Abstract P2-06-14: The role of SLC7A5 (LAT1) in endocrine therapy-resistant breast cancer

Abstract

Abstract Endocrine therapies are commonly used to treat estrogen receptor-positive (ER+) breast cancers, which comprise 70% of all new breast cancer cases. Unfortunately, emergence of resistance to these therapies presents a major clinical challenge. Cancer cells can adapt to the dysregulation of cellular metabolism induced by endocrine therapy in order to evade cell death.Central to this adaptation is the scavenging of free-formed amino acids from the tumor microenvironment. For example, we found 109 solute carrier (SLC) mRNAs to be differentially expressed between endocrine-sensitive and resistant cells. We began our mechanistic studies of these genes with SLC family 7 member 5 (SLC7A5 or LAT1). SLC7A5 is a key component of a transmembrane transporter, which can complex with CD98 and increase the uptake of large, neutral amino acids (such as leucine or tyrosine). We used a panel of endocrine therapy-resistant (LCC9) and sensitive (MCF7; LCC1) breast cancer cells. SLC7A5 expression was upregulated by estrogen in MCF7 and LCC1 cells; this induction was blocked by fulvestrant treatment. Basal expression of the SLC7A5 protein in the absence of estrogen was 2.75-fold higher in LCC9 cells compared with MCF7 cells; SLC7A5 mRNA expression was 71-fold higher. Fulvestrant treatment did not significantly alter SLC7A5 mRNA or protein expression in LCC9 cells. Inhibiting SLC7A5 function using either a pharmacological inhibitor (JPH203), or depleting expression using siRNA, led to significant suppression of LCC9 cell growth. Cell cycle analysis revealed that SLC7A5 depletion caused cells to accumulate in the G1-phase, with a concurrent reduction of cells in S-phase. In four publicly available datasets of ER+, tamoxifen treated breast cancer patients, high expression of SLC7A5 was significantly associated with poor relapse-free survival. This study uncovers a novel adaptive mechanism in endocrine therapy-resistant breast cancer cells that is facilitated by increased expression of SLC7A5, which enables them to supplement their increased metabolic needs and promoting cell growth. Blocking the functions of SLC7A5, perhaps in conjunction with inhibition of autophagy, may therefore offer a new avenue of potential therapeutic intervention against endocrine therapy-resistant breast cancers. Citation Format: Sevigny CM, Sengupta S, Luo Z, Jin L, Pearce D, Clarke R. The role of SLC7A5 (LAT1) in endocrine therapy-resistant breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P2-06-14.