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Inhibition of skeletal metastasis by ectopic ERalpha expression in ERalpha-negative human breast cancer cell lines
Abhik Bandyopadhyay1, Long Wang, Shiau Hui Chin
1Department of Cellular and Structural Biology, University of Texas Health Science Center, San Antonio, TX 78229-3900, USA.
Abstract:
Some hormone-independent breast cancers lack functional estrogen receptors (ERs) and show evidence of a more aggressive metastatic phenotype. A protective role of the ER has also been suggested in hormone-resistant breast cancer progression. In this study, we have investigated the effect of the ectopic expression of human ERalpha on the bone-metastatic potential of highly metastatic ERalpha-negative human breast cancer MDA-MB-231 and MDA-MB-435-F-L cell lines in an experimental model of bone metastasis in nude mice. ERalpha overexpression had no effect on the growth of both cell lines but reduced the expression of integrin alpha(v)beta(3) and the receptor activator of NF-kappaB, which are known to promote bone metastasis. A significant reduction in the incidence of osteolytic bone metastasis was observed by X-ray imaging of the legs and arms of mice inoculated with ERalpha-expressing clones of MDA-MB-231 cells in comparison to controls. Ectopic expression of ERalpha in MDA-MB-435-F-L cells also reduced their widespread skeletal metastasis to the legs, arms, spine, and mandible, as detected by whole-mouse enhanced green fluorescent protein imaging. Our study indicates for the first time that stable reintroduction of functional ERalpha in ERalpha-negative human breast cancer cells can inhibit their aggressive bone-metastatic potential in an experimental bone metastasis model.
Insights
Restoring estrogen receptor alpha (ERalpha) in ERalpha-negative breast cancer cells reduced their ability to spread to bone. This finding suggests ERalpha may inhibit aggressive bone metastasis in breast cancer.
Area of Science:
- Oncology
- Molecular Biology
- Endocrinology
Background:
- Hormone-independent breast cancers often lack estrogen receptors (ERs) and exhibit aggressive metastatic behavior.
- The role of ERs in hormone-resistant breast cancer progression is complex, with some evidence suggesting a protective function.
Purpose of the Study:
- To investigate the impact of introducing human ERalpha into ERalpha-negative breast cancer cells on their bone-metastatic potential.
- To evaluate the effect of ERalpha re-expression on key factors promoting bone metastasis.
Main Methods:
- Ectopic expression of human ERalpha in MDA-MB-231 and MDA-MB-435-F-L breast cancer cell lines.
- Assessment of cell growth, integrin alpha(v)beta(3), and receptor activator of NF-kappaB (RANK) expression.
- Experimental bone metastasis model in nude mice, utilizing X-ray imaging and whole-mouse fluorescence imaging to detect skeletal metastases.
Main Results:
- ERalpha overexpression did not affect cell growth but decreased the expression of integrin alpha(v)beta(3) and RANK.
- Significant reduction in osteolytic bone metastasis incidence in mice inoculated with ERalpha-expressing MDA-MB-231 cells.
- Reduced skeletal metastasis in legs, arms, spine, and mandible of mice with ERalpha-expressing MDA-MB-435-F-L cells.
Conclusions:
- Stable reintroduction of functional ERalpha into ERalpha-negative breast cancer cells can inhibit their bone-metastatic potential.
- ERalpha may exert its inhibitory effect by downregulating key mediators of bone metastasis, such as integrin alpha(v)beta(3) and RANK.
