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STAT3 activation by leptin receptor is essential for TNBC stem cell maintenance
- Source :
- Endocrine-Related Cancer. 24:415-426
- Publication Year :
- 2017
- Publisher :
- Bioscientifica, 2017.
-
Abstract
- Leptin (LEP) binds to the long form of the leptin receptor (LEPRb), leading to the activation of multiple signaling pathways that are potential targets for disrupting the obesity–breast cancer link. In triple-negative breast cancer (TNBC), LEP is hypothesized to predominantly mediate its tumorigenic effects via a subpopulation of LEPRb-positive tumor cells termed cancer stem cells (CSCs) that can initiate tumors and induce tumor progression. Previously, we showed that LEP promotes CSC survival in vivo. Moreover, silencing LEPRb in TNBC cells compromised the CSC state. The mechanisms by which LEPRb regulates TNBC CSC intracellular signaling are not clear. We hypothesized that activation of LEPRb signaling is sufficient to drive CSC maintenance in TNBC. Here, we show that activation of LEPRb in non-CSCs isolated using our CSC reporter system resulted in a transition to the stem cell state. In CSCs, LEP induced STAT3 phosphorylation, whereas LEP did not induce STAT3 phosphorylation in non-CSCs. Introduction of constitutively active STAT3 into LEPRb-transfected non-CSCs significantly induced NANOG, SOX2 and OCT4 expression compared with control non-CSCs. To determine the intracellular phospho-tyrosine residue of LEPRb that is necessary for the induction of the stem cell state in non-CSCs, we transfected the tyrosine residue point mutants L985, F1077 and S1138 into non-CSCs. Non-CSCs transfected with the L985 mutant exhibited increased STAT3 phosphorylation, increased SOCS3 expression and an induction of GFP expression compared with non-CSCs expressing the F1077 and S1138 mutants. Our data demonstrate that LEPRb-induced STAT3 activation is essential for the induction and maintenance of TNBC CSCs.
- Subjects :
- STAT3 Transcription Factor
0301 basic medicine
Homeobox protein NANOG
Cancer Research
Endocrinology, Diabetes and Metabolism
Triple Negative Breast Neoplasms
Article
03 medical and health sciences
0302 clinical medicine
Endocrinology
SOX2
Cancer stem cell
Cell Line, Tumor
Humans
Gene Silencing
SOCS3
Phosphorylation
Promoter Regions, Genetic
Leptin receptor
Chemistry
Nanog Homeobox Protein
Cell biology
030104 developmental biology
Oncology
030220 oncology & carcinogenesis
Neoplastic Stem Cells
Receptors, Leptin
Signal transduction
Stem cell
Signal Transduction
Subjects
Details
- ISSN :
- 14796821 and 13510088
- Volume :
- 24
- Database :
- OpenAIRE
- Journal :
- Endocrine-Related Cancer
- Accession number :
- edsair.doi.dedup.....9ae3e51966d39ca7870919c88d09890b