Raloxifene inhibits tumor growth and lymph node metastasis in a xenograft model of metastatic mammary cancer.
BACKGROUND
The effects of raloxifene, a novel selective estrogen receptor modulator, were studied in a mouse metastatic mammary cancer model expressing cytoplasmic ERα.


METHODS
Mammary tumors, induced by inoculation of syngeneic BALB/c mice with BJMC3879luc2 cells, were subsequently treated with raloxifene at 0, 18 and 27 mg/kg/day using mini-osmotic pumps.


RESULTS
In vitro study demonstrated that the ERα in BJMC3879luc2 cells was smaller (between 50 and 64 kDa) than the normal-sized ERα (66 kDa) and showed cytoplasmic localization. A statistically significant but weak estradiol response was observed in this cell line. When BJMC3879luc2 tumors were implanted into mice, the ERα mRNA levels were significantly higher in females than in males. In vitro studies showed that raloxifene induced mitochondria-mediated apoptosis and cell-cycle arrest in the G1-phase and a decrease in the cell population in the S-phase. In animal experiments, tumor volumes were significantly suppressed in the raloxifene-treated groups. The multiplicity of lymph node metastasis was significantly decreased in the 27 mg/kg group. Levels of apoptosis were significantly increased in the raloxifene-treated groups, whereas the levels of DNA synthesis were significantly decreased in these groups. No differences in microvessel density in tumors were observed between the control and raloxifene-treated groups. The numbers of dilated lymphatic vessels containing intraluminal tumor cells were significantly reduced in mammary tumors in the raloxifene-treated groups. The levels of ERα mRNA in mammary tumors tended to be decreased in the raloxifene-treated groups.


CONCLUSIONS
These results suggest that the antimetastatic activity of raloxifene in mammary cancer expressing cytoplasmic ERα may be a crucial finding with clinical applications and that raloxifene may be useful as an adjuvant therapy and for the chemoprevention of breast cancer development.
Department of Anatomy and Cell Biology, Division of Life Sciences, Osaka Medical College, 2-7 Daigaku-machi, Takatsuki, Osaka 569-8686, Japan. shibatam@art.osaka-med.ac.jp
Masa-Aki
MA
Shibata
Junji
J
Morimoto
Eiko
E
Shibata
Hitomi
H
Kurose
Kanako
K
Akamatsu
Zhong-Lian
ZL
Li
Moriaki
M
Kusakabe
Masahide
M
Ohmichi
Yoshinori
Y
Otsuki
D000818:Animals; D017209:Apoptosis; D001943:Breast Neoplasms / Q000188:drug therapy; D045744:Cell Line, Tumor; D002470:Cell Survival; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D005260:Female; D006801:Humans; D008207:Lymphatic Metastasis; D008297:Male; D015674:Mammary Neoplasms, Animal / Q000188:drug therapy* / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000188:drug therapy*; D020849:Raloxifene Hydrochloride / Q000494:pharmacology*; D020845:Selective Estrogen Receptor Modulators / Q000494:pharmacology; D012737:Sex Factors
D047628:Estrogen Receptor alpha; D020845:Selective Estrogen Receptor Modulators; D020849:Raloxifene Hydrochloride