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

Li Lin, Brian Hutzen, Hsiu Fang Lee, Zhengang Peng, Wenlong Wang, Chongqiang Zhao, Huey Jen Lin, Duxin Sun, Pui Kai Li, Chenglong Li, Hasan Korkaya, Max S. Wicha, Jiayuh Lin

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Article numbere82821
JournalPloS one
Volume8
Issue number12
DOIs
StatePublished - Feb 23 2013
Externally publishedYes

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breast neoplasms
Cells
Breast Neoplasms
Stem cells
Neoplastic Stem Cells
Phosphorylation
stem cells
Tumors
phosphorylation
Chemical activation
Apoptosis
Neoplasms
Cell Survival
neoplasms
cell viability
Oncology
neoplasm cells
Cell proliferation
apoptosis
Sorting

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Lin, L., Hutzen, B., Lee, H. F., Peng, Z., Wang, W., Zhao, C., ... Lin, J. (2013). Evaluation of STAT3 signaling in ALDH+ and ALDH+/CD44+/CD24- subpopulations of breast cancer cells. PloS one, 8(12), [e82821]. https://doi.org/10.1371/journal.pone.0082821

Evaluation of STAT3 signaling in ALDH+ and ALDH+/CD44+/CD24- subpopulations of breast cancer cells. / Lin, Li; Hutzen, Brian; Lee, Hsiu Fang; Peng, Zhengang; Wang, Wenlong; Zhao, Chongqiang; Lin, Huey Jen; Sun, Duxin; Li, Pui Kai; Li, Chenglong; Korkaya, Hasan; Wicha, Max S.; Lin, Jiayuh.

In: PloS one, Vol. 8, No. 12, e82821, 23.02.2013.

Research output: Contribution to journalArticle

Lin, L, Hutzen, B, Lee, HF, Peng, Z, Wang, W, Zhao, C, Lin, HJ, Sun, D, Li, PK, Li, C, Korkaya, H, Wicha, MS & Lin, J 2013, 'Evaluation of STAT3 signaling in ALDH+ and ALDH+/CD44+/CD24- subpopulations of breast cancer cells', PloS one, vol. 8, no. 12, e82821. https://doi.org/10.1371/journal.pone.0082821
Lin, Li ; Hutzen, Brian ; Lee, Hsiu Fang ; Peng, Zhengang ; Wang, Wenlong ; Zhao, Chongqiang ; Lin, Huey Jen ; Sun, Duxin ; Li, Pui Kai ; Li, Chenglong ; Korkaya, Hasan ; Wicha, Max S. ; Lin, Jiayuh. / Evaluation of STAT3 signaling in ALDH+ and ALDH+/CD44+/CD24- subpopulations of breast cancer cells. In: PloS one. 2013 ; Vol. 8, No. 12.
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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.",
author = "Li Lin and Brian Hutzen and Lee, {Hsiu Fang} and Zhengang Peng and Wenlong Wang and Chongqiang Zhao and Lin, {Huey Jen} and Duxin Sun and Li, {Pui Kai} and Chenglong Li and Hasan Korkaya and Wicha, {Max S.} and Jiayuh Lin",
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AU - Peng, Zhengang

AU - Wang, Wenlong

AU - Zhao, Chongqiang

AU - Lin, Huey Jen

AU - Sun, Duxin

AU - Li, Pui Kai

AU - Li, Chenglong

AU - Korkaya, Hasan

AU - Wicha, Max S.

AU - Lin, Jiayuh

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N2 - 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.

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