The Adipose Tissue-Derived Secretome (ADS) in Obesity Uniquely Induces L-Type Amino Acid Transporter 1 (LAT1) and mTOR Signaling in Estrogen-Receptor-Positive Breast Cancer Cells.

Chelsea Thompson,Uma Sundaram,Cecilia Sierra-Bakhshi,M Motiur Rahman,Soudamani Singh,Subha Arthur,Krista Denning,Travis Salisbury,Rebecca Russell

doi:10.3390/ijms22136706

Abstract

Obesity increases the risk of postmenopausal breast cancer (BC). This risk is mediated by obesity-induced changes in the adipose-derived secretome (ADS). The pathogenesis of BC in obesity is stimulated by mTOR hyperactivity. In obesity, leucine might support mTOR hyperactivity. Leucine uptake by BC cells is through L-Type Amino Acid Transporter 1 (LAT1). Our objective was to link obesity-ADS induction of LAT1 to the induction of mTOR signaling. Lean- and obese-ADS were obtained from lean and obese mice, respectively. Breast ADS was obtained from BC patients. Estrogen-receptor-positive BC cells were stimulated with ADS. LAT1 activity was determined by uptake of 3H-leucine. The LAT1/CD98 complex, and mTOR signaling were assayed by Western blot. The LAT1 antagonists, BCH and JPH203, were used to inhibit LAT1. Cell migration and invasion were measured by Transwell assays. The results showed obese-ADS-induced LAT1 activity by increasing transporter affinity for leucine. Consistent with this mechanism, LAT1 and CD98 expression were unchanged. Induction of mTOR by obese-ADS was inhibited by LAT1 antagonists. Breast ADS from patients with BMIs > 30 stimulated BC cell migration and invasiveness. Collectively, our findings show that obese-ADS induction of LAT1 supports mTOR hyperactivity in luminal BC cells.

Highlights

In the United States, 70% of adults are overweight and more than one-third (~40%) are obese [1,2]
The results showed that L-Type Amino Acid Transporter 1 (LAT1) activity, defined as BCH-sensitive uptake of 3 H-Leucine, was significantly induced in MCF7, T47D, and ZR-75-1 breast cancer (BC) cells by O-Adipose tissue (AT)-derived secretome (ADS) compared with L-ADS (Figure 1)
The results show that O-ADS stimulated LAT1 affinity (1/Km) for leucine without changing the maximal rate (Vmax) of leucine uptake (Figure 3a)

Summary

Introduction

In the United States, 70% of adults are overweight and more than one-third (~40%) are obese [1,2]. Prior reports show that obesity is an important risk factor for postmenopausal breast cancer (BC) [3,4,5]. Obesity is significantly associated with larger tumor size, positive lymph nodes, metastatic disease, higher risk of BC recurrence and significantly higher rates of BC mortality [3,4,5,6,7]. When considering there are approximately 70 million postmenopausal women in the United States [8] and that potentially 70% of these women are overweight to obese, it is possible that obesity places 28 million women at a greater risk for invasive BC in the U.S. When considering there are approximately 70 million postmenopausal women in the United States [8] and that potentially 70% of these women are overweight to obese, it is possible that obesity places 28 million women at a greater risk for invasive BC in the U.S. 4.0/).

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