title: A positive cross-regulation of HER2 and ER-α36 controls ALDH1 positive breast cancer cells.
abstract: Accumulating evidence supports the theory that breast cancer arises from a subpopulation of mammary stem/progenitor cell which posses the ability to self-renew. However, the involvement of estrogen signaling in regulation of breast cancer stem/progenitor cells has not been fully established, mainly because expression and function of ER-α in breast cancer stem cells remains controversial. Previously, our laboratory cloned a variant of ER-α, ER-α36, and found that ER-α36-mediated non-genomic estrogen signaling plays an important role in malignant growth of triple-negative breast cancer cells. In this study, we found that ER-α36 was highly expressed in ER-negative breast cancer SK-BR-3 cells and mediated non-genomic estrogen signaling such as activation of the MAPK/ERK signaling in these cells. Knock-down of ER-α36 expression in these cells using the shRNA method diminished their responsiveness to estrogen and significantly down-regulated HER2 expression. HER2 signaling activated ER-α36 transcription through an AP1 site in the ER-α36 promoter and ER-α36 physically interacted with HER2. We also found that ER-α36 is highly expressed in a subset of SK-BR-3 cells that was positive for ALDH1, a breast cancer stem cell marker, and knock-down of ER-α36 expression reduced the population of ALDH1 positive cells. Our results thus demonstrated that ER-α36 positively regulates HER2 expression and the population of ALDH1 positive breast cancer cells, and suggested that non-genomic estrogen signaling mediated by ER-α36 is involved in maintenance and regulation of breast cancer stem cells.
authors: Department of Medical Microbiology and Immunology, Creighton University Medical School, 2500 California Plaza, Omaha, NE 68178, USA.
authors: Lianguo
authors: L
authors: Kang
authors: Yuming
authors: Y
authors: Guo
authors: Xintian
authors: X
authors: Zhang
authors: Jun
authors: J
authors: Meng
authors: Zhao-Yi
authors: ZY
authors: Wang
mesh_terms: D000080924:Aldehyde Dehydrogenase 1 Family; D001483:Base Sequence; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D017931:DNA Primers; D047628:Estrogen Receptor alpha / Q000502:physiology*; D004967:Estrogens / Q000378:metabolism; D005260:Female; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D016133:Polymerase Chain Reaction; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000502:physiology*; D050697:Retinal Dehydrogenase / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D000080924:Aldehyde Dehydrogenase 1 Family; D017931:DNA Primers; D047628:Estrogen Receptor alpha; D004967:Estrogens; D007527:Isoenzymes; D018719:Erb-b2 Receptor Tyrosine Kinases; D050697:Retinal Dehydrogenase; C510223:ALDH1A1 protein, human