title: Metformin enhances tamoxifen-mediated tumor growth inhibition in ER-positive breast carcinoma.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.forename: Ji
authors.initials: J
authors.lastname: Ma
authors.forename: Yan
authors.initials: Y
authors.lastname: Guo
authors.forename: Suning
authors.initials: S
authors.lastname: Chen
authors.forename: Cuiping
authors.initials: C
authors.lastname: Zhong
authors.forename: Yan
authors.initials: Y
authors.lastname: Xue
authors.forename: Yuan
authors.initials: Y
authors.lastname: Zhang
authors.forename: Xiaofeng
authors.initials: X
authors.lastname: Lai
authors.forename: Yifang
authors.initials: Y
authors.lastname: Wei
authors.forename: Shentong
authors.initials: S
authors.lastname: Yu
authors.affiliation: The State Key Laboratory of Cancer Biology and Department of Oncology, Xijing Hospital, The Fourth Military Medical University, Xi'an 710032, China. biozhangj@hotmail.com.
authors.forename: Jian
authors.initials: J
authors.lastname: Zhang
authors.forename: Wenchao
authors.initials: W
authors.lastname: Liu
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D006801:Humans; D061986:MCF-7 Cells; D008325:Mammary Neoplasms, Experimental; D008687:Metformin / Q000494:pharmacology*; D051379:Mice; D008819:Mice, Nude; D011960:Receptors, Estrogen / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013629:Tamoxifen / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D011960:Receptors, Estrogen; D013629:Tamoxifen; D008687:Metformin