Estrogen receptor α signaling regulates breast tumor-initiating cells by down-regulating miR-140 which targets the transcription factor SOX2.

Publication Type:


J Biol Chem, Volume 287, Issue 49, p.41514-22 (2012)


Breast Neoplasms, Cell Line, Tumor, Cell Survival, Down-Regulation, Estrogen Receptor alpha, Gene Expression Regulation, Neoplastic, HEK293 Cells, Humans, MicroRNAs, Neoplastic Stem Cells, Promoter Regions, Genetic, Signal Transduction, SOXB1 Transcription Factors, Tumor Markers, Biological


<p>Several reports have indicated that miR-140, a possible tumor suppressor microRNA (miR), is down-regulated in breast tumors compared with normal breast tissues. However, the role of miR-140 in breast tumorigenesis is unclear. We initiated studies that examined estrogen receptor α (ERα) signaling in the tissue-specific regulation of miR-140 in breast cancer. We found that estrogen stimulation of ERα-positive breast cancer cells resulted in decreased miR-140 expression. We performed promoter analyses and examined predicted ERα binding elements in the miR-140 promoter using luciferase constructs of a miR-140 promoter deletion series. Our studies revealed that ERα binds to one specific estrogen response element flanking the miR-140 promoter and consequently suppresses miR-140 transcription. We found that the stem cell self-renewal regulator SOX2 is a novel target of miR-140, and that this miR-140/SOX2 pathway critically regulates breast tumor-initiating cell survival, providing a new link between ERα signaling and breast cancer stem cell maintenance.</p>