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Tenovus Cancer Research Center, Welsh School of Pharmacy, Cardiff University, Cathays Park, Cardiff, United Kingdom CF10 3XF
Address all correspondence and requests for reprints to: Prof. R. I. Nicholson, Tenovus Cancer Research Center, Welsh School of Pharmacy, Cardiff University, Redwood Building, King Edward VII Avenue, Cathays Park, Cardiff, United Kingdom CF10 3XF. E-mail: mcclellandra{at}cardiff.ac.uk
This paper describes the establishment of an antiestrogen-resistant
MCF7 breast cancer cell subline (FASMCF) by continuous culture of the
estrogen-responsive parental line in steroid-depleted, ICI 182,780
(Faslodex; 10-7 M)-supplemented
medium. After a 3-month period of growth suppression, cells began to
proliferate in ICI 182,780 at rates similar to those of untreated
wild-type cells. Immunocytochemistry showed these cells to have reduced
estrogen receptor and an absence of progesterone receptor proteins.
RT-PCR and transient transfection studies with estrogen response
element-reporter constructs confirmed that ICI 182,780-suppressed
estrogen response element-mediated signaling. FASMCF cells show
increased dependence upon epidermal growth factor receptor
(EgfR)/mitogen-activated protein kinase (MAPK)-mediated signaling.
Thus, EgfR protein and messenger RNA, growth responses to transforming
growth factor-
, and extracellular signal-regulated kinase 1/2 MAPK
activation levels are all increased. Unlike wild-type cells, FASMCF
cells are highly sensitive to growth inhibition by an EgfR-specific
tyrosine-kinase inhibitor (TKI), ZD1839 (Iressa), and an inhibitor of
the activation of MEK1 (MAPKK), PD098059.
Short-term (
3 weeks) withdrawal of cells from antiestrogen had no
effect on growth or phenotype, whereas longer withdrawal (>10 weeks)
appeared to partially reverse the cellular phenotype with increasing
estrogen receptor and decreasing EgfR levels.
In subsequent studies FASMCF cells were maintained in TKI, where their growth was again suppressed and secondary TKI resistance failed to develop within the 3-month period in which initial ICI 182,780 resistance arose. Furthermore, wild-type cells similarly maintained in combination ICI 182,780 and TKI treatment conditions remained growth arrested (>6 months), with notable cell loss through both reduced rates of cellular proliferation and increased cell death.
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