STAT3 activation in HER2-overexpressing breast cancer promotes epithelial-mesenchymal transition and cancer stem cell traits

Abstract

Clinically, HER2 proto-oncogene amplification is found in about 25–30% of human breast cancers, where it is correlated to a poor prognosis. Constitutive STAT3 activation is found in about 50–60% of the breast tumors and associated with tumorigenesis and drug resistance. In this study, we showed that STAT3 was phosphorylated in HER2-overexpressing, ER-positive human breast tumors and, furthermore, phosphorylated STAT3 promoted the stem-like cell phenotype. We examined the dysregulation of the stem cell markers (Oct-4, Sox-2 and CD44) and the tumorsphere formation in HER2-overexpressing human breast cancer cell lines. We demonstrated that the STAT3 inhibitor, Stattic, treatment abolished the cancer stem cell phenotype in HER2-positive breast cancers. Combined treatment of Herceptin and Stattic showed the synergistic effect on the cancer cell growth in vitro. In addition, when the STAT3 gene was knocked down, the expression of the stem cell markers Oct-4, Sox-2 and CD44 were downregulated and tumorsphere formation was abolished. HER2-elicited STAT3 signaling may provide a potential model for drug resistance induced by stem-like cell characteristics. This mechanism may be responsible for acquiring resistance to Herceptin in the treatment of HER2-overexpressing breast tumors. Based on our findings, targeting pSTAT3 could overcome Herceptin-induced resistance in HER2-overexpressing breast tumors.

Inhibition of the autocrine IL-6–JAK2–STAT3–calprotectin axis as targeted therapy for HR−/HER2+breast cancers

“…7G). Remarkably, the link between HER2, STAT3, and stem cell-like cells has also been described in HR + breast cancers, which could explain this effect (Marotta et al 2011;Chung et al 2014). Overall, the studies described here unveil the IL-6-JAK2-STAT3-calprotectin cascade as an Achilles' heel of HR − /HER2 + tumors.…”

“…It will be important to dissect the signaling pathways that connect S100A8/9 with AKT, as additional therapeutic alternatives may emerge. An additional consideration regarding the sensitivity of HR − /HER2 + cells is that STAT3 has been found activated in stem cell-like breast cancer cells, and its inhibition was shown to reduce their viability (Marotta et al 2011;Chung et al 2014). Thus, the anti-tumor response observed may also be a reflex of the inhibition of the stem cells inside HR − /HER2 + cancers.…”

Approaching non-canonical STAT3 signaling to redefine cancer therapeutic strategy

“…Her2 overexpression increases STAT3 phosphorylation and expression of stem cell markers like Oct-4, Sox-2 and CD44. Knockdown of STAT3 in Her2 overexpressing cells not only decreased the expression of stem cell markers but also diminished the tumor sphere formation ability indicating Her2-STAT3 signaling as a potential mechanism of drug resistance [56,57]. Studies based on tumor samples as well as in cell line models have identified different STAT3 target genes involved in cancer progression.…”

Targeting Cellular Signaling Pathways in Breast Cancer Stem Cells and its Implication for Cancer Treatment

“…They showed that the expression of these markers was down-regulated and spheroid formation was abolished after STAT3 inhibition by stattic. Moreover, they showed that combined treatment of Herceptin with stattic led to a higher rate of apoptosis than the separate treatments and this may help overcome the resistance derived from the enriched of cancer stem cells in breast tumors (103).…”