Raloxifene inhibits menin-dependent estrogen receptor activation in breast cancer cells.
BACKGROUND
Menin is a tumor suppressor encoded by Men1 that is mutated in the human-inherited tumor syndrome--multiple endocrine neoplasia type 1. Menin binds to estrogen receptors (ER) to enhance estrogen activity in breast cancer cells.


OBJECTIVE
Our clinical study showed that the outcome in the case of menin-positive tumors was worse than in the case of menin-negative tumors. We examined the role of raloxifene on the cell growth in a menin-positive breast cancer cell line.


METHODS
To examine the mechanism of raloxifene on menin-dependent activation of ER, we employed the mammalian two-hybrid system. We have established a breast cancer cell line that stably expresses menin. Using these cells, we have examined the effect of raloxifene and tamoxifen on cell growth of menin-transfected cells.


RESULTS
The expression of activation function (AF)-2 enhanced menin-mediated luciferase expression in the mammalian two-hybrid assay. Raloxifene attenuated the effect of menin on estrogen response element-luciferase activation, indicating that raloxifene inhibited the binding of menin to AF-2. Raloxifene significantly inhibited the growth of menin-transfected cells in a dose-dependent manner. Tamoxifen also inhibited menin-transfected MCF-7 cells; however, this inhibition was much less than that of raloxifene.


CONCLUSIONS
Raloxifene inhibits the binding of menin to the AF-2 domain of ERα, suggesting that raloxifene is one of the therapeutic options for menin-positive breast cancer.
Department of Advanced Medicine, Faculty of Medicine, Kagawa University, 1750-1 Miki-cho, Kita-gun, Kagawa 761-0793, Japan.
H
H
Imachi
X
X
Yu
T
T
Nishiuchi
Y
Y
Miyai
H
H
Masugata
K
K
Murao
D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D005260:Female; D006801:Humans; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000502:physiology*; D020849:Raloxifene Hydrochloride / Q000494:pharmacology*
C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; C105373:MEN1 protein, human; D011518:Proto-Oncogene Proteins; D020849:Raloxifene Hydrochloride