Abstract 1509: Leptin drives mammary stem cell self-renewal via the mTOR pathway

Abstract

Abstract Normal tissue stem cells exist in either a quiescent or proliferating/self-renewing phenotypic state with different patterns of gene expression. In the breast, the CD44+/CD24− cells are retained in a quiescent state, while the ALDH+ stem cells are actively self-renewing cells; the quiescent CD44+/CD24− cells must transition through a self-renewing ALDH+ state in order to differentiate into mature mammary cells. The adipose-rich stroma that makes up the stem cell niche in the human breast is a source of leptin that may alter stem cell phenotype in a paracrine manner. A larger population of proliferating breast stem cells could, in turn, increase the risk of breast cancer. We previously demonstrated that the increased local leptin/adiponectin ratio that commonly occurs in breast tissue of obese women promotes increased breast stem cell self-renewal leading to a larger population of stem cells in vivo, and that the mTOR pathway is activated in normal human mammary stem cells by physiologic concentrations of adipokines, including leptin. There was a physiologic dose response, with a measurable increase in mTOR activity over baseline with 31.25 ng/ml leptin, and a near maximal effect with 125 ng/ml. Here, we isolated the quiescent and proliferating stem cell fractions from human reduction mammoplasty samples and measured basal mTOR activity by ELISA for phosphorylated S6 ribosomal protein (pS6/tS6 ratio), which was greater in the proliferating ALDH+ cells. The quiescent stem cell fraction was treated with physiologic concentrations of leptin prior to resorting with FACS to measure a transition from a CD44+/CD24− to an ALDH+ proliferating phenotype. Parallel quiescent stem cells treated with the mTOR inhibitor everolimus simultaneously with leptin demonstrated that mTOR activity is necessary for this phenotypic switch. If inflammatory adipokines promote stem cell symmetric self-renewal by activating mTOR, targeted interventions may maintain potential tumor-initiating cells in a quiescent state and reduce cancer incidence. Citation Format: Ray Esper, Michael Dame, Shannon McClintock, Becky Simon, Max Wicha, Dean Brenner. Leptin drives mammary stem cell self-renewal via the mTOR pathway. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1509. doi:10.1158/1538-7445.AM2015-1509