Session: OR16-Cancers of Endocrine Organs: Mechanisms of Tumorigenesis & Progression
Room 206 (Moscone Center)
We previously reported that leptin, increased in obesity, promotes the survival of Cancer Stem Cells (CSCs) in vivo. Cancer Stem Cells (CSCs) sit at the apex and are thought to establish a hierarchy that gives rise to the cellular heterogeneity within the tumor but more importantly these cells are associated with chemotherapeutic resistance and metastasis. Here we will report that the Leptin Receptor (LEPR) expressed in mouse and human mammary cancer cells is necessary for maintaining a CSC-like state in cancer cells including self-renewal and metastatic characteristics. We focused on mammary cancer cells that exhibit mesenchymal and stem cell behaviors. Silencing of LEPR expression, via shRNA, leads to near complete inhibition of the stem cell transcription factor NANOG, a master regulator of self-renewal. The LEPR-NANOG signaling pathway is conserved across species as the mouse LepR can rescue NANOG expression in human LEPR-silenced breast cancer cells. We determined that LEPR and NANOG are coexpressed in subpopulation of breast cancer cells and LEPR marks the self-renewing stem cell population. Moreover, silencing LEPR results in reduced proliferation, self-renewal in tumorsphere assays, and tumor outgrowth in transplant studies. Finally, LEPR silenced mesenchymal breast cancer exhibit an epithelial morphology and express epithelial genes including the tight junction proteins ZO-1 and ZO-2 as well as the cell adhesion protein E-cadherin. Given the emergence of NANOG as a potent pro-carcinogenic protein in multiple cancers, these studies indicate that inhibition of LEPR may be a promising therapeutic to inhibit NANOG, compromising CSC survival and metastasis.
Nothing to Disclose: OR, QZ, AH, JDL
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