Inhibition of hormone-dependent and independent breast cancer cell growth in vivo and in vitro with the antiestrogen toremifene and recombinant human interferon-α2

The antiproliferative action of the antiestrogen toremifene and recombinant human interferon-α2a (IFN-α2a) were examined on human breast cancer cell lines grown in culture and in the athymic mouse. Solid tumors grew from an inoculation of a 99:1 ratio of hormone dependent (MCF-7) and hormone independent (MDA-MB-231) breast cancer cells without estrogen administration. However, estradiol supplementation significantly increased the rate of tumor growth. The daily administration of 1.35 × 10⁶ U of recombinant human IFN-α2a resulted in a marked reduction of tumor growth in both estradiol-treated and non-treated mice. Toremifene administration (130 μg/day from a sustained release preparation) markedly inhibited estradiol stimulation of mouse uterine weight and partially reduced estradiol-stimulated tumor growth. The combination of IFN-α2a (1.35 × 10⁶ u/day) with toremifene (130 μg/day) reduced estradiol-stimulated growth much below that of toremifene alone but not below that seen with interferon alone. Toremifene (10^-10-10^-6M) did not inhibit the growth of hormone-independent MDA-MB-231 breast cancer cells in vitro whereas it did inhibit the growth of hormone-dependent MCF-7 cells in phenol red containing media. IFN-α2a (1-10,000 u) inhibited the growth of both MCF-7 and MDA-MB-231 cells in culture; however, MCF-7 cells were approximately 10-fold more sensitive to interferon inhibition. This was consistent with the MCF-7 cells showing a greater sensitivity to interferon than MDA-MB-231 cells in the induction of 2′5′-oligoadenylate synthetase. The heterogeneous tumor model in the athymic mouse suggests that differential sensitivities of breast cancer cells to the antiproliferative actions of interferon may influence the effectiveness of combination therapies.