Abstract
Activated Ras utilises several downstream pathways, including the mitogen-activated protein kinase (MAPK) kinase (MEK)/MAPK pathway and the phosphoinositide 3-kinase (PI-3k)/Akt pathway, to promote cell proliferation and to inhibit apoptosis. To investigate which pathway plays a major role in Ras-induced drug resistance to chemotherapeutic agents in breast cancer cells, we transfected MCF7 breast cancer cells with a constitutively active H-RasG12V and examined the toxicities of three commonly used breast cancer chemotherapeutic agents, paclitaxel, doxorubicin, and 5-fluorouracil in these cells under the conditions that PI-3K or MEK were selectively inhibited by their respective specifc inhibitors or dominant negative expression vectors. We found that Ras-mediated drug resistance is well correlated with resistance to apoptosis induced by anticancer agents in MCF7 breast cancer cells. Although inhibition of MEK/MAPK or PI-3K/Akt can each enhance the cytotoxicity of paclitaxel, doxorubicin, or 5-fluorouracil, inhibition of the PI-3K/Akt pathway seems to have a greater effect than inhibition of the MEK/MAPK pathway in reversing Ras-mediated drug resistance. Our results indicate that the PI-3K pathway may play a more important role in receptor tyrosine kinase-mediated resistance to chemotherapy and suggest that PI-3K/Akt might be a critical target molecule for anticancer intervention in breast cancer.
Original language | English (US) |
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Pages (from-to) | 185-191 |
Number of pages | 7 |
Journal | British journal of cancer |
Volume | 89 |
Issue number | 1 |
DOIs | |
State | Published - Jul 7 2003 |
Keywords
- Akt
- Breast cancer
- Drug resistance
- MAPK
- Ras
ASJC Scopus subject areas
- Oncology
- Cancer Research