Abstract 820: Nuclear receptor TLX inhibits cancer cell intrinsic properties required for triple-negative breast cancer progression

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Abstract The primary purpose of our work was to characterize the effects of the nuclear receptor TLX (NR2E1) in triple-negative breast cancer (TNBC) in order to evaluate its potential therapeutic value in a subtype of breast cancer that has proven particularly challenging to treat, primarily due to the lack of targeted modes of intervention. Unfortunately, breast cancer continues to be the second deadliest form of cancer among women in the United States. Considering the substantial public health implications, development of new therapeutic strategies for highly aggressive breast cancer subtypes, such as TNBC, is imperative. While the function of nuclear receptors such as the estrogen and androgen receptors has been extensively characterized in cancers of the breast and prostate respectively, due in part to their amenable nature to ligand modulation, it is likely that other nuclear receptors may represent therapeutic targets for these malignancies. Indeed, probing of available clinical datasets demonstrated that nuclear receptor TLX is most highly expressed in basal and estrogen receptor (ER)-negative breast cancer patients, and that ER-negative patients with higher TLX expression had increased relapse-free and overall survival. Therefore, we hypothesized that TLX could influence the pathophysiology of TNBC. Utilizing a stable overexpression model in the TNBC cell lines, MDA-MB-231 and MDA-MB-468, we have shown that TLX can inhibit critical oncogenic properties in the in vitro setting, including proliferation, migration and invasion. Furthermore, xenograft and lung colonization studies demonstrated that TLX continued to exert anti-oncogenic effects in the in vivo environment. In agreement with these results, transcriptomic analysis of TLX-overexpressing cells and xenograft tumors showed that TLX can regulate genes and pathways that are known to play crucial roles in the growth and metastatic dissemination of cancer. As previously published works have identified several putative TLX ligands, our findings demonstrating that TLX functions as an anti-cancer factor in TNBC provides a strong rationale for future research aimed at therapeutically targeting this nuclear receptor. Citation Format: Adam T. Nelczyk, Hashni E. Vidana Gamage, Liqian Ma, Michael T. McHenry, Madeline A. Henn, Mohammed Kadiri, Yu Wang, Anasuya Das Gupta, Natalia Krawczynska, Sisi He, Michael J. Spinella, Erik R. Nelson. Nuclear receptor TLX inhibits cancer cell intrinsic properties required for triple-negative breast cancer progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 820.