TY - JOUR
T1 - Cooperative effect of gefitinib and fumitremorgin c on cell growth and chemosensitivity in estrogen receptor α negative fulvestrant-resistant MCF-7 cells
AU - Liu, Hong
AU - Cheng, Dong
AU - Weichel, Alyssa K.
AU - Osipo, Clodia
AU - Wing, Laura K.
AU - Chen, Bin
AU - Louis, Teresa E.
AU - Jordan, V. Craig
PY - 2006/11
Y1 - 2006/11
N2 - The selective ER downregulator, fulvestrant, is currently approved as a second line endocrine therapy after onset of resistance to prior antiestrogen therapy in post-menopausal breast cancer patients. Resistance to antihormonal therapies is common and, therefore, we anticipate that fulvestrant-resistance will occur as well. The current study was undertaken to investigate the underlying molecular changes after fulvestrant-resistance and find new therapeutic targets and agents for fulvestrant-resistant breast cancer cells. We developed a unique fulvestrant-resistant cell line (MCF-7/F), derived from MCF-7 estrogen receptor α (ERα)-positive human breast cancer cells, by culturing them in 1 μM fulvestrant containing medium for ∼18 months. MCF-7/F cells became irreversibly ERα negative as withdrawal of fulvestrant did not alter the ERα-negative phenotype, determined by real-time PCR, Western blot analysis, and ERE-luciferase transfection assays. MCF-7/F cells grew in a hormone-independent manner. Interestingly, MCF-7/F cells overexpressed both epidermal growth factor receptor (EGFR) and breast cancer resistant protein (BCRP). Gefitinib, a specific EGFR tyrosine kinase inhibitor, preferentially inhibited the growth of MCF-7/F cells relative to MCF-7 cells by inhibiting both MAPK44/42 and Akt phosphorylation. MCF-7/F cells became less sensitive to chemotherapeutic agents such as mitoxantrone. Moreover, fumitremorgin C, a specific BCRP inhibitor, significantly increased the efficacy of mitoxantrone in MCF-7/F cells. Gefitinib increased the inhibitory effect of mitoxantrone on cell growth. Similarly, fumitremorgin C increased the inhibitory effect of gefitinib on cell growth, suggesting that there is a bidirectional crosstalk between EGFR and BCRP. More importantly, these results provide a molecular basis for using gefitinib, BCRP inhibitors, and chemotherapeutic agents as combination therapy approaches in fulvestrant-resistant breast cancer.
AB - The selective ER downregulator, fulvestrant, is currently approved as a second line endocrine therapy after onset of resistance to prior antiestrogen therapy in post-menopausal breast cancer patients. Resistance to antihormonal therapies is common and, therefore, we anticipate that fulvestrant-resistance will occur as well. The current study was undertaken to investigate the underlying molecular changes after fulvestrant-resistance and find new therapeutic targets and agents for fulvestrant-resistant breast cancer cells. We developed a unique fulvestrant-resistant cell line (MCF-7/F), derived from MCF-7 estrogen receptor α (ERα)-positive human breast cancer cells, by culturing them in 1 μM fulvestrant containing medium for ∼18 months. MCF-7/F cells became irreversibly ERα negative as withdrawal of fulvestrant did not alter the ERα-negative phenotype, determined by real-time PCR, Western blot analysis, and ERE-luciferase transfection assays. MCF-7/F cells grew in a hormone-independent manner. Interestingly, MCF-7/F cells overexpressed both epidermal growth factor receptor (EGFR) and breast cancer resistant protein (BCRP). Gefitinib, a specific EGFR tyrosine kinase inhibitor, preferentially inhibited the growth of MCF-7/F cells relative to MCF-7 cells by inhibiting both MAPK44/42 and Akt phosphorylation. MCF-7/F cells became less sensitive to chemotherapeutic agents such as mitoxantrone. Moreover, fumitremorgin C, a specific BCRP inhibitor, significantly increased the efficacy of mitoxantrone in MCF-7/F cells. Gefitinib increased the inhibitory effect of mitoxantrone on cell growth. Similarly, fumitremorgin C increased the inhibitory effect of gefitinib on cell growth, suggesting that there is a bidirectional crosstalk between EGFR and BCRP. More importantly, these results provide a molecular basis for using gefitinib, BCRP inhibitors, and chemotherapeutic agents as combination therapy approaches in fulvestrant-resistant breast cancer.
KW - Breast cancer
KW - Breast cancer resistant protein
KW - Chemosensitivity
KW - EGFR
KW - Fulvestrant- resistance
UR - http://www.scopus.com/inward/record.url?scp=39049175084&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=39049175084&partnerID=8YFLogxK
U2 - 10.3892/ijo.29.5.1237
DO - 10.3892/ijo.29.5.1237
M3 - Article
C2 - 17016657
AN - SCOPUS:39049175084
SN - 1019-6439
VL - 29
SP - 1237
EP - 1246
JO - International journal of oncology
JF - International journal of oncology
IS - 5
ER -