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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.

Evaluation of STAT3 Signaling in ALDH+ and ALDH+/CD44+/CD24− Subpopulations of Breast Cancer Cells