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 microM anastrozole, with or without tamoxifen, and stimulated with 22.8 microM DHEA-S. Rapid colorimetric assays allowed calculation of growth percent change.


RESULTS
Clinically, development of metastatic disease correlated only with > or =90 microg/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 > or =90 microg/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.
Oregon Health & Science University, Division of Surgical Oncology, 3181 SW Sam Jackson Park Rd. L223A, Portland, OR 97201, USA.
Kristine
K
Calhoun
Rodney
R
Pommier
Julie
J
Cheek
William
W
Fletcher
SuEllen
S
Toth-Fejel
D000328:Adult; D000367:Age Factors; D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D002455:Cell Division / Q000187:drug effects; D019314:Dehydroepiandrosterone Sulfate / Q000097:blood* / Q000494:pharmacology*; D018450:Disease Progression; D004351:Drug Resistance; D004965:Estrogen Antagonists / Q000627:therapeutic use*; D005260:Female; D012739:Gonadal Steroid Hormones / Q000097:blood; D006801:Humans; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D011960:Receptors, Estrogen / Q000032:analysis; D012189:Retrospective Studies; D012307:Risk Factors; D013629:Tamoxifen / Q000627:therapeutic use*; D014407:Tumor Cells, Cultured / Q000187:drug effects
D018931:Antineoplastic Agents, Hormonal; D004965:Estrogen Antagonists; D012739:Gonadal Steroid Hormones; D011960:Receptors, Estrogen; D013629:Tamoxifen; D019314:Dehydroepiandrosterone Sulfate