Androgen receptor overexpression induces tamoxifen resistance in human breast cancer cells.
Although the androgen receptor (AR) is a known clinical target in prostate cancer, little is known about its possible role in breast cancer. We have investigated the role of AR expression in human breast cancer in response to treatment with the antiestrogen tamoxifen. Resistance to tamoxifen is a major problem in treating women with breast cancer. By gene expression profiling, we found elevated AR and reduced estrogen receptor (ER) alpha mRNA in tamoxifen-resistant tumors. Exogenous overexpression of AR rendered ERalpha-positive MCF-7 breast cancer cells resistant to the growth-inhibitory effects of tamoxifen in anchorage-independent growth assays and in xenograft studies in athymic nude mice. AR-overexpressing cells remained sensitive to growth stimulation with dihydrotestosterone. Treatment with the AR antagonist Casodex (bicalutamide) reversed this resistance, demonstrating the involvement of AR signaling in tamoxifen resistance. In AR-overexpressing cells, tamoxifen induced transcriptional activation by ERalpha that could be blocked by Casodex, suggesting that AR overexpression enhances tamoxifen's agonistic properties. Our data suggest a role for AR overexpression as a novel mechanism of hormone resistance, so that AR may offer a new clinical therapeutic target in human breast cancers.
De Amicis
Francesca
F
Breast Center, Baylor College of Medicine, Houston, TX 77030, USA.
Thirugnansampanthan
Janagi
J
Cui
Yukun
Y
Selever
Jennifer
J
Beyer
Amanda
A
Parra
Irma
I
Weigel
Nancy L
NL
Herynk
Matthew H
MH
Tsimelzon
Anna
A
Lewis
Michael T
MT
Chamness
Gary C
GC
Hilsenbeck
Susan G
SG
Andò
Sebastiano
S
Fuqua
Suzanne A W
SA
D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000378:metabolism*; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D020411:Oligonucleotide Array Sequence Analysis; D011944:Receptors, Androgen / Q000096:biosynthesis* / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013629:Tamoxifen / Q000494:pharmacology*; D014162:Transfection; D023041:Xenograft Model Antitumor Assays
D018931:Antineoplastic Agents, Hormonal; D011944:Receptors, Androgen; D013629:Tamoxifen