Novel link between estrogen receptor alpha and hedgehog pathway in breast cancer.
Ligand-dependent constitutive activation of the hedgehog (Hh) pathway is important in the development of various carcinomas including breast cancer. A link between estrogen receptor alpha (ERalpha) and the Hh pathway in human breast cancer is shown here for the first time. In ERalpha-positive cells, estrogen depletion decreased the expression of sonic hedgehog (Shh), a ligand of the Hh pathway, while estrogen supplementation triggered Shh up-regulation. This estrogen-induced Shh expression activated the Hh pathway in a ligand-dependent manner, and increased cell proliferation. These effects were suppressed by ERalpha inhibitors, including ICI 182,780 (ICI), the dominant negative form of ERalpha and small interfering RNA (siRNA) against ERalpha. Consistent with the in vitro data, a positive correlation between ERalpha and Shh expression was found in breast cancer tissues. These data suggest that ERalpha regulates the Hh pathway through Shh induction, and promotes breast cancer development.
Koga
Kenichiro
K
Department of Cancer Therapy and Research, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Nakamura
Masafumi
M
Nakashima
Hiroshi
H
Akiyoshi
Takashi
T
Kubo
Makoto
M
Sato
Norihiro
N
Kuroki
Syoji
S
Nomura
Masatoshi
M
Tanaka
Masao
M
Katano
Mitsuo
M
D001943:Breast Neoplasms; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D047628:Estrogen Receptor alpha; D004967:Estrogens / Q000494:pharmacology; D053823:Hedgehog Proteins / Q000378:metabolism*; D006801:Humans; D009376:Neoplasms, Hormone-Dependent / Q000378:metabolism; D015398:Signal Transduction
C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D004967:Estrogens; D053823:Hedgehog Proteins; C509239:SHH protein, human