Interaction Between Ionizing Radiation, Estrogens and Antiestrogens in the Modification of Tumor Microenvironment in Estrogen Dependent Multicellular Spheroids

Abstract

MCF7 human breast cancer cells growing as multicellular spheroids were examined as a model of three-dimensional cellular organization. Estrogen-free medium inhibited spheroid formation. In medium containing estrogens, the antiestrogen hydroxytamoxifen decreased the spheroid growth rate. Analyses with the recursion formula after Gompertz fitting showed that the rate of exponential decrease in growth rate (alpha) was alpha 0.099 +/- 0.013 d-1, and the decrease in alpha' was 0.061 +/- 0.015 d-1 for 0.1 microM hydroxytamoxifen and control spheroids respectively. MCF7 cells which had been growth arrested in an estrogen-free medium showed a significant decrease in radiosensitivity (surviving fraction at 2 Gy, SF2 = 63%) when compared with 0.1 nM 17 beta-estradiol-treated cells (SF2 = 38%). No differences in radiosensitivity were seen in MCF7 spheroids in estrogen-supplemented medium (radiation dose necessary to control 50% of spheroids (SCD50) was 5.51 Gy; derived alpha, beta and SF2 were 0.301 +/- 0.110 Gy-1, 0.018 +/- 0.005 Gy-2, and 51% respectively) when compared with monolayer cultures in the same medium (alpha = 0.316 +/- 0.059 Gy-1, beta = 0.023 +/- 0.006 Gy-2 and SF2 = 50%). In the spheroid model, manipulating the cellular environment, i.e., with estrogen treatment, modulates sensitivity to ionizing radiation.