Targeting the PI3K and Ras Signal Transduction Pathways in a Murine Model of Osteolytic Breast Cancer Metastasis
Date
2013-01-25
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Abstract
Bone metastasis frequently occurs in patients with advanced breast cancer, and leads to widespread bone destruction. Aberrant activation of the PI3K and Ras-MAPK pathways are consistently observed in high-grade metastatic breast cancers, making these pathways attractive targets for therapeutic intervention. Complex signal crosstalk between these pathways is implicated in cancer cell perpetuation; therefore, dual inhibition should theoretically provide maximal targeting. The PI3K and MEK inhibitors, PX866 and AZD6244 were employed to investigate the therapeutic potential in an in vivo model of MDA-MB-231-EGFP/Luc2 human breast cancer osteolytic metastases. PI3K inhibition did not directly affect bone-colonized cancer cells, however, it demonstrated an attenuation of bone loss, whereas MEK inhibition resulted in a significant reduction of both tumor growth and osteolysis. Simultaneous inhibition of PI3K and MEK resulted in a reduction of tumor growth, but paradoxically exhibited an exacerbation of bone damage. These findings suggest that MEK inhibition alone may be a valuable additional treatment for breast cancer osteolytic metastasis.
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Keywords
Biology--Molecular, Oncology, Biochemistry, Biology--Molecular
Citation
Bosma, N. (2013). Targeting the PI3K and Ras Signal Transduction Pathways in a Murine Model of Osteolytic Breast Cancer Metastasis (Master's thesis, University of Calgary, Calgary, Canada). Retrieved from https://prism.ucalgary.ca. doi:10.11575/PRISM/27979