PMID- 24322659
OWN - NLM
STAT- MEDLINE
DCOM- 20141010
LR  - 20211021
IS  - 1940-6215 (Electronic)
IS  - 1940-6207 (Print)
IS  - 1940-6215 (Linking)
VI  - 7
IP  - 2
DP  - 2014 Feb
TI  - Metformin selectively targets tumor-initiating cells in ErbB2-overexpressing 
      breast cancer models.
PG  - 199-210
LID - 10.1158/1940-6207.CAPR-13-0181 [doi]
AB  - Metformin is an oral biguanide used for type II diabetes. Epidemiologic studies 
      suggest a link between metformin use and reduced risk of breast and other types 
      of cancers. ErbB2-expressing breast cancer is a subgroup of tumors with poor 
      prognosis. Previous studies demonstrated that metformin is a potent inhibitor of 
      ErbB2-overexpressing breast cancer cells; metformin treatment extends the life 
      span and impedes mammary tumor development in ErbB2 transgenic mice in vivo. 
      However, the mechanisms of metformin associated antitumor activity, especially in 
      prevention models, remain unclear. We report here for the first time that 
      systemic administration of metformin selectively inhibits CD61(high)/CD49f(high) 
      subpopulation, a group of tumor-initiating cells (TIC) of mouse mammary tumor 
      virus (MMTV)-ErbB2 mammary tumors, in preneoplastic mammary glands. Metformin 
      also inhibited CD61(high)/CD49f(high) subpopulation in MMTV-ErbB2 tumor-derived 
      cells, which was correlated with their compromised tumor initiation/development 
      in a syngeneic tumor graft model. Molecular analysis indicated that metformin 
      induced downregulation of ErbB2 and EGFR expression and inhibited the 
      phosphorylation of ErbB family members, insulin-like growth factor-1R, AKT, mTOR, 
      and STAT3 in vivo. In vitro data indicate that low doses of metformin inhibited 
      the self-renewal/proliferation of cancer stem cells (CSC)/TICs in 
      ErbB2-overexpressing breast cancer cells. We further demonstrated that the 
      expression and activation of ErbB2 were preferentially increased in 
      CSC/TIC-enriched tumorsphere cells, which promoted their 
      self-renewal/proliferation and rendered them more sensitive to metformin. Our 
      results, especially the in vivo data, provide fundamental support for developing 
      metformin-mediated preventive strategies targeting ErbB2-associated 
      carcinogenesis.
FAU - Zhu, Pei
AU  - Zhu P
AD  - Julius L. Chambers Biomedical/Biotechnology Research Institute, North Carolina 
      Central University, North Carolina Research Campus, 500 Laureate Way, Room 4301, 
      Kannapolis, NC 28081. xyang@nccu.edu.
FAU - Davis, Meghan
AU  - Davis M
FAU - Blackwelder, Amanda J
AU  - Blackwelder AJ
FAU - Bachman, Nora
AU  - Bachman N
FAU - Liu, Bolin
AU  - Liu B
FAU - Edgerton, Susan
AU  - Edgerton S
FAU - Williams, Leonard L
AU  - Williams LL
FAU - Thor, Ann D
AU  - Thor AD
FAU - Yang, Xiaohe
AU  - Yang X
LA  - eng
GR  - U54 AA019765/AA/NIAAA NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20131209
PL  - United States
TA  - Cancer Prev Res (Phila)
JT  - Cancer prevention research (Philadelphia, Pa.)
JID - 101479409
RN  - 0 (Integrin alpha6)
RN  - 0 (Integrin beta3)
RN  - 9100L32L2N (Metformin)
SB  - IM
MH  - Animals
MH  - Cells, Cultured
MH  - Female
MH  - Gene Expression Regulation, Neoplastic
MH  - *Genes, erbB-2
MH  - Humans
MH  - Integrin alpha6/metabolism
MH  - Integrin beta3/metabolism
MH  - Mammary Neoplasms, Experimental/*genetics/*pathology
MH  - Metformin/*pharmacology
MH  - Mice
MH  - Mice, Transgenic
MH  - Neoplastic Stem Cells/*drug effects/metabolism/pathology
MH  - Organ Specificity/drug effects
PMC - PMC4497590
MID - NIHMS610694
COIS- Disclosure of Potential Conflicts of Interest No potential conflicts of interest 
      were disclosed.
EDAT- 2013/12/11 06:00
MHDA- 2014/10/11 06:00
PMCR- 2015/07/09
CRDT- 2013/12/11 06:00
PHST- 2013/12/11 06:00 [entrez]
PHST- 2013/12/11 06:00 [pubmed]
PHST- 2014/10/11 06:00 [medline]
PHST- 2015/07/09 00:00 [pmc-release]
AID - 1940-6207.CAPR-13-0181 [pii]
AID - 10.1158/1940-6207.CAPR-13-0181 [doi]
PST - ppublish
SO  - Cancer Prev Res (Phila). 2014 Feb;7(2):199-210. doi: 
      10.1158/1940-6207.CAPR-13-0181. Epub 2013 Dec 9.