17Beta-estradiol induces down-regulation of Cap43/NDRG1/Drg-1, a putative differentiation-related and metastasis suppressor gene, in human breast cancer cells.
OBJECTIVE
Cap43 is known as a nickel- and calcium-inducible gene. In the present study, we examined whether 17beta-estradiol (E2) could affect the expression of Cap43 in breast cancer.


METHODS
Real-time PCR, immunoblotting, and immunocytochemistry were used to examine the expression of Cap43 and estrogen receptor-alpha (ER-alpha) in breast cancer cell lines. MDA-MB-231 and SK-BR-3 cell lines were transfected with ER-alpha cDNA to establish cells overexpressing ER-alpha. Immunohistochemistry was used to evaluate the expression of the Cap43 protein in breast cancer patients (n = 96), and the relationship between Cap43 expression and clinicopathologic findings was examined.


RESULTS
Of the eight cell lines, four expressed higher levels of Cap43 with very low levels of ER-alpha, whereas the other four expressed lower levels of Cap43 with high ER-alpha levels. Treatment with E2 decreased the expression of Cap43 dose-dependently in ER-alpha-positive cell lines but not in ER-alpha-negative lines. Administration of antiestrogens, tamoxifen and ICI 182780, abrogated the E2-induced down-regulation of Cap43. Overexpression of ER-alpha in both ER-alpha-negative cell lines, SK-BR-3 and MDA-MB-231, resulted in down-regulation of Cap43. Immunostaining studies showed a significant correlation between Cap43 expression and the histologic grade of tumors (P = 0.0387). Furthermore, Cap43 expression was inversely correlated with the expression of ER-alpha (P = 0.0374).


CONCLUSIONS
E2-induced down-regulation of Cap43 seems to be mediated through ER-alpha-dependent pathways in breast cancer cells both in culture and in patients. Cap43 has potential as a molecular marker to determine the therapeutic efficacy of antiestrogenic anticancer agents in breast cancer.
Fotovati
Abbas
A
Center for Innovative Cancer Therapy of the 21st Century Center of Excellence Program for Medical Science and Departments of Surgery and Pathology, Kurume University, Kurume, Fukuoka, Japan.
Fujii
Teruhiko
T
Yamaguchi
Miki
M
Kage
Masayoshi
M
Shirouzu
Kazuo
K
Oie
Shinji
S
Basaki
Yuji
Y
Ono
Mayumi
M
Yamana
Hideaki
H
Kuwano
Michihiko
M
D018797:Cell Cycle Proteins; D049109:Cell Proliferation; D015536:Down-Regulation; D004958:Estradiol / Q000502:physiology*; D004965:Estrogen Antagonists / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000032:analysis; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007150:Immunohistochemistry; D047908:Intracellular Signaling Peptides and Proteins; D009369:Neoplasms / Q000235:genetics* / Q000473:pathology; D016133:Polymerase Chain Reaction; D011506:Proteins / Q000032:analysis* / Q000187:drug effects; D013629:Tamoxifen / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D000099259:N-myc Downstream-Regulated Gene 1 Protein
D018797:Cell Cycle Proteins; D004958:Estradiol; D004965:Estrogen Antagonists; D047628:Estrogen Receptor alpha; D047908:Intracellular Signaling Peptides and Proteins; D011506:Proteins; D013629:Tamoxifen; D000099259:N-myc Downstream-Regulated Gene 1 Protein