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Differential Effects of Phorbol Ester on Epidermal Growth Factor Receptors in Estrogen Receptor-positive and -negative Breast Cancer Cell Lines¹

Garvan Institute of Medical Research, St. Vincent's Hospital, Sydney, New South Wales 2010, Australia

A previous study from this laboratory (Koga et al., Cancer Res., 48: 2734–2739, 1988) demonstrated that the growth inhibitory effect of 1,25-dihydroxyvitamin D₃ in human breast cancer cells in vitro was associated with a decline in the concentration of epidermal growth factor receptor (EGF-R). In the present study experiments were undertaken with the phorbol ester, 12-O-tetradecanoyl-phorbol-13-acetate (TPA), an agent known to decrease EGF-R binding, in order to further define the relationship between changes in EGF-R binding and changes in growth rates in 10 human breast cancer cell lines.

Treatment with TPA decreased the rate of cell proliferation in all cell lines except BT 474 in which a slight increase in proliferation rate was observed. Sensitivity to TPA was unrelated to estrogen receptor (ER) status and a wide spectrum of sensitivities was apparent. The concentrations of TPA that produced a 25% decrease in cell number ranged from <0.25 nM for MCF 7M and BT 20 cells to >10 nM for the HBL 100, T 47D, and ZR 75-1 cell lines. Growth inhibition was associated with a block in cell cycle progression in the G₁ and G₂ + M phases of the cell cycle. In all cell lines studied, except BT 474, TPA treatment resulted in a reduction in the ability of cells to bind EGF. Saturation analysis revealed marked differences between the effects of TPA on EGF binding in ER+ and ER- cell lines. In ER+ cell lines, 2-h treatment with 10 nM TPA resulted in a marked reduction in the number of high affinity EGF-R sites and a significant decrease in binding affinity. Among this group of cell lines there was a significant positive correlation between the ability of TPA to decrease cell growth and the TPA-induced decrease in the number of EGF-R sites/cell (r = 0.82, P < 0.03). In ER- cell lines, TPA-induced growth inhibition and the minor changes in EGF-R concentration were unrelated. However, growth inhibition was negatively correlated with TPA-induced changes in apparent affinity of the EGF-R (r = 1.00, P < 0.003) and in the same rank order as the EGF-R concentration in control cells.

These data demonstrate differential relationships between TPA-induced changes in growth and EGF-R binding in ER+ and ER- breast cancer cells, thus supporting the view that growth regulatory pathways are markedly different in these two subtypes of human breast cancer.

¹ Supported by the New South Wales State Cancer Council, the National Health and Medical Research Council of Australia, and MLC-Life Ltd.

² Dr. Koga was a visiting Research Fellow from the Third Department of Internal Medicine, Osaka University Hospital, Osaka, Japan, supported by a grant-in-aid from the Mochida Memorial Foundation for Medical and Pharmaceutical Research, and is presently at that address.

³ Ph.D. scholar supported by the Government Employees Assistance to Medical Research Fund.

⁴ To whom requests for reprints should be addressed, at the Garvan Institute of Medical Research, St. Vincent's Hospital, Sydney, N.S.W. 2010, Australia.

Received 5/ 3/89. Revised 5/ 8/90.

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