Estrogen receptor signaling mediates leptin-induced growth of breast cancer cells via autophagy induction.

Pawan Kumar Raut,Pil-Hoon Park,Jee Heon Jeong,Dong Young Choi,Sang Hyun Kim,Jin Tae Hong,Taeg Kyu Kwon

doi:10.18632/oncotarget.22684

Abstract

Leptin, a hormone derived from adipose tissue, promotes growth of cancer cells via multiple mechanisms. Estrogen receptor signaling is also known to stimulate the growth of breast cancer cells. However, the involvement of estrogen receptor signaling in the oncogenic actions of leptin and its underlying mechanisms are not clearly understood. Herein, we investigated mechanisms for estrogen receptor signaling-mediated growth of breast cancer cells, particularly focusing on autophagy, which plays a crucial role in leptin-induced tumor growth. Inhibition of estrogen receptor signaling via gene silencing or treatment with a pharmacological inhibitor (tamoxifen) abolished leptin-induced growth of MCF-7 human breast cancer cells. Interestingly, leptin-induced autophagy activation, determined by up-regulation of autophagy-related genes and autophagosome formation, was also significantly suppressed by inhibiting estrogen receptor signaling. Moreover, inhibition of estrogen receptor markedly prevented leptin-induced activation of AMPK/FoxO3A axis, which plays a crucial role in autophagy induction. Leptin-induced cell cycle progression and Bax down-regulation were also prevented by treatment with tamoxifen. The pivotal roles of estrogen receptor signaling in leptin-induced cell cycle progression, apoptosis suppression, and autophagy induction were further confirmed in MCF-7 tumor xenograft model. Taken together, these results demonstrate that estrogen receptor signaling plays a key role in leptin-induced growth of breast cancer cells via autophagy activation.

Highlights

Leptin, a hormone primarily produced by adipose tissue, has been well known to modulate appetite and regulate energy balance through binding with its receptors localized in the hypothalamus [1, 2]
We investigated the molecular mechanisms underlying leptin-induced growth of breast cancer cells, with focus on the role of estrogen receptor (ER) signaling in relation to autophagy induction
Leptin-induced growth of breast cancer cells is mediated via estrogen receptor signaling

Summary

Introduction

A hormone primarily produced by adipose tissue, has been well known to modulate appetite and regulate energy balance through binding with its receptors localized in the hypothalamus [1, 2]. In addition to its critical role in the maintenance of energy homeostasis, there is a growing appreciation that leptin signaling is implicated in the wide spectrum of physiological functions. Leptin administration reverses alcoholinduced lipid accumulation in liver, and leptin deficiency www.impactjournals.com/oncotarget contributes to the pathogenesis of alcoholic fatty liver via modulation of AMPK and STAT3 signaling [6], implying the protective role of leptin from alcoholic liver disease. Activation of leptin signaling contributes to the development and/or progression of cancer through multiple mechanisms [8,9,10]. Leptin is known to activate diverse signaling cascades, such as the JAK/STAT, MAPK, and PI3 kinase/AKT pathways, most of which are implicated in differentiation and proliferation of cancer cells [10]. Leptin treatment has been demonstrated to suppress apoptosis [11] and accelerate cell cycle progression through induction of the genes related with cell cycle [12]

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