Metformin enhances tamoxifen-mediated tumor growth inhibition in ER-positive breast carcinoma
- Equal contributors
1 The State Key Laboratory of Cancer Biology and Department of Oncology, Xijing Hospital, The Fourth Military Medical University, Xi’an 710032, China
2 The State Key Laboratory of Cancer Biology and Department of Biochemistry and Molecular Biology, Xijing Hospital, The Fourth Military Medical University, Xi’an 710032, China
3 Department of Breast Surgery, Lanzhou General Hospital of PLA, Lanzhou 730000, China
4 Department of Pharmacy, Xijing Hospital, The Fourth Military Medical University, Xi’an 710032, China
5 Department of Ear Nose Throat Surgery, Lanzhou General Hospital of PLA, Lanzhou 730000, China
BMC Cancer 2014, 14:172 doi:10.1186/1471-2407-14-172Published: 11 March 2014
Tamoxifen, an endocrine therapy drug used to treat breast cancer, is designed to interrupt estrogen signaling by blocking the estrogen receptor (ER). However, many ER-positive patients are low reactive or resistant to tamoxifen. Metformin is a widely used anti-diabetic drug with noteworthy anti-cancer effects. We investigated whether metformin has the additive effects with tamoxifen in ER-positive breast cancer therapy.
The efficacy of metformin alone and in combination with tamoxifen against ER-positive breast cancer was analyzed by cell survival, DNA replication activity, plate colony formation, soft-agar, flow cytometry, immunohistochemistry, and nude mice model assays. The involved signaling pathways were detected by western blot assay.
When metformin was combined with tamoxifen, the concentration of tamoxifen required for growth inhibition was substantially reduced. Moreover, metformin enhanced tamoxifen-mediated inhibition of proliferation, DNA replication activity, colony formation, soft-agar colony formation, and induction of apoptosis in ER-positive breast cancer cells. In addition, these tamoxifen-induced effects that were enhanced by metformin may be involved in the bax/bcl-2 apoptotic pathway and the AMPK/mTOR/p70S6 growth pathway. Finally, two-drug combination therapy significantly inhibited tumor growth in vivo.
The present work shows that metformin and tamoxifen additively inhibited the growth and augmented the apoptosis of ER-positive breast cancer cells. It provides leads for future research on this drug combination for the treatment of ER-positive breast cancer.