Expression of sigma 1 receptor in human breast cancer.
The sigma 1 receptor (S1R) represents a unique drug-binding site that is distinct from any other receptors. We examined S1R expression in human breast cancer and assessed the activity of S1R ligands in breast cancer cell lines. One-hundred nine breast specimens from normal breast, benign breast disease and cancer were examined with immunohistochemistry or RT-PCR and six different cell lines were also evaluated. S1R mRNA overexpression was detected in 64% of breast cancers compared to normal breast tissue. Immunohistochemistry showed positive epithelial cell staining in 60% of invasive and 41% of in situ cancers, 75% of ductal hyperplasia and in 33% of normal breast. The pattern of expression was more diffuse in invasive breast carcinoma compared to other conditions (p = 0.02). S1R expression was neither a prognostic nor a predictive factor for efficacy of adjuvant chemotherapy but the study only included 58 cancer patients and therefore the statistical power is limited. MDA-MB-361, MDA-MB-435, BT20 and MCF7 cells all expressed S1R protein by Western blot. The non-specific S1R ligands haloperidol, reduced haloperidol and progesterone produced a dose-dependent inhibition of the growth at high (>10 microM) concentrations. Reduced haloperidol also showed additive cytotoxic effects when combined with doxorubicin, vinorelbine , paclitaxel and docetaxel in vitro. The S1R-specific ligand, SKF 10047 demonstrated the least growth inhibitory activity and showed no interaction with chemotherapy. These results demonstrate that some normal and most neoplastic breast epithelial cells and cell lines commonly express S1R. High concentrations of haloperidol inhibit the growth of these cells and potentiate the effect of chemotherapy in vitro.
Wang
B
B
Department of Breast Medical Oncology, The University of Texas MD, Anderson Cancer Center, TX 77030-4009, USA.
Rouzier
R
R
Albarracin
C T
CT
Sahin
A
A
Wagner
P
P
Yang
Y
Y
Smith
T L
TL
Meric-Bernstam
F
F
Marcelo Aldaz
C
C
Marcelo
A C
AC
Hortobagyi
G N
GN
Pusztai
L
L
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D015153:Blotting, Western; D001940:Breast / Q000378:metabolism*; D001943:Breast Neoplasms / Q000378:metabolism*; D045744:Cell Line, Tumor / Q000187:drug effects / Q000378:metabolism; D017931:DNA Primers; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D012333:RNA, Messenger / Q000032:analysis; D012334:RNA, Neoplasm / Q000032:analysis; D017480:Receptors, sigma / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction
D017931:DNA Primers; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D017480:Receptors, sigma