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.
Department of Cancer Therapy and Research, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Kenichiro
K
Koga
Masafumi
M
Nakamura
Hiroshi
H
Nakashima
Takashi
T
Akiyoshi
Makoto
M
Kubo
Norihiro
N
Sato
Syoji
S
Kuroki
Masatoshi
M
Nomura
Masao
M
Tanaka
Mitsuo
M
Katano
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