on pulmonary metastasis, while Stat3 inhibition (CPA7) increased metastasis, indicating that Stat3 may have a protective function in metastatic breast cancer. Finally Src and the Stat3 target gene, Cyclin D1, were found to correlate with distinct clinico-pathological parameters in a human breast cancer cohort. My study has identified a Src/Stat3-regulated Met pathway in human invasive breast cancer. These findings further provide insight into the minimal effectiveness of Src and Met inhibitors as single agent therapeutics in breast cancer treatment. === Thesis (Ph.D, Pathology & Molecular Medicine) -- Queen's University, 2014-01-23 23:36:06.52