Mouse Models to Study Leptin in Breast Cancer Stem Cells

Abstract

Leptin is a hormone originally identified as the gene mutated in the obese mouse and its receptor (LEPR) was identified as the gene mutated in the diabetic mouse. Both the obese and diabetic mice exhibit early onset obesity and have been extensively studied to delineate mechanisms of obesity and associated morbidities. Leptin/LEPR signaling regulate body fat via activation of brain pathways and deficiency in either gene is sufficient to induce obesity. Leptin/LEPR represent members of the druggable genome and over the past decade have been proposed as a link between obesity and breast cancer with studies focused on disrupting this pathway to inhibit breast cancer progression. This chapter reviews the roles of leptin and LEPR in breast cancer with a focus on tumor initiating or cancer stem cells (CSCs) in tumor progression. CSCs are cancer cells that exhibit resistance to chemo- and radio-therapy and are associated with recurrence and metastasis. Recently, leptin/LEPR have been shown to be necessary for survival of breast CSCs via induction in expression of the embryonic stem cell transcription factors NANOG, SOX2, and OCT4. These transcription factors are necessary for maintaining CSC self-renewal and pluripotency. Emerging studies strongly suggest that targeting CSC survival could inhibit cancer progression. The review will provide evidence for leptin/LEPR as a therapeutic target for inhibition of breast cancer progression and explore the mouse models to study this process.KeywordsLeptin receptorCancer stem cellsTranscription factorsNANOGSOX 2OCT 4Janus kinaseSignal transduction and activator of transcriptionob/ob obese micedb/db diabetic mice