In vitro analysis of the cellular proliferative response to 17-beta-estradiol of human breast cancer

In human breast cancer the proliferating cells appear to differ from those containing estrogen receptors (ER) as shown by studies on isolated cellular subpopulations. In this paper the in vitro effect of 17-beta-estradiol on cell proliferation in 30 primary breast tumors was studied. The effect of several estradiol concentrations was assayed, and the influence of diethylstilbestrol, tamoxifen, and nafoxidine was also tested. The response to these compounds was measured through the thymidine labeling index (TLI). When exposed to 10(-9) mol/l and 10(-8) mol/l estradiol, 14 of 19 ER-positive tumors and six of 11 ER-negative tumors were induced to further proliferate. The TLI increase over the control was 219% (P less than 0.05) at 10(-9) mol/l E2 and 258% (P less than 0.05) at 10(-8) mol/l E2 for ER-positive tumors, and 233% (0.1 less than P less than 0.2) at 10(-9) mol/l E2 and 321% (0.1 less than P less than 0.2) at 10(-8) mol/l E2 for ER-negative tumors. The addition of diethylstilbestrol and antiestrogens in vitro inhibited, to varying degrees, the estradiol-induced increase in the TLI irrespective of the ER-status. The response to E2 was correlated with the expression of the ras p21 protein and carcinoembryonic antigen. It was found that the ras p21 protein is preferentially expressed in ER-negative tumors, the opposite being true for carcinoembryonic antigen. The ras p21 protein is preferentially expressed in those ER-positive tumors that do not respond to estradiol with an increase in the TLI.