The effect of high dehydroepiandrosterone sulfate levels on tamoxifen blockade and breast cancer progression

Background: We investigated the stimulatory potential of dehydroepiandrosterone sulfate (DHEA-S) on tamoxifen-treated cells and assessed its effect on cancer progression in the adjuvant setting. Methods: Mean serial serum levels of sex hormones from 44 patients receiving tamoxifen were correlated with follow-up status. T-47D (ER+/PR+) and HCC1937 (ER-/PR-) breast cancer cells were pretreated with 100 μM anastrozole, with or without tamoxifen, and stimulated with 22.8 μM DHEA-S. Rapid colorimetric assays allowed calculation of growth percent change. Results: Clinically, development of metastatic disease correlated only with ≥90 μg/dL DHEA-S (P = 0.005). In vitro, T-47D cells stimulated with DHEA-S after anastrozole showed 35% increased growth. Addition of 0.01 nM tamoxifen demonstrated-7% inhibition. Increasing the DHEA-S/tamoxifen ratio reversed suppression to +25%. Conclusions: DHEA-S ≥90 μg/dL is a risk factor for recurrence in the adjuvant setting. In vitro, although tamoxifen inhibits cell growth at high doses it can be circumvented by DHEA-S. These results indicate that DHEA-S contributes to tamoxifen resistance and disease progression.