STAT3 Signaling Is Activated Preferentially in Tumor-Initiating Cells in Claudin-Low Models of Human Breast Cancer

Abstract

In breast cancer, a subset of tumor-initiating cells (TIC) or "cancer stem cells" are thought to be responsible for tumor maintenance, treatment resistance, and disease recurrence. While current breast cancer stem cell markers (e.g., CD44 high /CD24 low/neg , ALDH positive) have allowed enrichment for such cells, they are not universally expressed and may actually identify distinct TIC subpopulations in the same tumor. Thus, additional markers of functional stem cells are needed. The STAT3 pathway is a critical regulator of the function of normal stem cells, and evidence is accumulating for its important role in breast cancer stem cells. However, due to the lack of a method for separating live cells based on their level of STAT3 activity, it remains unknown whether STAT3 functions in the cancer stem cells themselves, or in surrounding niche cells, or in both. To approach this question, we constructed a series of lentiviral fluorescent (enhanced green fluorescent protein, EGFP) reporters that enabled flow cytometric enrichment of cells differing in STAT3-mediated transcriptional activity, as well as in vivo/in situ localization of STAT3 responsive cells. Using in vivo claudin-low cell line xenograft models of human breast cancer, we found that STAT3 signaling reporter activity (EGFP 1 ) is associated with a subpopulation of cancer cells enriched for mammosphere-forming efficiency, as well as TIC function in limiting dilution transplantation assays compared to negative or unsorted populations. Our results support STAT3 signaling activity as another functional marker for human breast cancer stem cells thus making it an attractive therapeutic target for stem-cell-directed therapy in some breast cancer subtypes.

Highly Tumorigenic Diffuse Large B Cell Lymphoma Cells Are Produced by Coculture with Stromal Cells

“…The expression of STAT3 can vary, which may partly explain why some GCB cases of DLBCL become refractory. However, contrary to previous studies, p-STAT3-bearing adherent lymphoma cells were not the most tumorigenic [42, 43]. After Notch pathway activation was perturbed by DAPT, the expression of p-STAT3 was abrogated.…”

Surgery-induced wound response promotes stem-like and tumor-initiating features of breast cancer cells,viaSTAT3 signaling

“…It has been proposed that cancer cells displaying stem-like features play a critical role in the onset of local relapse, propagation of metastasis, as well as in drug resistance. Accumulating evidences support a role for STAT3 pathway in cancer stem cell functions, particularly in breast tumor-initiating cells [9]. Despite the fact that a sizable body of evidences highlight that STAT3 is inappropriately activated in a vast percentage of breast tumors, its biological significance is controversial and its concrete role in breast cancer initiation and/or progression is not fully established [10-12].…”

Implications of Different Cancer Stem Cell Phenotypes in Breast Cancer

“…In fact, the ability of these cells to replicate in an in vitro model following at least four generations of xenograft transplanted mice has also suggested their significant role in tumor relapse and metastasis (23). Potential mechanisms of chemotherapy and radiation resistance associated with this phenotype were shown to include the presence of lower concentration of reactive oxygen species, cell dormancy, efficient DNA-repair mechanisms, overexpression of EMT markers, and activation of WNT/β-catenin, Hedgehog and NOTCH signaling pathways and signal transducer and activator of transcription 1 (STAT1) and STAT3 signaling (5,24,(25)(26)(27)(28)(29)(30). As a consequence, the CD44 + /CD24 −/low phenotype in breast cancer is currently being assessed as a therapeutic target.…”