2-Methoxyestradiol suppresses osteolytic breast cancer tumor progression in vivo.
2-Methoxyestradiol (2ME(2)), a physiologic metabolite of 17beta-estradiol (estrogen), has emerged as a promising cancer therapy because of its potent growth-inhibitory and proapoptotic effects on both endothelial and tumor cells. 2ME(2) also suppresses osteoclast differentiation and induces apoptosis of mature osteoclasts, and has been shown to effectively repress bone loss in an animal model of postmenopausal osteoporosis. Given these observations, we have examined whether 2ME(2) could effectively target metastasis to bone, osteolytic tumors, and soft tissue tumors. A 4T1 murine metastatic breast cancer cell line was generated that stably expressed Far Red fluorescence protein (4T1/Red) to visualize tumor development and metastasis to bone. In an intervention study, 4T1/Red cells were injected into bone marrow of the left femur and the mammary pad. In the latter study, 2ME(2) (10, 25, and 50 mg/kg/d) treatment began on the same day as surgery and was continued for the 16-day duration of study. Tumor cell growth and metastasis to bone were monitored and bone volume was determined by micro-computed tomography. 2ME(2) inhibited tumor growth in soft tissue, metastasis to bone, osteolysis, and tumor growth in bone, with maximum effects at 50 mg/kg/d. Furthermore, tumor-induced osteolysis was significantly reduced in mice receiving 2ME(2). In vitro, 2ME(2) repressed osteoclast number by inducing apoptosis of osteoclast precursors as well as mature osteoclasts. Our data support the conclusion that 2ME(2) could be an important new therapy in the arsenal to fight metastatic breast cancer.
Cicek
Muzaffer
M
Endocrine Research Unit, Mayo Clinic College of Medicine, Rochester, MN 55905, USA. Muzaffer.Cicek@Mayo.edu .
Iwaniec
Urszula T
UT
Goblirsch
Michael J
MJ
Vrabel
Anne
A
Ruan
Ming
M
Clohisy
Denis R
DR
Turner
Russell R
RR
Oursler
Merry Jo
MJ
D000077584:2-Methoxyestradiol; D000818:Animals; D001859:Bone Neoplasms / Q000517:prevention & control / Q000556:secondary; D045744:Cell Line, Tumor; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D004958:Estradiol / Q000031:analogs & derivatives* / Q000627:therapeutic use; D005260:Female; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D010010:Osteoclasts / Q000187:drug effects; D010014:Osteolysis / Q000517:prevention & control*
D004958:Estradiol; D000077584:2-Methoxyestradiol