Background:
Metformin has been reported to inhibit the growth of various types of
cancers, including
breast cancer. Yet the mechanisms underlying the anticancer effects of
metformin are not fully understood. Growing evidence suggests that
metformin's anticancer effects are mediated at least in part by modulating
microRNAs, including miR-200c, which has a
tumor suppressive role in
breast cancer. We hypothesized that miR-200c has a role in the antitumorigenic effects of
metformin on
breast cancer cells. Methods: To delineate the role of miR-200c in the effects of
metformin on
breast cancer, plasmids containing pre-miR-200c or miR-200c inhibitor were transfected into
breast cancer cell lines. The MDA-MB-231, BT549, MCF-7, and T-47-D cells' proliferation, apoptosis, migration, and invasion were assessed. The antitumor role of
metformin in vivo was investigated in a MDA-MB-231 xenograft
tumor model in SCID mice. Results:
Metformin significantly inhibited the growth, migration, and invasion of
breast cancer cells, and induced their apoptosis; these effects were dependent on both dose and time.
Metformin also suppressed MDA-MB-231
tumor growth in SCID mice in vivo.
Metformin treatment was associated with increased miR-200c expression and decreased c-Myc and AKT2
protein expression in both
breast cancer cells and
tumor tissues. Overexpression of miR-200c exhibited effects on
breast cancer cells similar to those of
metformin treatment. In contrast, inhibiting the expression of miR-200c increased the growth, migration, and invasion of MCF-7 and MDA-MB-231 cells. Conclusion:
Metformin inhibits the growth and invasiveness of
breast cancer cells by upregulation of miR-200c expression by targeting AKT2. These findings provide novel insight into the molecular functions of
metformin that suggest its potential as an
anticancer agent.