All trans-retinoic acid modulates the procoagulant activity of human breast cancer cells

Abstract

All trans-retinoic acid (ATRA) induces apoptosis and/or differentiation in solid tumors, including breast cancer, and has become a therapeutic tool in this disease. In human promyelocytic leukemia ATRA reduces the expression of cellular procoagulant activities (PCA), i.e. Tissue Factor (TF) and Cancer Procoagulant (CP). There are no studies on the effects of ATRA on the PCA of solid tumors, i.e. breast cancer cells. We analyzed different human breast cancer cell lines in order to: 1. characterize the expression of TF and CP; 2. evaluate whether these activities are affected by ATRA; and 3. verify whether a reduction in tumor cell procoagulants may occur in association to apoptosis and growth inhibition induced by ATRA. Two estrogen receptor positive (ER-positive; i.e. MCF7 and ZR75.1) and one estrogen receptor negative (ER-negative; i.e. MDA.MB.231) cell lines were included into the study. The results show that ATRA affected TF in a dose-dependent fashion only in ER-positive cell lines. In particular, at 1uM ATRA, TF significantly (p<0.05) decreased by 57%, 44% in MCF7, ZR75.1 cells, respectively. Differently the results show that ATRA dose-dependently affected CP expression in all three cell lines. Specifically, at 1uM ATRA, CP significantly decreased by 44%, 50% and 25% in MCF7, ZR75.1, and MDA.MB.231. Only in ER-positive cell lines, there was a dose-dependent inhibition of cell growth that became statistically significant at 1uM ATRA, which was associated to a slight but significant increase in the percentage of apoptotic cells. In conclusion, this study demonstrates for the first time that ATRA downregulates the expression of TF and CP in breast cancer cells. Due to the pivotal role of coagulation activation in tumor progression, the capacity of ATRA to affect also tumor procoagulants, in parallel to cell apoptosis, open new perspectives in tumor therapy.