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Published on: August 13, 2019
2-Methoxyestradiol suppresses osteolytic breast cancer tumor progression in vivo
Muzaffer Cicek1, Urszula T Iwaniec, Michael J Goblirsch
1Endocrine Research Unit, Mayo Clinic College of Medicine, Rochester, MN 55905, USA. Muzaffer.Cicek@Mayo.edu .
Abstract:
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.
Insights
2-Methoxyestradiol (2ME(2)), an estrogen metabolite, effectively inhibits breast cancer growth, metastasis to bone, and osteolysis. This compound shows promise as a novel therapy for metastatic breast cancer by targeting tumor cells and bone destruction.
Area of Science:
- Oncology
- Endocrinology
- Bone Biology
Background:
- 2-Methoxyestradiol (2ME(2)), a metabolite of 17beta-estradiol, exhibits anti-cancer properties.
- 2ME(2) inhibits endothelial and tumor cell proliferation and induces apoptosis.
- It also suppresses osteoclast activity, preventing bone loss.
Purpose of the Study:
- To investigate the efficacy of 2ME(2) in targeting bone metastasis, osteolytic tumors, and soft tissue tumors.
- To evaluate 2ME(2)'s effects on tumor growth, bone metastasis, and osteolysis in a murine model.
Main Methods:
- A 4T1 murine metastatic breast cancer cell line (4T1/Red) was used.
- Cells were injected into the bone marrow and mammary fat pad.
- Mice received varying doses of 2ME(2) (10, 25, 50 mg/kg/d) or vehicle control.
- Tumor growth, metastasis, and bone volume (micro-CT) were monitored.
Main Results:
- 2ME(2) significantly inhibited soft tissue tumor growth, bone metastasis, and osteolysis.
- Maximum efficacy was observed at 50 mg/kg/d.
- In vitro studies confirmed 2ME(2) induced apoptosis in osteoclast precursors and mature osteoclasts, reducing osteoclast numbers.
Conclusions:
- 2ME(2) demonstrates potent anti-metastatic and anti-osteolytic effects.
- It effectively reduces tumor burden and bone destruction in metastatic breast cancer models.
- 2ME(2) represents a potential therapeutic agent for managing metastatic breast cancer.
