BackgroundAlthough long-term estrogen (E2) exposure is associated with increased breast cancer (BC) risk, and E2 appears to sustain growth of BC cells that express functional estrogen receptors (ERs), its role in promoting BC stem cells (CSCs) remains unclear. Considering that Gli1, part of the Sonic hedgehog (Shh) developmental pathway, has been shown to mediate CSCs, we investigated whether E2 and Gli1 could promote CSCs and epithelial-mesenchymal transition (EMT) in ER+ BC cell lines.MethodsWe knocked down Gli1 in several BC cells using a doxycycline-controlled vector, and compared Gli1-knockdown cells and Gli1+ cells in behavior and expression of ER, Gli1, ALDH1 (BC-CSC marker), Shh, Ptch1 (Shh receptor) and SOX2, Nanog and Bmi-1 (CSC-associated transcriptions factors), using PCR; tissue microarrays, western blot; chromatin immunoprecipitation q-PCR, confocal immunofluorescence microscopy; fluorescence-activated cell sorting; annexin–flow cytometry (for apoptosis); mammosphere culture; and colony formation, immunohistochemistry, Matrigel and wound-scratch assays.ResultsBoth mRNA and protein expressions of ER correlated with those of Gli1 and ALDH1. E2 induced Gli1 expression only in ER+ BC cells. E2 promoted CSC renewal, invasiveness and EMT in ER+/Gli1+ cells but not in Gli1-knockdown cells.ConclusionsOur results indicate that estrogen acts via Gli1 to promote CSC development and EMT in ER+ BC cells. These findings also imply that Gli1 mediates cancer stem cells, and thus could be a target of a novel treatment for ER+ breast cancer.

3 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018;48:916-926.

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Angiogenesis is the development of new blood vessels, which is required for tumor growth and metastasis. Signal transducer and activator of transcription factor 3 (STAT3) is a transcription factor that regulates a variety of cellular events including proliferation, differentiation and apoptosis. Previous studies revealed that activation of STAT3 promotes tumor angiogenesis. In this review, we described the activities of STAT3 signaling in different cell types involved in angiogenesis. Particularly, we elucidated the molecular mechanisms of STAT3-mediated gene regulation in angiogenic endothelial cells in response to external stimulations such as hypoxia and inflammation. The potential for STAT3 as a therapeutic target was also discussed. Overall, this review provides mechanistic insights for the roles of STAT3 signaling in tumor angiogenesis.