Abstract
BackgroundSTAT3 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 ResultsWe 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−.ConclusionThese 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.
Highlights
A large number of chemotherapeutic agents have been developed which are capable of producing regression of metastatic breast cancers, these tumors usually recur following chemotherapy treatment
These studies demonstrate an important role for STAT3 signaling in ALDH+ and ALDH+/CD44+/CD242 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
Expresses High Levels of STAT3 Phosphorylation To determine the expression of the activated P-STAT3 in breast cancer stem cells, we separated the ALDH+ and ALDH2 subpopulations of three breast cancer cell lines, MDA-MB-231, SUM159, SK-BR-3 and determined the level of P-STAT3 by Western blot
Summary
A large number of chemotherapeutic agents have been developed which are capable of producing regression of metastatic breast cancers, these tumors usually recur following chemotherapy treatment. Cancer stem cells have self-renewal capacity, which drives tumorigenicity, recurrence, and metastasis. They have the capability to differentiate, albeit aberrantly, giving rise to a heterogeneous subpopulation of constituting the tumor bulk. Recent experimental evidence suggests the existence of a small population of tumorigenic stem/progenitor cells responsible for breast tumor initiation, resistance to chemotherapy and radiation, invasion and metastasis [3,4,5]. ALDHpositive (ALDH+) breast cancer cells display cancer stem cells properties both in vitro and in vivo, including tumorsphere-forming capacity in anchorage-independent conditions, self-renewal, increased invasiveness, tumor-generating capacity, and metastatic potential [4,5,6]. Recent experimental evidence suggests ALDH-positive (ALDH+), or cell surface molecule CD44-positive (CD44+) but CD24-negative (CD242) breast cancer cells have cancer stem cell properties. The role of STAT3 signaling in ALDH+ and ALDH+/CD44+/CD242 subpopulations of breast cancer cells is unknown
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