A new hormonal therapy for estrogen receptor-negative breast cancer.
BACKGROUND
We postulate that the androgen dehydroepiandrosterone sulfate (DHEAS) may represent an innovative hormonal treatment for estrogen (ER), progesterone (PR) receptor-negative, but androgen receptor (AR)-positive breast cancers by inhibiting breast cancer cell growth through AR stimulation.


METHODS
Three ER,PR-negative breast cancer cell lines (HCC 1137, 1954, and 38), were treated with DHEAS. DHEAS-induced growth was measured by a methylthiotetrazole (MTT) proliferation assay and apoptosis by TUNEL fluorescence. Androgen receptor gene expression levels were determined using quantitative real-time polymerase chain reaction (q-RT-PCR).


RESULTS
HCC cell lines 1954 and 1937 were positive for AR expression; HCC 38 was weakly positive. MTT analysis showed DHEAS-induced decreases in cell proliferation of 47% in HCC 1937, 27% in HCC 1954, and 0.4% in HCC 38. Ten days of culturing HCC 1954 cells after the removal of DHEAS resulted in a 3.5-fold increase in growth. Continuous treatment for the same duration induced a 2.8-fold decrease in growth. Parallel experiments showed no significant changes in HCC 38 cultures. TUNEL assays showed DHEAS-induced apoptosis fold increases of 2.8 in HCC 1937, 1.9 in HCC 1954, and no significant difference in HCC 38 cultures. Q-RT-PCR of HCC 1954 cells showed a 6-fold DHEAS-induced decrease in AR gene expression at 4 h. Co-treatment with Casodex nullified this effect.


CONCLUSIONS
DHEAS inhibited growth of ER,PR-negative, AR-positive breast cancer cells. DHEAS was cytotoxic to these breast cancer cells via the apoptosis pathway. DHEAS may be an effective treatment for a population previously excluded from hormone therapy.
Hardin
Chelsea
C
Division of Surgical Oncology, Department of General Surgery, Oregon Health & Science University, Portland, Oregon 97201, USA.
Pommier
Rodney
R
Calhoun
Kristine
K
Muller
Patrick
P
Jackson
Terisa
T
Pommier
SuEllen
S
D001943:Breast Neoplasms / Q000188:drug therapy*; D019314:Dehydroepiandrosterone Sulfate / Q000494:pharmacology*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D020287:In Situ Nick-End Labeling; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism; D011980:Receptors, Progesterone / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016896:Treatment Outcome; D014407:Tumor Cells, Cultured
D011944:Receptors, Androgen; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D019314:Dehydroepiandrosterone Sulfate