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PLoS One. 2013 Dec 23;8(12):e82821. doi: 10.1371/journal.pone.0082821. eCollection 2013.

Evaluation of STAT3 signaling in ALDH+ and ALDH+/CD44+/CD24- subpopulations of breast cancer cells.

Author information

  • 1Divison of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People's Republic of China ; Center for Childhood Cancer, The Research Institute at Nationwide Children's Hospital, Department of Pediatrics, Columbus, Ohio, United States of America.
  • 2Center for Childhood Cancer, The Research Institute at Nationwide Children's Hospital, Department of Pediatrics, Columbus, Ohio, United States of America ; Molecular, Cellular, and Developmental Biology Program, The Ohio State University, Columbus, Ohio, United States of America.
  • 3Department of Pharmaceutical Sciences, College of Pharmacy, The University of Michigan, Ann Arbor, Michigan, United States of America.
  • 4Medical Technology Division, School of Allied Medical Professions, Columbus, Ohio, United States of America.
  • 5Divison of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People's Republic of China.
  • 6Medical Technology Division, School of Allied Medical Professions, Columbus, Ohio, United States of America ; Department of Medical Laboratory Sciences, College of Health Sciences, University of Delaware, Newark, Delaware, United States of America.
  • 7Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, Ohio, United States of America.
  • 8Department of Internal Medicine, The University of Michigan Comprehensive Cancer Center, Ann Arbor, Michigan, United States of America.

Abstract

BACKGROUND:

STAT3 activation is frequently detected in breast cancer and this pathway has emerged as an attractive molecular target for cancer treatment. Recent experimental evidence suggests ALDH-positive (ALDH(+)), or cell surface molecule CD44-positive (CD44(+)) but CD24-negative (CD24(-)) breast cancer cells have cancer stem cell properties. However, the role of STAT3 signaling in ALDH(+) and ALDH(+)/CD44(+)/CD24(-) subpopulations of breast cancer cells is unknown.

METHODS AND RESULTS:

We examined STAT3 activation in ALDH(+) and ALDH(+)/CD44(+)/CD24(-) subpopulations of breast cancer cells by sorting with flow cytometer. We observed ALDH-positive (ALDH(+)) cells expressed higher levels of phosphorylated STAT3 compared to ALDH-negative (ALDH(-)) cells. There was a significant correlation between the nuclear staining of phosphorylated STAT3 and the expression of ALDH1 in breast cancer tissues. These results suggest that STAT3 is activated in ALDH(+) subpopulations of breast cancer cells. STAT3 inhibitors Stattic and LLL12 inhibited STAT3 phosphorylation, reduced the ALDH(+) subpopulation, inhibited breast cancer stem-like cell viability, and retarded tumorisphere-forming capacity in vitro. Similar inhibition of STAT3 phosphorylation, and breast cancer stem cell viability were observed using STAT3 ShRNA. In addition, LLL12 inhibited STAT3 downstream target gene expression and induced apoptosis in ALDH(+) subpopulations of breast cancer cells. Furthermore, LLL12 inhibited STAT3 phosphorylation and tumor cell proliferation, induced apoptosis, and suppressed tumor growth in xenograft and mammary fat pad mouse models from ALDH(+) breast cancer cells. Similar in vitro and tumor growth in vivo results were obtained when ALDH(+) cells were further selected for the stem cell markers CD44(+) and CD24(-).

CONCLUSION:

These studies demonstrate an important role for STAT3 signaling in ALDH(+) and ALDH(+)/CD44(+)/CD24(-) subpopulations of breast cancer cells which may have cancer stem cell properties and suggest that pharmacologic inhibition of STAT3 represents an effective strategy to selectively target the cancer stem cell-like subpopulation.

PMID:
24376586
[PubMed - in process]
PMCID:
PMC3871589
Free PMC Article
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