Estrogen metabolite 2-methoxyestradiol inhibits growth of HER2 positive mammary cancer
Introduction
Breast cancer is the most common cancer among women. It is a leading cause of cancer-related death in women. Human epidermal growth factor receptor 2 (HER2) genomic locus is amplified and the protein is overexpressed in 20-30% of breast cancers. These type of breast cancers are highly aggressive and metastatic. There are some treatments available for HER2 positive breast cancer but their efficacy is not optimal and a high percent of patients develop resistance to the treatment. Earlier, we have shown that pregnancy levels of estradiol was effective in inhibiting mammary carcinogenesis. Here we investigate the effect of estradiol metabolite 2-methoxyestradiol on HER2 positive mammary cancer.
Methods
Seven-week old activated MMTV-Her2/neu transgenic mice were used to study the effect of estradiol metabolite 2-methoxyestradiol on mammary carcinogenesis. Different doses of 2-methoxyestradiol (10, 20, 50 and 100µg) were administered subcutaneously through silastic capsules for 1, 2 and 3 weeks. Serum levels of 2-methoxyestradiol was measured using enzyme immunoassay. Mammary cancer incidence, multiplicity and latency was measured. The cancer pathway finder RT2 profiler array was used to study the effect of 2-methoxyestradiol treatments on mammary cancers. Immunoblotting and immunohistochemistry was performed to validate the expression of key markers identified in the cancer pathway finder array.
Results
We observed a dose-dependent increase in serum levels of 2-methoxyestradiol. Mammary cancer incidence and multiplicity was significantly decreased, while mammary cancer latency was prolonged in 2-methoxyestradiol treated groups. Cancer pathway finder array data demonstrated that 2-methoxyestradiol regulated some key genes involved in proliferation, apoptosis and metastasis.
Conclusion
Short-term treatment with 2-methoxyestradiol is effective in inhibiting HER2 positive mammary carcinogenesis. Further studies are needed to understand the mechanism by which this is accomplished for clinical translation.