OR16-2 Leptin Signaling Is Necessary For Stem Cell And Metastatic Behaviors In Breast Cancer

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: OR16-Cancers of Endocrine Organs: Mechanisms of Tumorigenesis & Progression
Sunday, June 16, 2013: 11:15 AM-12:45 PM
Presentation Start Time: 11:30 AM
Room 206 (Moscone Center)
Ofer Reizes, Qiao Zheng*, Anita Hjlemeland and Justin D Lathia
Cleveland Clinic Foundation, Cleveland, OH
Breast cancer is the most common noncutaneous cancer in US women, and while early detection and therapeutic advances have improved outcome, nearly 25% of diagnosed patients go on to develop secondary tumors at either primary or distant sites. These secondary tumors are the cause of the poor outcomes and reduced survival. Obesity is an established breast cancer risk factor in postmenopausal women, and leads to poorer breast cancer outcomes in both pre- and postmenopausal women. An estimated 20% of cancer deaths in US women have been attributed to obesity. Our findings reveal new insights on the obesity-breast cancer link focusing on the role of adipose cytokine leptin.

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

*Please take note of The Endocrine Society's News Embargo Policy at http://www.endo-society.org/endo2013/media.cfm

Sources of Research Support: Case Comprehensive Cancer Center Stem Cell Pilot grant; Case Comprehensive Cancer Center Special Funds in Aging Cancer Energy Balance Research (P30 CA043703); American Cancer Society Pilot Funds (Grant #IRG-91-022-15); and Case Western Reserve University/Cleveland Clinic CTSA UL1RR024989 to OR.