Increased local tumor tissue expression of versican in breast cancer patients is predictive of relapse and has a negative impact on survival rates. It is recognized that bone is a common anatomic site of breast cancer metastasis. The C-terminal G3 domain of versican influences local and systemic tumor invasiveness in pre-clinical murine models. However, the mechanism(s) by which G3 influences breast tumor growth and metastasis is not well characterized. We exogenously expressed a G3 construct in mouse breast cancer cell line 66c14, and found that G3 expression enhanced breast cancer cell proliferation and migration, and spontaneous metastasis to bone in an orthotopic model by upregulating the EGFR-mediated signaling pathway. Possessing anti-apoptotic and drug resistant properties, overexpression of versican was accompanied by selective sensitization to several chemotherapeutic agents. The dual roles of G3 in modulating breast cancer cell resistance to chemotherapeutic agents may, in part, explain breast cancer cell resistance to chemotherapy and EGFR therapy. The apoptotic effects of chemotherapeutics depend upon the activation and balance of down stream signals in the EGFR pathway. New knowledge gained by our experiments includes the understanding that GSK-3β (S9P) appears to function as a key check-point in this balance. In addition, versican G3 enhanced breast cancer cell self-renewal in vitro and in vivo. Versican was expressed at high levels in breast cancer mammosphere cells, which contained a high percentage of SP cells. Reduction of versican’s functionality through anti-versican shRNA or knocking out the EGF-like motifs using G3ΔEGF reduced the effect of versican on enhancing mammosphere and colony formation. Versican promoted breast cancer cell self-renew appears to play a role in enhanced chemotherapeutic drug resistance (including Docetaxel, Doxorubicin, and Epirubicin), which relates partly to its upregulated expression of EGFR signaling. Versican enhances breast cancer bone metastasis not only by enhancing tumor cell mobility, invasion, and survival in bone tissues, but also through mechanisms inhibiting osteoblast cell growth and differentiation, affording favorable microenvironments for tumor metastasis.
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:OTU.1807/33983 |
| Date | 11 December 2012 |
| Creators | Du, Weidong |
| Contributors | Yee, Albert, Yang, Burton |
| Source Sets | Library and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada |
| Language | en_ca |
| Detected Language | English |
| Type | Thesis |
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